Particles, capsids, compositions, packaging cells, production methods, targeting methods, and uses of recombinant adeno-associated viruses (AAVs) in mosaic and chimeric forms, including non-primate animal AAVs, avian AAVs, sea lion AAVs, and reptile AAVs, resistant to neutralizing antibodies, for nucleic acid molecule delivery and applications in gene therapy and gene transfer in vitro and in vivo.

Description

Particles, capsids, compositions, cells of Packaging, production methods, targeting methods, and uses of recombinant adeno-associated viruses (AAVs) in mosaic and chimeric forms, including non-primate animal AAVs, avian AAVs, sea lion AAVs, and reptile AAVs, resistant to neutralizing antibodies, for nucleic acid molecule delivery and applications in gene therapy and gene transfer in vitro and in vivo. Split from BR112021023692-9, deposited on 05 / 22 / 2020. REFERENCE TO A SEQUENCE LISTING SENT AS A TEXT FILE VIA EFS NETWORK

[001] The Sequence Listing written in the file The file 10364WO01_ST25.txt is 269 kilobytes in size, was created on May 19, 2020, and is incorporated into this document by reference. TECHNICAL FIELDS

[002] The disclosure in this document refers to methods of production and use of recombinant AAV particles comprising capsid proteins from a non-primate animal AAV and / or a remote AAV. FUNDAMENTALS OF THE INVENTION

[003] Gene delivery to specific target cells has become one of the most important technologies in modern medicine for the potential treatment of a variety of chronic and genetic diseases. To date, progress in the clinical application of gene therapy has been limited by the lack of ideal gene delivery vehicles.

[004] Ideally, a gene delivery vehicle is capable of (1) stably introducing genetic material into the desired cells, (2) preventing the introduction of genetic material into non-target cells, and (3) avoiding neutralization by a patient's immune system, for example, antibodies from Petition 870260072813, dated 07 / 22 / 2026, page 15 / 407 / 240 a patient. Although several non-pathogenic vehicles are currently available, the ability of these vehicles to transduce specific cells and remain invisible to host immune responses remains less than ideal.

[005] For example, viral particles based on adeno-associated viruses (AAVs) isolated from primates, particularly humans, for example, the AAV serotypes AAV2, AAV4, AAV6, AAV7, AAV8, and AAV9, have been the focus of much research, since AAVs are able to transduce a wide range of primate species and tissues in vivo without evidence of toxicity or pathogenicity. (Muzyczka, et al. (1992) Current Topics in Microbiology and Immunology, 158:97-129). Furthermore, AAV safely transduces post-mitotic tissues. Although the virus can occasionally integrate into host chromosomes, this occurs very infrequently at a safe-harbor locus on human chromosome 19, and only when replication proteins (Rep) are provided in trans. AAV genomes circulate rapidly and concatenate in infected cells, existing in a stable, episomal state within those cells to provide stable, long-term expression of their payloads.

[006] Furthermore, it has been possible to manipulate and redirect AAV infection from primates to specific cells in recent years. Many of the advances in targeted gene therapy using viral particles can be summarized as non-recombinatorial (non-genetic) or recombinatorial (genetic) modification of the viral particle, resulting in pseudotyping, expansion, and / or redirection of the viral particle's natural tropism. (Reviewed in Nicklin and Baker (2002) Gene Curr. Ther. 2:273-93; Verheiji and Rottier (2012) Advances Virol 2012:1-15).

[007] In a direct recombinatorial targeting approach, a targeting ligand is inserted directly into, or coupled to, a Petition 870260072813, dated 07 / 22 / 2026, page 16 / 407 / 240 viral capsid, that is, viral capsid protein genes are modified to express capsid proteins comprising a heterologous targeting ligand. The targeting ligand then redirects, for example, binds to, a receptor or marker preferentially or exclusively expressed on a target cell. (Stachler et al. (2006) Gene Ther. 13:926-931; White et al. (2004) Circulation 109:513-519; see also Park et al., (2007) Frontiers in Bioscience 13:2653-59; Girod et al. (1999) Nature Medicine 5:1052-56; Grifman et al. (2001) Molecular Therapy 3:964-75; Shi et al. (2001) Human Gene Therapy 12:1697-1711; Shi and Bartlett (2003) Molecular Therapy 7:515-525).

[008] In indirect recombinatorial approaches, a viral capsid is modified with a heterologous scaffold structure, which then binds to an adapter that includes a targeting ligand. The adapter binds to the scaffold structure and to the target cell. (Arnold et al. (2006) Mol. Ther. 5:125132; Ponnazhagen et al. (2002) J. Virol. 76: 12900-907; see also WO 97 / 05266) Scaffold structures such as (1) Fc-binding molecules (e.g., Fc receptors, Protein A, etc.), which bind to the Fc of antibody adapters, (2) (strepto)avidin, which binds to biotinylated adapters, (3) biotin, which binds to adapters fused with (strepto)avidin, (4) a detectable marker, which is useful for detection and / or isolation of viral particles, linked by a bispecific adapter capable of non-covalently binding to the detectable marker and the target molecule, and recently (5) protein: protein-binding pairs that form isopeptide linkages have been described for a variety of viral particles. (See, for example, Gigout et al. (2005) Molecular Therapy 11:856-865; Stachler et al. (2008) Molecular Therapy 16:1467-1473; Quetglas et al. (2010) Virus Research 153:179-196; Ohno et al. (1997) Nature Biotechnology 15:763-767; Klimstra et al.

[009] Despite the advances that provide the ability to Petition 870260072813, dated 07 / 22 / 2026, p. 17 / 407 / 240, targeting AAV infection, the redirected AAV as a gene delivery vehicle remains less than ideal due to the presence of neutralizing antibodies against AAV capsids (NAbs). The presence of AAV NAbs in children suggests that AAV infection occurs early in life (Calcedo et al. (2011) ASGCT; Huser et al. (2017) J. Virol. 91:e0213716). It has been shown that antibodies generated by early-life AAV infection can compromise the subsequent use of an AAV-derived gene therapy vector that are recognized and neutralized by those pre-existing antibodies. (Hurlbut et al. (2010) Mol. Ther. 18:1983-94; Jiang et al. (2006) Blood 108:3321-8; Manno et al. (2006) Nat. Med. 12:342-7; Scallan et al. (2006) Blood 107:1810-7; Wang et al. (2010) Mol. Ther.Furthermore, the presence of neutralizing antibody titers against an AAV serotype is clinically significant, since patients with high titers are considered ineligible for any treatment involving that serotype (Jeune et al. (2013) Hum Gene Ther Methods 24:59-67).

[0010] Thus, there remains a need for viral systems that are non-pathogenic, adaptable for the targeted transfer of nucleic acids of interest to a variety of target cells, and that overcome the obstacle represented by pre-existing antibodies in patients requiring treatment. SUMMARY OF THE INVENTION

[0011] This document describes a strategy that can simultaneously mitigate several problems associated with previous and current approaches to treating adeno-associated virus (AAV) particles. Without wishing to be bound by theory, it is expected that most humans would not have pre-existing NAbs against an AAV to which prior human exposure is low. However, the ability of such AAV serotypes to be successfully manipulated for use as a gene therapy vector capable of targeting and infecting specific cells and / or avoiding reactivity is a concern. Petition 870260072813, dated 07 / 22 / 2026, page 18 / 407 / 240 cross-reactivity by any pre-existing antibodies in the human population remained unknown until then.

[0012] This document shows that an AAV capsid protein from a non-primate animal species can be modified to allow targeted introduction of a nucleotide of interest into mammalian cells of a different animal species. Furthermore, this document shows evidence that a modified non-primate animal AAV particle remains less likely than current AAV therapeutic modalities, which are based on well-characterized human AAV serotypes, to be recognized and / or detected by pre-existing antibodies found in the human population. Consequently, this document describes recombinant AAV viral particles that are capable of infecting a cell of choice and are more able to evade neutralization by pre-existing antibodies.

[0013] Recombinant AAV viral particles are described in this document comprising (i) an AAV capsid comprising AAV capsid proteins VP1, VP2 and VP3, and (ii) packaged within the AAV capsid, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein at least one of: a) the VP1 capsid protein of AAV, b) any portion of the VP1 capsid protein of AAV, c) the VP2 capsid protein of AAV, d) any portion of the VP2 capsid protein of AAV, e) the VP3 capsid protein of AAV, and (f) any portion of the VP3 capsid protein of AAV comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of a capsid protein from an animal AAV. Petition 870260072813, dated 07 / 22 / 2026, p. 19 / 407 / 240 not a primate or portion thereof, or a remote AAV or a portion thereof, where I. At least one of the AAV capsid proteins VP1, VP2, and VP3 comprises a selected modification of the group consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV viral particle, (b) a detectable marker, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV viral particle and / or creates a detectable marker, (d) a chimeric amino acid sequence, and (e) any combination of (a), (b), (c), and (d), and / or II. the ITR sequence, or a portion thereof, comprises a nucleic acid sequence with significant sequence identity, for example, at least 95% identity, with the ITR sequence of a second AAV or portion thereof, wherein the second AAV is not the same as the non-primate animal AAV or the remote AAV, and wherein the recombinant AAV viral particle is capable of infecting a mammalian host, preferably a primate host.

[0014] In some embodiments, a recombinant AAV viral particle comprises (i) an AAV capsid comprising AAV capsid proteins VP1, VP2 and VP3, and (ii) packaged within the AAV capsid, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein at least one of: a) the VP1 capsid protein of AAV, Petition 870260072813, dated 07 / 22 / 2026, p. 20 / 407 / 240 b) the VP2 capsid protein of AAV, and (c) the AAV capsid protein VP3 comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of a capsid protein from a non-primate animal AAV or a remote AAV, wherein I. At least one of the AAV capsid proteins VP1, VP2, and VP3 comprises a selected modification of the group consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV viral particle, (b) a detectable marker, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV viral particle and / or creates a detectable marker, (d) a chimeric amino acid sequence, and (e) any combination of (a), (b), (c), and (d), and / or II. the ITR sequence, or a portion thereof, comprises a nucleic acid sequence with significant sequence identity, for example, at least 95% identity, with the ITR sequence of a second AAV or portion thereof, wherein the second AAV is not the same as the non-primate animal AAV or the remote AAV, and wherein the recombinant AAV viral particle is capable of infecting a mammalian host, preferably a primate host.

[0015] In some embodiments, a recombinant AAV viral particle comprises (i) an AAV capsid comprising AAV capsid proteins VP1, VP2 and VP3, and (ii) packaged within the capsid of Petition 870260072813, dated 07 / 22 / 2026, p. 21 / 407 / 240 AAV, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein at least one of the following: a. any portion of the VP1 capsid protein of AAV, b. any portion of the VP2 capsid protein of AAV, and c. any portion of the VP3 capsid protein of AAV comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of a capsid protein of a non-primate animal AAV or a portion thereof, or a remote AAV or a portion thereof, wherein I. At least one of the AAV capsid proteins VP1, VP2, and VP3 comprises a selected modification of the group consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV viral particle, (b) a detectable marker, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV viral particle and / or creates a detectable marker, (d) a chimeric amino acid sequence, and (e) any combination of (a), (b), (c), and (d), and / or II. The ITR sequence, or a portion thereof, comprises a nucleic acid sequence with significant sequence identity, for example, at least 95% identity, with the ITR sequence of a second AAV or portion thereof, where the second AAV is not the same as the non-primate animal AAV or the remote AAV, and Petition 870260072813, dated 07 / 22 / 2026, page. 22 / 407 / 240 wherein the recombinant AAV viral particle is capable of infecting a mammalian host, preferably a primate host

[0016] In some embodiments of recombinant AAV viral particle, the recombinant viral particle comprises (i) an AAV capsid comprising AAV capsid proteins VP1, VP2 and VP3, and (ii) packaged within the AAV capsid, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein at least one of the AAV capsid protein VP1, any portion of the AAV capsid protein VP1, the AAV capsid protein VP2, any portion of the AAV capsid protein VP2, the AAV capsid protein VP3, and any portion of the AAV capsid protein VP3 comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity,with the amino acid sequence of a capsid protein from a non-primate animal AAV or portion thereof, wherein at least one of the AAV capsid proteins VP1, VP2 and VP3 comprises a modification selected from the group consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV viral particle, (b) a detectable marker, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV viral particle and / or creates a detectable marker, (d) a chimeric amino acid sequence, and (e) any combination of (a), (b), (c) and (d), wherein the entire ITR amino acid sequence or a portion of the ITR sequence comprises a nucleic acid sequence with significant sequence identity, for example, at least 95% identity, for AAV ITR Petition 870260072813, dated 22 / 07 / 2026, p. 23 / 407 / 240 of a non-primate animal, optionally wherein the ITR sequence comprises a chimeric nucleic acid sequence, and wherein a portion of the chimeric nucleic acid sequence has significant sequence identity, for example, at least 95% identity, to the ITR of the non-primate AAV or a portion thereof is operationally linked to a portion of the chimeric nucleic acid sequence with significant sequence identity, for example, at least 95% identity, to the ITR of a second AAV or portion thereof, wherein the second AAV is not the same as the non-primate animal AAV, and wherein the recombinant AAV viral particle is capable of infecting a mammalian host, preferably a primate host.

[0017] In some embodiments, a recombinant AAV viral particle comprises (i) an AAV capsid comprising AAV capsid proteins VP1, VP2 and VP3, and (ii) packaged within the AAV capsid, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein at least one of the AAV capsid protein VP1, any portion of the AAV capsid protein VP1, the AAV capsid protein VP2, any portion of the AAV capsid protein VP2, the AAV capsid protein VP3, and any portion of the AAV capsid protein VP3 comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of a non-primate animal AAV capsid protein or portion thereof, wherein the ITR sequence, or portion of the same, it comprises a nucleic acid sequence with significant sequence identity, for example,at least 95% identity with the ITR sequence of a second AAV or portion thereof, wherein the second AAV is not the same as the non-primate animal AAV, wherein the recombinant AAV viral particle is capable of infecting a mammalian host, preferably a primate host, and Petition 870260072813, dated 22 / 07 / 2026, p. 24 / 407 / 240 optionally, wherein at least one of the AAV capsid proteins VP1, VP2 and VP3 comprises a selected modification of the group consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV viral particle, (b) a detectable marker, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV viral particle and / or creates a detectable marker, and (d) any combination of (a)-(c).

[0018] In some embodiments, a recombinant AAV viral particle comprises (i) an AAV capsid comprising AAV capsid proteins VP1, VP2, and VP3, and (ii) packaged within the AAV capsid, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein at least one of the AAV capsid protein VP1, any portion of the AAV capsid protein VP1, the AAV capsid protein VP2, any portion of the AAV capsid protein VP2, the AAV capsid protein VP3, and any portion of the AAV capsid protein VP3 comprises a chimeric amino acid sequence comprising (A) an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of a non-primate animal AAV capsid protein, or a portion of even operationally linked to (B) an amino acid sequence with significant sequence identity,For example, at least 95% identity with the amino acid sequence of a second AAV capsid protein, or a portion thereof, where the second AAV is not identical to the non-primate animal AAV, where the recombinant AAV viral particle is capable of infecting a mammalian host. Petition 870260072813, dated 07 / 22 / 2026, p. 25 / 407 / 240 preferably, a primate host, and optionally in which at least one of the AAV capsid protein VP1, any portion of the AAV capsid protein VP1, the AAV capsid protein VP2, any portion of the AAV capsid protein VP2, the AAV capsid protein VP3, and any portion of the AAV capsid protein VP3 comprising a chimeric amino acid sequence further comprises a modification selected from the group consisting of (a) a first member of a protein:protein linkage pair, (b) a detectable marker, and (c) a combination of (a) and (b).

[0019] In some embodiments of recombinant AAV viral particles, the recombinant viral particle comprises (i) an AAV capsid comprising AAV capsid proteins VP1, VP2, and VP3, and (ii) packaged within the AAV capsid, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein at least one of the AAV capsid protein VP1, any portion of the AAV capsid protein VP1, the AAV capsid protein VP2, any portion of the AAV capsid protein VP2, the AAV capsid protein VP3, and any portion of the AAV capsid protein VP3 comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of a remote AAV capsid protein or portion thereof, and wherein at least one of the proteins VP1 capsid,VP2 and VP3 of AAV comprise a selected modification of the group consisting of: (a) a first member of a protein:protein binding pair, wherein the protein:protein binding pair directs the tropism of the AAV viral particle, (b) a detectable marker, Petition 870260072813, dated 07 / 22 / 2026, p. 26 / 407 / 240 (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV viral particle and / or creates a detectable marker, (d) a chimeric amino acid sequence, and (e) any combination of (a), (b), (c) and (d), wherein the entire ITR sequence or a portion of the ITR sequence comprises a nucleic acid sequence with significant sequence identity, for example, at least 95% identity, to the remote AAV ITR, optionally wherein the ITR sequence comprises a chimeric nucleic acid sequence, and wherein a portion of the chimeric nucleic acid sequence has significant sequence identity, for example, at least 95% identity, to the remote AAV ITR or a portion thereof is operationally linked to a portion of the chimeric nucleic acid sequence with significant sequence identity, for example, at least 95% identity,for the ITR of a second AAV or portion thereof, wherein the second AAV is not the same as the remote AAV, and wherein the recombinant AAV viral particle is capable of infecting a mammalian host, preferably a primate host.

[0020] In some embodiments, a recombinant AAV viral particle comprises (i) an AAV capsid comprising AAV capsid proteins VP1, VP2 and VP3, and (ii) packaged within the AAV capsid, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein at least one of the AAV capsid protein VP1, any portion of the AAV capsid protein VP1, the AAV capsid protein VP2, any portion of the AAV capsid protein VP2, the AAV capsid protein VP3, and any portion of the AAV capsid protein VP3 comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of a protein of Petition 870260072813, dated 07 / 22 / 2026, p. 27 / 407 / 240 capsid of a remote AAV or portion thereof, wherein the ITR sequence, or portion thereof, comprises a nucleic acid sequence with significant sequence identity, for example, at least 95% identity, with the ITR sequence of a second AAV or portion thereof, wherein the second AAV is not the same as the remote AAV, wherein the recombinant AAV viral particle is capable of infecting a mammalian host, preferably a primate host, and optionally, wherein at least one of the AAV capsid proteins VP1, VP2 and VP3 comprises a selected modification of the group consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV viral particle, (b) a detectable marker, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV viral particle and / or creates a detectable marker, and (d) any combination of (a)-(c).

[0021] In some embodiments, a recombinant AAV viral particle comprises (i) an AAV capsid comprising AAV capsid proteins VP1, VP2, and VP3, and (ii) packaged within the AAV capsid, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein at least one of the AAV capsid protein VP1, any portion of the AAV capsid protein VP1, the AAV capsid protein VP2, any portion of the AAV capsid protein VP2, the AAV capsid protein VP3, and any portion of the AAV capsid protein VP3 comprises a chimeric amino acid sequence comprising (A) an amino acid sequence Petition 870260072813, dated 07 / 22 / 2026, p. 28 / 407 / 240 with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of a remote AAV capsid protein, or a portion thereof, operationally linked to (B) an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of a second AAV capsid protein, or a portion thereof, wherein the second AAV is not the same as the remote AAV, wherein the recombinant AAV viral particle is capable of infecting a mammalian host, preferably a primate host, and optionally wherein at least one of the following is present: AAV capsid protein VP1, any portion of AAV capsid protein VP1, AAV capsid protein VP2, any portion of AAV capsid protein VP2, AAV capsid protein VP3,and any portion of the AAV VP3 capsid protein comprising a chimeric amino acid sequence further comprises a selected group modification consisting of (a) a first member of a protein:protein linkage pair, (b) a detectable marker, and (c) a combination of (a) and (b).

[0022] In some embodiments of the invention, an AAV viral particle comprises an AAV capsid, wherein at least one AAV capsid protein (for example, an AAV capsid protein VP1, an AAV capsid protein VP2, and / or an AAV capsid protein VP3) of said AAV capsid comprises at least a portion of an amino acid sequence of a capsid protein selected from the group consisting of a capsid protein from a non-primate animal AAV, a capsid protein from a remote AAV, and a combination thereof, and wherein at least one AAV capsid protein of said AAV capsid is modified to comprise (a) at least one first member of a protein:protein linkage pair, (b) a detectable marker, Petition 870260072813, dated 22 / 07 / 2026, p. 29 / 407 / 240 (c) a point mutation, (d) a chimeric amino acid sequence comprising a portion of an amino acid sequence of another, for example, a second, AAV capsid protein that is operationally linked to said amino acid sequence of the capsid protein selected from the group consisting of the non-primate animal AAV capsid protein, the remote AAV capsid protein, or a combination thereof, and (e) any combination of (a), (b), (c), and (d). In some embodiments of the invention, an AAV viral particle comprises an AAV capsid, wherein at least one AAV capsid protein (for example, an AAV capsid protein VP1, an AAV capsid protein VP2, and / or an AAV capsid protein VP3) of said AAV capsid or portion thereof has significant sequence identity, for example, at least 95% identity.with a capsid protein selected from the group consisting of a capsid protein from a non-primate animal AAV, a portion of a capsid protein from a non-primate animal AAV, a capsid protein from a remote AAV, a portion of a capsid protein from a remote AAV, and a combination thereof, and wherein at least one capsid protein from said AAV capsid is modified to comprise (a) at least one first member of a protein:protein linkage pair, (b) a detectable marker, (c) a point mutation, (d) a chimeric amino acid sequence comprising a portion of an amino acid sequence from another, for example, a second AAV capsid protein that is operationally linked to said amino acid sequence of the capsid protein selected from the group consisting of the capsid protein from the non-primate animal AAV, the capsid protein from the remote AAV, or a combination thereof,and (e) any combination of (a), (b), (c), and (d). In some embodiments of the invention, an AAV viral particle comprises an AAV capsid, wherein at least one protein of, Petition 870260072813, dated 07 / 22 / 2026, page. 30 / 407 / 240 AAV capsid (for example, an AAV capsid protein VP1, an AAV capsid protein VP2, and / or an AAV capsid protein VP3) of said AAV capsid comprises at least a portion of an amino acid sequence of a non-primate animal AAV capsid protein (for example, wherein at least one AAV capsid protein comprises an amino acid sequence with significant sequence identity, for example, at least 95% sequence identity, with a non-primate animal AAV capsid protein), wherein at least one AAV capsid protein of said AAV capsid is modified to comprise (a) at least one first member of a protein:protein linkage pair, (b) a detectable marker, (c) a point mutation, (d) a chimeric amino acid sequence comprising a portion of an amino acid sequence of another, for example, a second,AAV capsid protein that is operationally linked to said amino acid sequence of non-primate animal AAV capsid, and (e) any combination of (a), (b), (c), and (d).

[0023] In some embodiments of the invention, an AAV viral particle comprises an AAV capsid, wherein at least one AAV capsid protein (for example, an AAV capsid protein VP1, an AAV capsid protein VP2, and / or an AAV capsid protein VP3) of said AAV capsid comprises at least a portion of an amino acid sequence of a capsid protein of a remote AAV (for example, wherein at least one AAV capsid protein comprises an amino acid sequence with significant sequence identity, for example, at least 95% sequence identity, with a capsid protein of a remote AAV), wherein at least one AAV capsid protein of said AAV capsid is modified to comprise (a) at least one first member of a protein:protein linkage pair, (b) a detectable marker, (c) a point mutation, (d) Petition 870260072813, dated 07 / 22 / 2026, p. 31 / 407 / 240 a chimeric amino acid sequence comprising a portion of an amino acid sequence from another, for example, a second AAV capsid protein that is operationally linked to said amino acid sequence of the remote AAV capsid protein, and (e) any combination of (a), (b), (c), and (d).

[0024] In some embodiments of the invention, an AAV viral particle comprises (A) at least one AAV capsid protein, for example, an AAV capsid protein VP1, an AAV capsid protein VP2, and / or an AAV capsid protein VP3, comprising an amino acid sequence identical to or with significant identity, for example, at least 95% sequence identity, with an amino acid sequence selected from the group consisting of (i) an amino acid sequence of a capsid protein of a non-primate animal AAV, (ii) an amino acid sequence of a capsid protein of a distant primate AAV, and (iii) an amino acid sequence of a combination thereof, and (B) an AAV genome comprising a nucleotide of interest and an AAV ITR comprising at least a portion of an ITR sequence of another, for example, a second AAV,where the other AAV is neither identical to the AAV of a non-primate animal nor identical to the AAV of a distant primate.

[0025] In some embodiments of the invention, an AAV viral particle comprises (A) at least one AAV capsid protein (for example, an AAV capsid protein VP1, an AAV capsid protein VP2, and / or an AAV capsid protein VP3) comprising an amino acid sequence identical or with significant identity, for example, at least 95% sequence identity, to an amino acid sequence of a capsid protein from a non-primate animal AAV, and (B) an AAV genome comprising a nucleotide of interest and an AAV ITR comprising at least a portion of a sequence of Petition 870260072813, dated 07 / 22 / 2026, p. 32 / 407 / 240 ITR of another AAV, for example, a second AAV, where the other AAV is not identical to the AAV of a non-primate animal.

[0026] In some embodiments of the invention, an AAV viral particle comprises (A) at least one AAV capsid protein (for example, an AAV capsid protein VP1, an AAV capsid protein VP2, and / or an AAV capsid protein VP3) comprising an amino acid sequence identical or with significant identity, for example, at least 95% sequence identity, to an amino acid sequence of a capsid protein from a remote AAV, and (B) an AAV genome comprising a nucleotide of interest and an AAV ITR comprising at least a portion of an ITR sequence from another AAV, for example, a second AAV, wherein the other AAV is not identical to the remote primate AAV.

[0027] In some embodiments of the AAV viral particle of the invention, the capsid protein comprising an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity to, an amino acid sequence of the non-primate animal AAV capsid protein, the remote AAV capsid protein, or a combination thereof, is modified to comprise (a) at least one first member of a protein:protein linkage pair, (b) a detectable marker, (c) a point mutation.

[0028] In some embodiments of the AAV viral particle of the invention, the capsid protein comprising an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity to, an amino acid sequence of the capsid protein, the non-primate animal AAV, the remote AAV capsid protein, or a combination thereof, comprises an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity to, an amino acid sequence of Petition 870260072813, dated 22 / 07 / 2026, p. 33 / 407 / 240 a VP3 capsid protein from a non-primate animal AAV and / or an amino acid sequence from a VP3 capsid protein from a remote AAV. In some embodiments, the capsid protein comprising an amino acid sequence identical to or with significant identity, for example, at least 95% sequence identity, with the amino acid sequence of the capsid protein from a non-primate animal AAV, the capsid protein from a remote AAV, or a combination thereof, comprises an amino acid sequence identical to or with significant identity, for example, at least 95% sequence identity, with an amino acid sequence from a VP2 capsid protein from a non-primate animal AAV and / or an amino acid sequence from a VP2 capsid protein from a remote AAV.In some embodiments, the capsid protein comprising an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity, with the amino acid sequence of the non-primate animal AAV capsid protein, the remote AAV capsid protein, or a combination thereof, comprises an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity, with an amino acid sequence of a non-primate animal AAV VP1 capsid protein and / or an amino acid sequence of a remote AAV VP1 capsid protein.

[0029] In some embodiments of the AAV viral particle of the invention, the capsid of said particle comprises (i) a VP1 capsid protein that is (a) a chimeric AAV VP1 capsid protein, optionally wherein the chimeric VP1 capsid protein comprises a VP1-exclusive (VP1-u) region of another, for example, second, AAV operationally linked to a common VP1 / VP2 region and a VP3 region of the non-primate AAV or remote AAV, or (b) a VP1 capsid protein of the non-primate AAV or remote AAV, (ii) a VP2 capsid protein Petition 870260072813, dated 22 / 07 / 2026, p. 34 / 407 / 240 which is (a) a chimeric AAV VP2 capsid protein, optionally wherein the chimeric VP2 capsid protein comprises a common VP1 / VP2 region of another, for example, second, AAV operationally linked to a VP3 region of the non-primate or remote AAV, or (b) a VP2 capsid protein of the non-primate or remote AAV, and (iii) the VP3 capsid protein of the non-primate or remote AAV.In some embodiments, the capsid of said particle comprises (i) a chimeric AAV VP1 capsid protein, optionally wherein the chimeric VP1 capsid protein comprises a VP1-exclusive (VP1-u) region of another, for example, second, AAV operationally linked to a common VP1 / VP2 region and a VP3 region of the non-primate AAV or remote AAV, (ii) a chimeric AAV VP2 capsid protein, optionally wherein the chimeric VP2 capsid protein comprises a common VP1 / VP2 region of another, for example, second, AAV operationally linked to a VP3 region of the non-primate AAV or remote AAV, and (iii) the VP3 capsid protein of the non-primate AAV or remote AAV.In some embodiments, the capsid of said particle comprises (i) a chimeric AAV VP1 capsid protein, optionally wherein the chimeric VP1 capsid protein comprises a VP1-exclusive (VP1-u) region of another, for example, second AAV operationally linked to a common VP1 / VP2 region and a VP3 region of the non-primate AAV or remote AAV, (ii) a non-primate AAV VP2 capsid protein or remote AAV, and (iii) the non-primate AAV VP3 capsid protein or remote AAV. In some embodiments, the capsid comprises (i) a VP1 capsid protein from a non-primate AAV or a remote AAV, (ii) a VP2 capsid protein from a non-primate AAV or a remote AAV, and (iii) a VP3 capsid protein from a non-primate AAV or a remote AAV, and optionally wherein the particle comprises a V genome comprising at least one AATR portion of an AAV in an AAV sequence. In some. Petition 870260072813, dated 07 / 22 / 2026, p. 35 / 407 / 240 modalities, the other AAV is not identical to the AAV of a non-primate animal.

[0030] In some recombinant AAV viral particle embodiments, (i) the VP1 capsid protein comprises (a) a chimeric amino acid sequence, optionally wherein the VP1-exclusive (VP1-u) region of the chimeric AAV VP1 capsid protein comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the VP1-u amino acid sequence of a second AAV and wherein the common VP1 / VP2 region and the VP3 region of the chimeric AAV VP1 capsid comprise an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of the common VP1 / VP2 region and the VP3 region of a non-primate animal AAV, or (b) an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the VP1 capsid protein of the non-primate animal AAV,(ii) the VP2 capsid protein comprises (a) a chimeric amino acid sequence, optionally wherein the VP1 / VP2 common region of the chimeric AAV VP2 capsid protein comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of the VP1 / VP2 common region of a second AAV and wherein the VP3 region of the chimeric VP2 capsid protein comprises at least 95% identity with the VP3 region of the non-primate animal AAV, or (b) an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the VP2 capsid protein of the non-primate animal AAV, and (iii) the VP3 capsid protein comprising an amino acid sequence with significant sequence identity, for example, at least 95% identity, with an amino acid sequence of the VP3 capsid protein of the non-primate animal AAV. In some sports,(i) the VP1 capsid protein comprises a sequence of, Petition 870260072813, dated 07 / 22 / 2026, p. 36 / 407 / 240 chimeric amino acids, optionally wherein the VP1-exclusive region (VP1u) of the VP1 capsid protein of chimeric AAV comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the VP1-u amino acid sequence of a second AAV and wherein the common VP1 / VP2 region and the VP3 region of the VP1 capsid of chimeric AAV comprise an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of the common VP1 / VP2 region and the VP3 region of a non-primate animal AAV, (ii) the VP2 capsid protein comprises a chimeric amino acid sequence, optionally wherein the common VP1 / VP2 region of the VP2 capsid protein of chimeric AAV comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity,with the amino acid sequence of the common VP1 / VP2 region of a second AAV and wherein the VP3 region of the chimeric VP2 capsid protein comprises at least 95% identity to the VP3 region of the non-primate animal AAV, and (iii) the VP3 capsid protein comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with an amino acid sequence of the VP3 capsid protein of the non-primate animal AAV. In some embodiments, (i) the VP1 capsid protein of the AAV comprises a chimeric amino acid sequence, optionally wherein the VP1-exclusive (VP1-u) region of the chimeric AAV VP1 capsid protein comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity,with the amino acid sequence of VP1-u of a second AAV and wherein the common VP1 / VP2 region and the VP3 region of the VP1 capsid of the chimeric AAV comprise an amino acid sequence with significant sequence identity, for example, at least 95% identity, with the amino acid sequence of the common VP1 / VP2 region and the VP3 region of the AAV, Petition 870260072813, dated 22 / 07 / 2026, p. 37 / 407 / 240 of a non-primate animal, (ii) the VP2 capsid protein comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with an amino acid sequence of the VP2 capsid protein of a non-primate animal AAV, and (iii) the VP3 capsid protein comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, to the amino acid sequence of a VP3 capsid protein of a non-primate animal AAV.In some embodiments, (i) the VP1 capsid protein comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with an amino acid sequence of the VP1 capsid protein of a non-primate animal AAV, (ii) the VP2 capsid protein comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with an amino acid sequence of the VP2 capsid protein of a non-primate animal AAV, and (iii) the VP3 capsid protein comprises an amino acid sequence with significant sequence identity, for example, at least 95% identity, with an amino acid sequence of the VP3 capsid protein of a non-primate animal AAV, and optionally wherein the particle comprises an AAV genome comprising an AAV ITR comprising at least a portion of an ITR sequence of another, for example, a second AAV, within the capsid.In some modalities, the other AAV is not identical to the AAV of a non-primate animal.

[0031] In some embodiments of the AAV viral particle of the invention, the other, for example, second, AAV is a primate AAV or a combination of primate AAVs. In some embodiments, the other AAV is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13 and a combination thereof. In some embodiments, the other AAV is AAV2. Petition 870260072813, dated 07 / 22 / 2026, p. 38 / 407 / 240

[0032] In some embodiments of the AAV viral particle of the invention, the non-primate animal AAV is a non-primate AAV listed in Table 2. In some embodiments, the non-primate AAV is an avian AAV (AAAV), a sea lion AAV, or a bearded dragon AAV. In some embodiments, the non-primate animal AAV is an AAAV and, optionally, an amino acid sequence of an AAAV capsid protein comprises a modification at position I444 or I580 of an AAAV VP1 capsid protein. In some embodiments, the non-primate animal AAV is a scale AAV, for example, a bearded dragon AAV, and optionally, an amino acid sequence of a bearded dragon AAV comprises a modification at position I573 or I436 of a bearded dragon AAV VP1 capsid protein.In some embodiments, the non-primate animal AAV is a mammalian AAV, for example, a sea lion AAV, and optionally, an amino acid sequence of a sea lion AAV comprises a modification at a selected position from the group consisting of I429, I430, I431, I432, I433, I434, I436, I437 and A565 of a VP1 capsid protein from a sea lion AAV.

[0033] In some embodiments of AAV viral particles of the invention, the protein:protein binding pair is selected from SpyTag:SpyCatcher, SpyTag:KTag, Isopeptag:pilin-C, SnoopTag:SnoopCatcher and SpyTag002:SpyCatcher002. In some embodiments, the first member of a protein:protein linking pair comprises c-myc comprising a sequence established as SEQ ID NO:44. In some embodiments, the detectable marker comprises the B1 epitope comprising an amino acid sequence of IGTRYLTR (SEQ ID NO: 45).

[0034] In some embodiments, an AAV particle of the invention comprises a VP3 capsid protein from non-primate animal AAV, remote AAV, or a combination thereof, wherein the capsid protein Petition 870260072813, dated 07 / 22 / 2026, p. 39 / 407 / 240 VP3 is modified to comprise (a) at least one first member of a protein:protein linking pair, optionally wherein the protein:protein linking pair is selected from the group consisting of SpyTag:SpyCatcher, SpyTag:KTag, Isopeptag:pilin-C, SnoopTag:SnoopCatcher, and SpyTag002:SpyCatcher002, (b) a detectable marker, optionally wherein the detectable marker comprises the amino acid sequence established as SEQ ID NO: 44 or the amino acid sequence established as SEQ ID NO: 45, (c) a point mutation, or (d) any combination of (a), (b), and (c). In some embodiments, the VP3 capsid protein of non-primate animal AAV, remote AAV, or a combination thereof is modified to comprise (a) at least a SpyTag comprising an amino acid sequence established as SEQ ID NO:43 and / or (b) a detectable marker comprising an amino acid sequence established as SEQ ID NO:45.

[0035] In some embodiments, an AAV particle of the invention comprises a first and / or second linker operationally linking a first member of a protein:protein linking pair and / or a detectable marker to a capsid protein of the capsid of said AAV particle. In some embodiments, the first and second linkers are not identical. In some embodiments, the first and second linkers are identical. In some embodiments, the first and / or second linker is 10 amino acids in length.

[0036] In some viral particle embodiments of the invention, at least one of the capsid proteins VP1, VP2, and VP3, optionally at least the VP3 capsid, is modified to comprise (a) a first member of a protein:protein linkage pair, (b) a detectable marker, (c) a point mutation, or (d) any combination of (a), (b), and / or (c). In some embodiments, the first member of a protein:protein linkage pair and / or the detectable marker or the point mutation is placed Petition 870260072813, dated 07 / 22 / 2026, p. 40 / 407 / 240 within a variable region of the capsid protein. In some embodiments, the first member of a protein:protein binding pair or the detectable marker is flanked by a first linker and / or a second linker. In some embodiments, the first and / or second linker is 1-10 amino acids long. In some embodiments, the first and second linkers are not identical. In some embodiments, the first and second linkers are identical.

[0037] In some viral particle embodiments, an AAAV VP3 capsid protein comprises a modification, optionally a first member of a protein:protein linkage pair, optionally wherein the modification is at position(s) I444 (e.g., G444) and / or I580 (e.g., K580). In some embodiments, an AAAV VP3 capsid protein comprises a modification, optionally a first member of a protein:protein linkage pair, optionally wherein the modification is at position(s) I444 (e.g., G444) and / or I580 (e.g., K580). In some embodiments, a bearded dragon AAV VP3 capsid protein comprises a modification, optionally a first member of a protein:protein linkage pair, optionally wherein the modification is at position(s) I573 (e.g., T573) and / or I436 (e.g., G436).In some embodiments, a sea lion VP3 capsid protein comprises a modification, optionally a first member of a protein:protein linkage pair, optionally wherein the modification is at a position selected from the group consisting of I429 (e.g., N429), I430 (e.g., P430), I431 (e.g., T431), I432 (e.g., G432), I433 (e.g., S433), I434 (e.g., T434), I436 (e.g., R436), I437 (e.g., D437), and I565 (A565).

[0038] In some viral particle embodiments of the invention, at least one capsid protein, optionally at least the VP3 capsid, Petition 870260072813, dated 22 / 07 / 2026, page 41 / 407 / 240 is modified to comprise a first member of a protein:protein linkage pair. In some embodiments, the first member of a protein:protein linkage pair comprises a first member of a protein:protein linkage pair. In some embodiments, the first member of a protein:protein linkage pair comprises a second cognate member of the protein:protein linkage pair. In some embodiments, the first and second members of the protein:protein linkage pair are linked by a covalent bond, for example, an isopeptide bond. In some embodiments, the first member of the protein:protein linkage pair is SpyTag and, optionally, the second member of the protein:protein linkage pair is SpyCatcher or KTag. In some embodiments, the first member of the protein:protein linking pair is KTag and, optionally, the second member of the protein:protein linking pair is SpyTag.In some embodiments, the first member of the protein:protein linkage pair is SnoopTag and the second member of the protein:protein linkage pair is SnoopCatcher. In some embodiments, the first member of the protein:protein linkage pair is isopeptag and the second member of the protein:protein linkage pair is Pilina-C. In some embodiments, the first member of the protein:protein linkage pair is SpyTag002 and the second member of the protein:protein linkage pair is SpyCatcher002. In some embodiments, the second member of the protein:protein linkage pair is linked to a targeting ligand, for example, a binding fragment, for example, an antibody or a fragment thereof. In some embodiments, the targeting ligand may be fused to a second member of a protein:protein linkage pair, for example, SpyCatcher, optionally through a ligand at the C-terminus of the second member, and the ligand is fused to SpyCatcher at the C-terminus of the ligand.In some embodiments, the ligand comprises the sequence GSGESG (SEQ ID NO:49). In some embodiments, the first member of a protein:protein binding pair comprises a detectable marker. In some... Petition 870260072813, dated 22 / 07 / 2026, p. 42 / 407 / 240 modalities, the first member of a protein-protein binding pair comprises a detectable marker c-myc.

[0039] In some viral particle embodiments of the invention, at least one capsid protein, optionally at least the VP3 capsid, is modified to comprise a detectable marker. In some embodiments, the detectable marker comprises the AAV B1 epitope, for example, the amino acid sequence IGTRYLTR (SEQ ID NO: 45).

[0040] In some viral particle embodiments of the invention, at least one capsid protein, optionally at least the VP3 capsid, is modified to comprise (a) a first member of a protein:protein linkage pair comprising at least one member of a protein:protein linkage pair, optionally wherein the protein:protein linkage pair is selected from the group consisting of SpyTag:SpyCatcher, SpyTag:KTag, Isopeptag:pilin-C, SnoopTag:SnoopCatcher, SpyTag002:SpyCatcher002, and c-myc:anti-c-myc antibody. (b) a detectable marker, optionally wherein the detectable marker comprises the amino acid sequence established as SEQ ID NO:44 or the amino acid sequence established as SEQ ID NO:45, (c) a point mutation, or (d) any combination of (a), (b) and (c).

[0041] In some viral particle embodiments of the invention, at least one capsid protein, optionally at least the VP3 capsid, is modified to comprise (a) a first member of a protein:protein linkage pair comprising at least a SpyTag comprising an amino acid sequence set forth as SEQ ID NO:43 and / or (b) a detectable marker comprising an amino acid sequence set forth in SEQ ID NO:45. Petition 870260072813, dated 07 / 22 / 2026, page 43 / 407 / 240

[0042] In some embodiments, an AAV particle of the invention comprises a capsid protein comprising an amino acid sequence selected from the group consisting of (a) an amino acid sequence established as SEQ ID NO: 2, (b) an amino acid sequence established as SEQ ID NO: 4, (c) an amino acid sequence established as SEQ ID NO: 6, (d) an amino acid sequence established as SEQ ID NO: 8, (e) an amino acid sequence established as SEQ ID NO: 10, (f) an amino acid sequence established as SEQ ID NO: 12, (g) an amino acid sequence established as SEQ ID NO: 14, (h) an amino acid sequence established as SEQ ID NO: 16, (i) an amino acid sequence established as SEQ ID NO: 18, (j) an amino acid sequence established as SEQ ID NO: 20, (k) an amino acid sequence established as SEQ ID NO: 22, (l) an amino acid sequence established as SEQ ID NO: 24,(m) an amino acid sequence established as SEQ ID NO: 26, (n) an amino acid sequence established as SEQ ID NO: 28, (o) an amino acid sequence established as SEQ ID NO: 30, (p) an amino acid sequence established as SEQ ID NO: 32, (q) an amino acid sequence established as SEQ ID NO: 34, (r) an amino acid sequence established as SEQ ID NO: 36, (s) the amino acid sequence established as SEQ ID NO: 53, (t) the amino acid sequence established as SEQ ID NO: 55, (u) the amino acid sequence established as SEQ ID NO: 57, (v) the amino acid sequence established as SEQ ID NO: 59, (w) the amino acid sequence established as SEQ ID NO: 61, (x) the amino acid sequence established as SEQ ID NO: 63, (y) the amino acid sequence established as SEQ ID NO: 65, (z) the amino acid sequence established as SEQ ID NO: 67, (aa) the sequence of, Petition 870260072813, dated 07 / 22 / 2026, p. 44 / 407 / 240 amino acids established as SEQ ID NO: 69, (bb) the amino acid sequence established as SEQ ID NO: 71, (cc) an amino acid sequence with at least 95% identity to SEQ ID NO: 2, NO DE ID SEQ: 4, NO DE ID SEQ: 6, NO DE ID SEQ: 8, NO DE ID SEQ: 10, NO DE ID SEQ: 12, NO DE ID SEQ: 14, NO DE ID SEQ: 16, NO DE ID SEQ: 18, NO DE ID SEQ: 20, NO DE ID SEQ: 22, NO DE ID SEQ: 24, NO DE ID SEQ: 26, NO DE ID SEQ: 28, NO DE ID SEQ: 30, NO DE ID SEQ: 32, NO DE ID SEQ: 34, NO DE ID SEQ: 36, NO DE ID SEQ: 53, NO DE ID SEQ: 55, NO DE ID SEQ: 57, NO DE ID SEQ: 59, NO DE ID SEQ: 61, NO DE ID SEQ: 63, NO DE ID SEQ: 65, NO DE ID SEQ: 67, NO DE ID SEQ: 69, or SEQ ID NO: 71, and (dd) an amino acid sequence from any portion of VP2 and / or VP3 amino acid sequences set forth in any one of (a)-(cc).

[0043] In some embodiments of the viral particle of the invention, wherein at least one of the AAV capsid proteins VP1, VP2 and VP3 comprises a modification, for example, a first member of a protein:protein linkage pair, the viral particle further comprises a reference capsid protein, optionally a capsid protein corresponding to at least one of the AAV capsid proteins VP1, VP2 and VP3, except for the modification, such that the capsid is a mosaic capsid. In some embodiments, a mosaic capsid comprises the VP1 capsid protein modified with a first member of a protein:protein linkage pair and a reference VP1 capsid protein. In some embodiments, a mosaic capsid comprises the VP2 capsid protein modified with a first member of a protein:protein linkage pair and a reference VP2 capsid protein.In some embodiments, a mosaic capsid comprises the VP3 capsid protein modified with a first member of a protein:protein linkage pair and a reference VP3 capsid protein. Petition 870260072813, dated 07 / 22 / 2026, page 45 / 407 / 240

[0044] Viral particles of the invention comprising AAV capsid proteins of the invention are also described. In some embodiments of the invention, an AAV capsid protein of the invention comprises an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity, with an amino acid sequence of a capsid protein of a non-primate animal AAV or a remote AAV, wherein the AAV capsid protein is selected from the group consisting of (a) a chimeric AAV VP1 capsid protein, optionally wherein the chimeric animal AAV VP1 capsid protein is modified to comprise at least one first member of a protein:protein linkage pair, a detectable marker, and / or a point mutation, (b) a non-chimeric AAV VP1 capsid protein modified to comprise at least one first member of a protein:protein linkage pair and / or a detectable marker,(c) a chimeric VP2 capsid protein, optionally wherein the chimeric AAV VP2 capsid protein is modified to comprise at least one first member of a protein:protein linkage pair, a detectable marker, and / or a point mutation, (d) a non-chimeric AAV VP2 capsid protein is modified to comprise at least one first member of a protein:protein linkage pair, a detectable marker, and / or a point mutation, (e) a chimeric AAV VP3 capsid protein modified to comprise at least one first member of a protein:protein linkage pair, a detectable marker, and / or a point mutation, and (f) a non-chimeric AAV VP3 capsid protein modified to comprise at least one first member of a protein:protein linkage pair, a detectable marker, and / or a point mutation.

[0045] In some embodiments of AAV capsid protein of the invention, the first member of a protein:protein linkage pair and / or Petition 870260072813, dated 07 / 22 / 2026, p. 46 / 407 / 240 detectable marker is flanked on one or both sides, respectively, by a first and / or second linker that links the first member of a protein:protein linkage pair and / or detectable marker to the capsid protein, wherein the first and / or second linker each independently has at least one amino acid in length. In some embodiments, the first and second linkers are not identical. In some embodiments, the first and second linkers are identical and have 10 amino acids in length.

[0046] In some embodiments, an AAV capsid protein of the invention comprises a detectable marker, optionally wherein the detectable marker comprises a B1 epitope comprising an amino acid sequence established as SEQ ID NO:45. In some embodiments, a detectable marker comprises c-myc.

[0047] In some embodiments, an AAV capsid protein of the invention comprises a first member and a second cognate member of the protein:protein linkage pair, optionally wherein the first and second members are linked by a covalent bond, optionally an isopeptide bond. In some embodiments, the first member of a protein:protein linkage pair is SpyTag and, optionally, the second cognate member is SpyCatcher or KTag. In some embodiments, the first member is KTag and the second cognate member is SpyTag. In some embodiments, the first member is SnoopTag and the second cognate member is SnoopCatcher. In some embodiments, the first member is isopeptag and the second cognate member is Pilina-C. In some embodiments, the first member is SpyTag002 and the second cognate member is SpyCatcher002.In some embodiments, the first member comprises a detectable marker, such as, but not limited to, c-myc, wherein its binding pair is an anti-c-myc antibody or a portion thereof. In some embodiments, the second member is operationally linked to a ligand of... Petition 870260072813, dated 07 / 22 / 2026, p. 47 / 407 / 240 targeting, optionally where the targeting ligand is a binding fraction, which optionally targets a cell marker. In some embodiments, the binding fraction is an antibody or a portion thereof. In some embodiments, the binding fraction is operationally linked to a second member of the protein:protein linking pair, optionally via a covalent linkage (such as, but not limited to, an isopeptide linkage) or a linker. In some embodiments, the binding fraction is fused to a second member of the protein:protein linking pair via a linker fused to the C-terminus of the binding fraction, wherein the linker is fused to the second C-terminus member of the linker, optionally wherein the linker comprises a sequence established as SEQ ID NO:49 (GSGESG).In some embodiments, the first member of the protein:protein linkage pair is at an amino acid position found in VR I, VR II, VR III, VR IV, VR V, VR VI, VR VII, VR VIII, VR IX or in the HI loop of the capsid protein, optionally at VR VIII or VR IV of the capsid protein.

[0048] In some embodiments of the AAV capsid protein of the invention, the non-primate animal AAV is a non-primate AAV listed in Table 2. In some embodiments, the non-primate AAV is an avian AAV (AAAV), a sea lion AAV, or a bearded dragon AAV. In some embodiments, the non-primate animal AAV is an AAAV and, optionally, an amino acid sequence of an AAAV capsid protein comprises a modification at position I444 or I580 of an AAAV VP1 capsid protein. In some embodiments, the non-primate animal AAV is a scale AAV, for example, a bearded dragon AAV, and optionally, an amino acid sequence of a bearded dragon AAV comprises a modification at position I573 or I436 of a bearded dragon VP1 capsid protein. In some modalities, the AAV of a non-primate animal is an AAV of a mammal, for example, an AAV Petition 870260072813, dated 22 / 07 / 2026, p. 48 / 407 / 240 of sea lion and, optionally, an amino acid sequence of a sea lion AAV comprises a modification at the selected position of the group consisting of I429, I430, I431, I432, I433, I434, I436, I437 and A565 of a VP1 capsid protein of a sea lion AAV.

[0049] The non-primate animal VP3 capsid proteins of the invention include non-primate VP3 capsids (a) that encapsulate the genome of another, for example, second, AAV and / or (b) that are mutated. In some embodiments, the non-human animal AAV VP3 capsid protein of the invention encapsulates the genome of a second AAV that is not from the non-primate animal. In some embodiments, a non-primate animal AAV VP3 capsid protein of the invention may be operationally linked to a first member of a protein:protein linkage pair (optionally via a first and / or second linker) and / or comprise a point mutation, for example, such that the natural tropism of the capsid protein is reduced to null and / or such that the capsid marker comprises a detectable protein. In some embodiments, a first member of a protein:protein linkage pair comprises a detectable marker.In some embodiments, a first member of a protein:protein linkage pair comprises the detectable marker comprising c-myc (SEQ ID NO:44). In some embodiments, the first member of a protein:protein linkage pair comprises the first member and, optionally, the second member of a protein:protein linkage pair that forms a covalent bond. In some embodiments, the protein:protein linkage pair is selected from the group consisting of (a) SpyTag:SpyCatcher, (b) SpyTag:KTag, (c) Isopeptag:pilin C, (d) SnoopTag:SnoopCatcher and (e) SpyTag002:SpyCatcher002. In some embodiments, a VP3 capsid protein from a non-primate animal AAV may comprise (a) a B1 epitope (SEQ ID NO:45), (b) SpyTag, (c) SpyCatcher, or any combination of (a)-(c). Petition 870260072813, dated 07 / 22 / 2026, p. 49 / 407 / 240

[0050] In some embodiments, a VP3 capsid protein of a non-primate animal AAV of the invention comprises a first member of a protein:protein linkage pair operationally linked to it, optionally through a first or second linker. In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a VP3 capsid of a non-primate animal AAV at an amino acid position found in a variable region (VR) or portion of the VP3 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the VP3 capsid through a first and / or second linker.In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a VP3 capsid of a non-primate animal AAV at an amino acid position found in VR I, VR II, VR III, VR IV, VR V, VR VI, VR VII, VR VIII, VR IX or in the HI loop of the VP3 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the VP3 capsid through a first and / or second linker. In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a VP3 capsid of a non-primate animal AAV at an amino acid position found in VR VIII or VR IV of the VP3 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the VP3 capsid through a first and / or second linker.In some embodiments, a VP3 capsid protein from a non-primate animal AAV is a VP3 capsid protein from a non-primate animal AAV selected from the non-primate animal AAVs provided in Table 2. In some embodiments, a VP3 capsid protein from a non-primate animal AAV is a VP3 capsid protein from an avian AAV (AAAV). In some embodiments, a VP3 capsid protein from an AAAV comprises a first member of a protein:protein linking pair (e.g., SpyTag) operationally. Petition 870260072813, dated 22 / 07 / 2026, p. 50 / 407 / 240 linked, optionally through a first and / or second linker, at position I444 or I580. In some embodiments, a VP3 capsid protein from a non-primate animal AAV is a VP3 capsid protein from a bearded dragon AAV. In some embodiments, a VP3 capsid protein from a bearded dragon AAV comprises a first member of a protein:protein linkage pair (e.g., SpyTag) operationally linked, optionally through a first and / or second linker, at position I573 or I436. In some embodiments, a VP3 capsid protein from a non-primate animal AAV is a VP3 capsid protein from a sea lion AAV.In some embodiments, a VP3 capsid protein of a sea lion AAV comprises a first member of a protein-protein linkage pair (e.g., SpyTag) operationally linked, optionally via a first and / or second linker, at a position selected from the group consisting of I429, I430, I431, I432, I433, I434, I436, I437 and I565, and optionally at a position selected from the group consisting of I429, I430, I431, I432, I433, I436 and I437; optionally at I432.

[0051] The non-primate animal VP2 capsid proteins of the invention include non-primate VP2 capsids (a) that encapsulate the genome of another, for example, second, AAV and / or (b) that are mutated. In some embodiments, a VP2 capsid protein of a non-primate animal AAV of the invention encapsulates the genome of another, for example, second, AAV. In some embodiments, a VP2 capsid protein of a non-primate animal AAV of the invention may be operationally linked to a first member of a protein:protein linkage pair and / or comprise a point mutation, for example, such that the natural tropism of the capsid protein is reduced to null and / or such that the capsid protein comprises a detectable marker. In some embodiments, a first member of a protein:protein linkage pair Petition 870260072813, dated 22 / 07 / 2026, p. 51 / 407 / 240 comprises a detectable marker. In some embodiments, a first member of a protein:protein linkage pair comprises a detectable marker comprising c-myc (SEQ ID NO:44). In some embodiments, the first member of a protein:protein linkage pair comprises the first member and, optionally, the second member of a protein:protein linkage pair that forms a covalent bond. In some embodiments, the protein:protein linkage pair is selected from the group consisting of (a) SpyTag:SpyCatcher, (b) SpyTag:KTag, (c) Isopeptag:pilin C, (d) SnoopTag:SnoopCatcher, and (e) SpyTag002:SpyCatcher002. In some embodiments, a VP2 capsid protein from a non-primate animal AAV may comprise (a) a B1 epitope (SEQ ID NO:45), (b) SpyTag, (c) SpyCatcher, or any combination of (a)-(c).

[0052] In some embodiments, a VP2 capsid protein of a non-primate animal AAV of the invention comprises a first member of a protein:protein linkage pair operationally linked to it, optionally through a first and a second linker. In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a VP2 capsid of a non-primate animal AAV at an amino acid position found in a variable region (VR) or portion of the VP2 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the VP2 capsid through a first and / or second linker.In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a VP2 capsid of a non-primate animal AAV at an amino acid position found in VR I, VR II, VR III, VR IV, VR V, VR VI, VR VII, VR VIII, VR IX or loop HI of the VP2 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the VP2 capsid via a first and / or second linker. In some embodiments, a first member of a protein:protein linkage pair is... Petition 870260072813, dated 07 / 22 / 2026, p. 52 / 407 / 240 operationally linked to a VP2 capsid of a non-primate animal AAV at an amino acid position found in VR VIII or VR IV of the VP2 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the VP2 capsid via a first and / or second linker. In some embodiments, a VP2 capsid protein of a non-primate animal AAV is a VP2 capsid protein of a non-primate animal AAV selected from the non-primate animal AAVs provided in Table 2. In some embodiments, a VP2 capsid protein of a non-primate animal AAV is a VP2 capsid protein of an avian AAV (AAAV). In some embodiments, an AAAV VP2 capsid protein comprises a first member of a protein:protein linkage pair (e.g., SpyTag) operationally linked, optionally via a first and / or second linker, at the I444 or I580 position.In some embodiments, a VP2 capsid protein from a non-primate animal AAV is a VP2 capsid protein from a bearded dragon AAV. In some embodiments, a VP2 capsid protein from a bearded dragon AAV comprises a first member of a protein:protein linkage pair (e.g., SpyTag) operationally linked, optionally through a first and / or second linker, at position I573 or I436. In some embodiments, a VP2 capsid protein from a non-primate animal AAV is a VP2 capsid protein from a sea lion AAV.In some embodiments, a VP2 capsid protein of a sea lion AAV comprises a first member of a protein-protein linkage pair (e.g., SpyTag) operationally linked, optionally via a first and / or second linker, at a position selected from the group consisting of I429, I430, I431, I432, I433, I434, I436, I437 and I565; optionally at a position selected from the group consisting of I429, I430, I431, I432, I433, I436 and I437; optionally at I431. Petition 870260072813, dated 07 / 22 / 2026, p. 53 / 407 / 240

[0053] In some embodiments, a VP2 capsid protein of the invention may be a chimeric VP2 capsid protein comprising, in operable linkage, a portion of a VP2 capsid protein from a non-primate animal AAV and a portion of a VP2 capsid protein from another, for example, second, AAV. In some embodiments, a chimeric VP2 capsid protein comprises, from N-terminus to C-terminus (a) a portion of the VP2 capsid protein from another, for example, second, AAV operably linked to (b) a portion of the VP2 capsid from a non-primate animal AAV comprising at least the amino acid sequence of the VP3 capsid protein from a non-primate animal AAV. In some embodiments, a chimeric VP2 capsid protein may comprise, from the N-terminus to the C-terminus, (a) an amino acid sequence from the common VP1 / VP2 region of the other operationally linked AAV and (b) an amino acid sequence from the VP3 capsid protein of the non-primate animal AAV.In some modalities, the other AAV is a non-primate animal AAV. In some other modalities, the other AAV is a primate AAV.

[0054] In some embodiments, a chimeric VP2 capsid protein of the invention comprises (a) a portion of the VP2 capsid protein of a primate AAV operationally linked to (b) a portion of the VP2 capsid of a non-primate animal AAV comprising at least the amino acid sequence of the VP3 capsid protein of a non-primate animal AAV. In some embodiments, a chimeric VP2 capsid protein may comprise, from the N-terminus to the C-terminus, (a) an amino acid sequence of the common VP1 / VP2 region of a primate AAV operationally linked to (b) an amino acid sequence of a VP3 capsid protein of a non-primate animal AAV. In some embodiments, the primate AAV is AAV1. In some embodiments, the primate AAV is AAV2. In some embodiments, the primate AAV is AAV3. In some embodiments, the primate AAV is AAV4. In some sports, the AAV Petition 870260072813, dated 07 / 22 / 2026, p. 54 / 407 / 240. The primate AAV is AAV5. In some modalities, the primate AAV is AAV6. In some modalities, the primate AAV is AAV7. In some modalities, the primate AAV is AAV8. In some modalities, the primate AAV is AAV9. In some modalities, the non-primate animal AAV is selected from the group of non-primate animal AAVs provided in Table 2. In some modalities, the non-primate animal AAV is an avian AAV, a bearded dragon AAV, or a sea lion AAV.

[0055] In some embodiments, a chimeric VP2 capsid protein of the invention comprises (a) a VP2 capsid protein portion of AAV2 operatively linked to (b) a VP2 capsid portion of a non-primate animal AAV comprising at least the amino acid sequence of the VP3 capsid protein of the non-primate animal AAV. In some embodiments, a chimeric VP2 capsid protein may comprise, from the N-terminus to the C-terminus, (a) an amino acid sequence of the common VP1 / VP2 region of AAV2 operatively linked to (b) an amino acid sequence of a VP3 capsid protein of a non-primate animal AAV.

[0056] In some embodiments, a chimeric AAV2 / AAAV VP2 capsid protein of the invention comprises (a) a portion of the AAV2 VP2 capsid protein operationally linked to (b) a portion of the VP2 capsid protein of an avian AAV (AAAV) comprising at least the amino acid sequence of the AAAV VP3 capsid protein. In some embodiments, a chimeric AAV2 / AAAV VP2 capsid protein may comprise, from the N-terminus to the C-terminus, (a) an amino acid sequence of the common VP1 / VP2 region of AAV2 operationally linked to (b) an amino acid sequence of an AAAV VP3 capsid protein.

[0057] In some embodiments, a chimeric VP2 capsid protein of sea lion AAV2 / AAV of the invention comprises (a) a Petition 870260072813, dated 22 / 07 / 2026, p. 55 / 407 / 240 portion of the VP2 capsid protein of AAV2 operationally linked to (b) a portion of the VP2 capsid protein of a sea lion AAV comprising at least the amino acid sequence of the VP3 capsid protein of the sea lion AAV. In some embodiments, a chimeric VP2 capsid protein of AAV2 / sea lion AAV may comprise, from the N-terminus to the C-terminus, (a) an amino acid sequence of the common VP1 / VP2 region of AAV2 operationally linked to (b) an amino acid sequence of a VP3 capsid protein of a sea lion AAV.

[0058] In some embodiments, a chimeric VP2 capsid protein of AAV2 / bearded dragon AAV of the invention comprises (a) a portion of the VP2 capsid protein of AAV2 operatively linked to (b) a portion of the VP2 capsid protein of a bearded dragon AAV comprising at least the amino acid sequence of the VP3 capsid protein of the bearded dragon AAV. In some embodiments, a chimeric VP2 capsid protein of AAV2 / bearded dragon AAV may comprise, from the N-terminus to the C-terminus, (a) an amino acid sequence of the common VP1 / VP2 region of AAV2 operatively linked to (b) an amino acid sequence of a VP3 capsid protein of a bearded dragon AAV.

[0059] In some embodiments, a chimeric VP2 capsid protein of the invention can be operationally linked to a first member of a protein:protein linkage pair and / or comprise a point mutation, for example, such that the natural tropism of the capsid protein is reduced to abolished and / or such that the capsid protein comprises a detectable marker. In some embodiments, a first member of a protein:protein linkage pair comprises a detectable marker. In some embodiments, a first member of a protein:protein linkage pair comprises the detectable marker comprising cmyc (SEQ ID NO:44). In some embodiments, the first member of a Petition 870260072813, dated 22 / 07 / 2026, p. 56 / 407 / 240. A protein:protein linkage pair comprises the first member and, optionally, the second member of a protein:protein linkage pair that forms a covalent bond. In some embodiments, the protein:protein linkage pair is selected from the group consisting of (a) SpyTag:SpyCatcher, (b) SpyTag:KTag, (c) Isopeptag:pilin C, (d) SnoopTag:SnoopCatcher, and (e) SpyTag002:SpyCatcher002. In some embodiments, a chimeric VP2 capsid protein may comprise (a) a B1 epitope (SEQ ID NO:45), (b) SpyTag, (c) SpyCatcher, or any combination of (a)-(c).

[0060] In some embodiments, a chimeric primate / non-primate animal VP2 capsid protein of the invention (for example, a chimeric AAV2 / AAAV VP2 capsid protein, a chimeric AAV2 / AAV sea lion VP2 capsid protein, a chimeric AAV2 / AAV bearded dragon VP2 capsid protein, etc.) comprises a first member of a protein:protein linkage pair operationally linked thereto, optionally via a first or second linker. In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a chimeric primate / non-primate animal VP2 capsid protein (e.g., a chimeric AAV2 / AAAV VP2 capsid protein, a chimeric AAV2 / AAV VP2 capsid protein from a sea lion, a chimeric AAV2 / AAV VP2 capsid protein from a bearded dragon, etc.).) at an amino acid position found in a variable region (VR) or portion thereof of the chimeric primate / non-primate animal VP2 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the chimeric primate / non-primate animal VP2 capsid protein via a first and / or second linker. In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a VP2 capsid protein. Petition 870260072813, dated 07 / 22 / 2026, p. 57 / 407 / 240 chimeric primate / non-primate animal at an amino acid position found in VR I, VR II, VR III, VR IV, VR V, VR VI, VR VII, VR VIII VR IX or in the HI loop of the VP2 capsid protein chimeric primate / non-primate animal, optionally wherein the first member of a protein:protein linkage pair is linked to the VP2 capsid through a first and / or second linker. In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a chimeric primate / non-primate animal VP2 capsid protein (e.g., a chimeric AAV2 / AAAV VP2 capsid protein, a chimeric AAV2 / AAV VP2 capsid protein from a sea lion, a chimeric AAV2 / AAV VP2 capsid protein from a bearded dragon, etc.).) at an amino acid position found in VR VIII or VR IV of the chimeric primate / non-primate animal VP2 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the chimeric primate / non-primate animal VP2 capsid protein through a first and / or second linker. In some embodiments, a chimeric AAV2 / AAAV VP2 capsid protein comprises a first member of a protein:protein linkage pair (e.g., SpyTag) operationally linked, optionally through a first and / or second linker, at position I444 or I580. In some embodiments, a chimeric AAV2 / AAV bearded dragon VP2 capsid protein comprises a first member of a protein:protein linkage pair (e.g., SpyTag) operationally linked, optionally through a first and / or second linker, at position I573 or I436.In some embodiments, a chimeric VP2 capsid protein of sea lion AAV2 / AAV comprises a first member of a protein:protein linkage pair (e.g., SpyTag) operationally linked, optionally through a first and / or second linker, at a position selected from the I429, I430, I431, I432, I433, I434, I436, I437 and I565 groups, optionally in one. Petition 870260072813, dated 22 / 07 / 2026, p. 58 / 407 / 240 selected position from the group consisting of I429, I430, I431, I432, I433, I436 and I437; optionally in I431.

[0061] The non-primate animal VP1 capsid proteins of the invention include non-primate animal VP1 capsids (a) that encapsulate the genome of another, for example, second, AAV and / or (b) that are mutated. In some embodiments, a non-primate animal VP1 capsid protein of the invention encapsulates the genome of another, for example, second, AAV. In some embodiments, a non-primate animal VP1 capsid protein of the invention may be operationally linked to a first member of a protein:protein linkage pair and / or comprise a point mutation, for example, such that the natural tropism of the capsid protein is reduced to null and / or such that the capsid protein comprises a detectable marker. In some embodiments, a first member of a protein:protein linkage pair comprises a detectable marker.In some embodiments, a first member of a protein:protein linkage pair comprises the detectable marker c-myc (SEQ ID NO:44). In some embodiments, the first member of a protein:protein linkage pair comprises the first member and, optionally, the second member of a protein:protein linkage pair that forms a covalent bond. In some embodiments, the protein:protein linkage pair is selected from the group consisting of (a) SpyTag:SpyCatcher, (b) SpyTag:KTag, (c) Isopeptag:pilin C, (d) SnoopTag:SnoopCatcher, and (e) SpyTag002:SpyCatcher002. In some embodiments, a VP3 capsid protein from a non-primate animal AAV may comprise (a) a B1 epitope (SEQ ID NO:45), (b) SpyTag, (c) SpyCatcher, or any combination of (a)-(c).

[0062] In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a VP1 capsid of a non-primate animal AAV of the invention at an amino acid position. Petition 870260072813, dated 07 / 22 / 2026, p. 59 / 407 / 240 found in a variable region (VR) or portion thereof of the VP1 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the VP1 capsid via a first and / or second linker. In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a VP1 capsid of a non-primate animal AAV at an amino acid position found in VR I, VR II, VR III, VR IV, VR V, VR VI, VR VII, VR VIII, VR IX or in the HI loop of the VP1 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to a VP1 capsid via a first and / or second linker.In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a VP1 capsid of a non-primate animal AAV at an amino acid position found in VR VIII or VR IV of the VP1 capsid protein, optionally where the first member of a protein:protein linkage pair is linked to the VP1 capsid through a first and / or second linker. In some embodiments, a VP1 capsid protein of a non-primate animal AAV is a VP1 capsid protein of a non-primate AAV selected from the group of non-primate animal AAVs provided in Table 2. In some embodiments, a VP1 capsid protein of a non-primate animal AAV is a VP1 capsid protein of an avian AAV (AAAV).In some embodiments, a VP1 capsid protein of AAAV comprises a first member of a protein:protein linkage pair (e.g., SpyTag) operationally linked, optionally through a first and / or second linker, at the I444 or I580 position. In some embodiments, a VP1 capsid protein of a non-primate animal AAV is a VP31 capsid protein of a bearded dragon AAV. In some embodiments, a VP1 capsid protein of a bearded dragon AAV comprises a first member of a protein:protein linkage pair (e.g., SpyTag) operationally linked. Petition 870260072813, dated 22 / 07 / 2026, p. 60 / 407 / 240 optionally through a first and / or second linker, at position I573 or I436. In some embodiments, a VP1 capsid protein of a non-primate animal AAV is a VP1 capsid protein of a sea lion AAV. In some embodiments, a VP1 capsid protein of a sea lion AAV comprises a first member of a protein:protein linkage pair (e.g., SpyTag) operationally linked, optionally through a first and / or second linker, at the selected position of the group consisting of I429, I430, I431, I432, I433, I434, I436, I437 and I565; optionally in a selected position from the group consisting of I429, I430, I431, I432, I433, I436 and I437; optionally in I431.

[0063] In some other embodiments, a VP1 capsid protein of the invention may be a chimeric VP1 capsid protein comprising in operational linkage a portion of a VP1 capsid protein from a non-primate animal AAV and a portion of the VP1 capsid protein from another AAV, wherein the other AAV is not the non-primate animal AAV. In some embodiments, a chimeric VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) a portion of the VP1 capsid protein from the other AAV comprising at least one PLA2 domain from the other AAV and (b) a portion of the VP1 capsid from the non-primate animal AAV comprising at least the amino acid sequence of the VP3 capsid protein from the non-primate animal AAV.In some embodiments, a chimeric VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) a portion of the VP1 capsid protein of the other AAV comprising at least one VP1-u domain of the other AAV and (b) a portion of the VP1 capsid of the non-primate animal AAV comprising at least the amino acid sequence of the VP3 capsid protein of the non-primate animal AAV. In some embodiments, a chimeric VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) an amino acid sequence of a domain. Petition 870260072813, dated 07 / 22 / 2026, p. 61 / 407 / 240 VP1-u and a common VP1 / VP2 region of another, for example, second, AAV and (b) an amino acid sequence of the VP3 capsid protein of the non-primate animal AAV. In some embodiments, the other AAV is a non-primate animal AAV. In some other embodiments, the other AAV is a primate AAV.

[0064] In some embodiments, a chimeric VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) a portion of the VP1 capsid protein of a primate AAV comprising at least one PLA2 domain of the primate AAV and (b) a portion of the VP1 capsid of a non-primate animal AAV comprising at least the amino acid sequence of the VP3 capsid protein of the non-primate animal AAV. In some embodiments, a chimeric VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) a portion of the VP1 capsid protein of a primate AAV comprising at least one VP1-u domain of the primate AAV and (b) a portion of the VP1 capsid of a non-primate animal AAV comprising at least the amino acid sequence of the VP3 capsid protein of the non-primate animal AAV.In some embodiments, a chimeric VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) an amino acid sequence from a VP1-u domain and a common VP1 / VP2 region of a primate AAV and (b) an amino acid sequence from the VP3 capsid protein of a non-primate animal AAV. In some embodiments, the primate AAV is AAV1. In some embodiments, the primate AAV is AAV2. In some embodiments, the primate AAV is AAV3. In some embodiments, the primate AAV is AAV4. In some embodiments, the primate AAV is AAV5. In some embodiments, the primate AAV is AAV6. In some embodiments, the primate AAV is AAV7. In some embodiments, the primate AAV is AAV8. In some embodiments, the primate AAV is AAV9. In some modalities, the non-primate animal AAV is selected from the group of non-animal AAVs. Petition 870260072813, dated 07 / 22 / 2026, p. 62 / 407 / 240 primate provided in Table 2. In some modalities, the non-primate animal AAV is an avian AAV, a bearded dragon AAV, or a sea lion AAV.

[0065] In some embodiments, a chimeric VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) a portion of the AAV2 VP1 capsid protein comprising at least one AAV2 PLA2 domain and (b) a portion of the non-primate animal AAV VP1 capsid comprising at least the amino acid sequence of the non-primate animal AAV VP3 capsid protein. In some embodiments, a chimeric VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) a portion of the AAV2 VP1 capsid protein comprising at least one AAV2 VP1-u domain and (b) a portion of the non-primate animal AAV VP1 capsid comprising at least the amino acid sequence of the non-primate animal AAV VP3 capsid protein.In some embodiments, a chimeric VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) an amino acid sequence of a VP1-u domain and a common VP1 / VP2 region of AAV2 and (b) an amino acid sequence of the VP3 capsid protein from the non-primate animal.

[0066] In some embodiments, a chimeric AAV2 / AAAV VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) a portion of the AAV2 VP1 capsid protein comprising at least one AAV2 PLA2 domain and (b) a portion of the VP1 capsid of an avian AAV (AAAV) comprising at least the amino acid sequence of the AAAAV VP3 capsid protein. In some embodiments, a chimeric AAV2 / AAAV VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) a portion of the AAV2 VP1 capsid protein comprising at least one AAV2 VP1-u domain and (b) a portion of the AAAV VP1 capsid comprising at least the amino acid sequence of the AAAV VP3 capsid protein. In some Petition 870260072813, dated 07 / 22 / 2026, p. 63 / 407 / 240 embodiments, a chimeric VP1 capsid protein of AAV2 / AAAV comprises, from the N-terminus to the C-terminus, (a) an amino acid sequence of a VP1-u domain and a common VP1 / VP2 region of AAV2 and (b) an amino acid sequence of the VP3 capsid protein of AAAV. In some embodiments, a chimeric VP1 capsid protein of AAV2 / AAAV comprises the amino acid sequence established as SEQ ID NO:2.

[0067] In some embodiments, a chimeric AAV2 / sea lion VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) a portion of the AAV2 VP1 capsid protein comprising at least one AAV2 PLA2 domain and (b) a portion of the sea lion AAV VP1 capsid comprising at least the amino acid sequence of the sea lion VP3 capsid protein. In some embodiments, a chimeric AAV2 / sea lion VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) a portion of the AAV2 VP1 capsid protein comprising at least one AAV2 VP1-u domain and (b) a portion of the sea lion VP1 capsid comprising at least the amino acid sequence of the sea lion VP3 capsid protein.In some embodiments, a chimeric AAV2 / sea lion VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) an amino acid sequence of a VP1-u domain and a common VP1 / VP2 region of AAV2 and (b) an amino acid sequence of the VP3 capsid protein of a sea lion. In some embodiments, a chimeric AAV2 / sea lion VP1 capsid protein comprises the amino acid sequence established as SEQ ID NO:4.

[0068] In some embodiments, a chimeric AAV2 / bearded dragon VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) an AAV2 VP1 capsid protein portion comprising at least one AAV2 PLA2 domain and (b) a VP1 capsid portion of a Petition 870260072813, dated 07 / 22 / 2026, p. 64 / 407 / 240 A chimeric bearded dragon AAV2 capsid protein comprising at least the amino acid sequence of the bearded dragon VP3 capsid. In some embodiments, a chimeric bearded dragon AAV2 / VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) a portion of the AAV2 VP1 capsid protein comprising at least one AAV2 VP1-u domain and (b) a portion of the bearded dragon VP1 capsid comprising at least the amino acid sequence of the bearded dragon VP3 capsid protein. In some embodiments, a chimeric bearded dragon AAV2 / VP1 capsid protein comprises, from the N-terminus to the C-terminus, (a) an amino acid sequence of a VP1-u domain and a common VP1 / VP2 region of AAV2 and (b) an amino acid sequence of the bearded dragon VP3 capsid protein. In some embodiments, a chimeric VP1 capsid protein of AAV2 / bearded dragon comprises the amino acid sequence established as SEQ ID NO:6.

[0069] In some embodiments, a chimeric VP1 capsid protein may be operationally linked to a first member of a protein:protein linkage pair and / or comprise a point mutation, for example, such that the natural tropism of the capsid protein is reduced to abolished and / or such that the capsid protein comprises a detectable marker. In some embodiments, a first member of a protein:protein linkage pair comprises a detectable marker. In some embodiments, a first member of a protein:protein linkage pair comprises the detectable marker comprising c-myc (SEQ ID NO:44). In some embodiments, the first member of a protein:protein linkage pair comprises the first member and, optionally, the second member of a protein:protein linkage pair that forms a covalent bond.In some embodiments, the protein:protein binding pair is selected from the group consisting of (a) SpyTag:SpyCatcher, (b) SpyTag:KTag, (c) Isopeptag:pilin-C, (d) SnoopTag:SnoopCatcher and (e). Petition 870260072813, dated 07 / 22 / 2026, p. 65 / 407 / 240 SpyTag002:SpyCatcher002. In some embodiments, a chimeric VP1 capsid protein may comprise (a) a B1 epitope (SEQ ID NO:45), (b) SpyTag, (c) SpyCatcher, and any combination of (a)-(c).

[0070] In some embodiments, a chimeric primate / non-primate animal VP1 capsid protein (e.g., a chimeric AAV2 / AAAV VP1 capsid protein, a chimeric AAV2 / AAV sea lion VP1 capsid protein, a chimeric AAV2 / AAV bearded dragon VP1 capsid protein, etc.) comprises a first member of a protein:protein linkage pair operationally linked to it, optionally via a first or second linker. In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a chimeric primate / non-primate animal VP1 capsid protein (e.g., a chimeric AAV2 / AAAV VP1 capsid protein, a chimeric AAV2 / AAV VP1 capsid protein from a sea lion, a chimeric AAV2 / AAV VP1 capsid protein from a bearded dragon, etc.).) at an amino acid position found in a variable region (VR) or portion thereof of the chimeric primate / non-primate animal VP1 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the chimeric primate / non-primate animal VP1 capsid protein via a first and / or second linker. In some embodiments, a first member of a protein:protein linkage pair is operationally linked to a VP1 capsid of a chimeric primate / non-primate animal VP1 capsid protein at an amino acid position found in VR I, VR II, VR III, VR IV, VR V, VR VI, VR VII, VR VIII, VR IX or in the HI loop of the chimeric primate / non-primate animal VP1 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the chimeric primate / non-primate animal VP1 capsid protein through a first and / or second linker. In some embodiments, a first. Petition 870260072813, dated 07 / 22 / 2026, page 66 / 407 / 240, a member of a protein:protein linkage pair is operationally linked to a chimeric primate / non-primate animal VP1 capsid protein (e.g., a chimeric AAV2 / AAAV VP1 capsid protein, a sea lion chimeric AAV2 / AAV VP1 capsid protein, a bearded dragon chimeric AAV2 / AAV VP1 capsid protein, etc.) at an amino acid position found in VR VIII or VR IV of the chimeric primate / non-primate animal VP1 capsid protein, optionally wherein the first member of a protein:protein linkage pair is linked to the chimeric primate / non-primate animal VP1 capsid protein through a first and / or second linker.

[0071] In some embodiments, a chimeric AAV2 / AAAV VP1 capsid protein comprises a first member of an operationally linked protein:protein linkage pair, optionally through a first and / or second linker, at position I444 or I580. In some embodiments, a chimeric AAV2 / AAAV VP1 capsid protein comprises an operationally linked SpyTag, optionally through a first and a second linker sequence, at position I444. In some embodiments, a chimeric AAV2 / AAAV VP1 capsid protein comprises an amino acid sequence established as SEQ ID NO:8. In some embodiments, a chimeric AAV2 / AAAV VP1 capsid protein comprises an operationally linked SpyTag, optionally through a first and a second linker sequence, at position I580. In some embodiments, a chimeric VP1 capsid protein of AAV2 / AAAV comprises an amino acid sequence established as SEQ ID NO:10.

[0072] In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises a first member of an operationally linked protein:protein linkage pair, optionally through a first and / or second linker, at a position Petition 870260072813, dated 07 / 22 / 2026, p. 67 / 407 / 240 selected from the group consisting of I429, I430, I431, I432, I433, I434, I436, I437 and I565. optionally at a selected position from the group consisting of I429, I430, I431, I432, I433, I436 and I437; optionally at I432. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises operationally linked SpyTag, optionally via a first and a second linker sequence, at position I432. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:12. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an operationally linked SpyTag, optionally via a first and a second linker sequence, at position I565.In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:14. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an operationally linked SpyTag, optionally through a first and a second linker sequence, at position I429. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:16. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an operationally linked SpyTag, optionally through a first and a second linker sequence, at position I430. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:18.In some embodiments, a chimeric VP1 capsid protein from sea lion AAV2 / AAV comprises operationally linked SpyTag, optionally via a first and second linker sequence, at position I431. In some... Petition 870260072813, dated 07 / 22 / 2026, p. 68 / 407 / 240 embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:20. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an operationally linked SpyTag, optionally through a first and a second linker sequence, at position I433. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:22. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an operationally linked SpyTag, optionally through a first and a second linker sequence, at position I434. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:24.In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an operationally linked SpyTag, optionally through a first and a second linker sequence, at position I435. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:26. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an operationally linked SpyTag, optionally through a first and a second linker sequence, at position I436. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:28. In some embodiments, a chimeric VP1 capsid protein from sea lion AAV2 / AAV comprises operationally linked SpyTag, optionally via a first and second linker sequence, at position I437.In some forms, a VP1 capsid protein. Petition 870260072813, dated 07 / 22 / 2026, p. 69 / 407 / 240 chimeric sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:30. In some embodiments, a chimeric sea lion AAV2 / AAV capsid protein comprises an operationally linked SpyTag, optionally via a first and second linker sequence, at position I432. In some embodiments, a chimeric sea lion AAV2 / AAV capsid protein comprises an amino acid sequence established as SEQ ID NO:32. In some embodiments, a chimeric sea lion AAV2 / AAV capsid protein comprises an amino acid sequence established as SEQ ID NO:53. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:55.In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:57. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:59. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:61. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:63. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:65. In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:67.In some embodiments, a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:69. In some... Petition 870260072813, dated 07 / 22 / 2026, p. 70 / 407 / 240, states that a chimeric VP1 capsid protein of sea lion AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:71.

[0073] In some embodiments, a chimeric bearded dragon AAV2 / AAV VP1 capsid protein comprises a first member of an operationally linked protein:protein linkage pair, optionally through a first and / or second linker, at position I436 or I573. In some embodiments, a chimeric bearded dragon AAV2 / AAV VP1 capsid protein comprises an operationally linked SpyTag, optionally through a first and a second linker sequence, at position I436. In some embodiments, a chimeric bearded dragon AAV2 / AAV VP1 capsid protein comprises an amino acid sequence established as SEQ ID NO:34. In some embodiments, a chimeric bearded dragon AAV2 / AAV VP1 capsid protein comprises an operationally linked SpyTag, optionally through a first and a second linker sequence, at position I573.In some embodiments, a chimeric VP1 capsid protein of bearded dragon AAV2 / AAV comprises an amino acid sequence established as SEQ ID NO:36.

[0074] In some embodiments, a capsid protein of the invention further comprises a first member and a second member of a protein:protein linkage pair, optionally wherein the second member is operationally linked to a targeting linker, optionally wherein the targeting linker is a linking fragment. In some embodiments, the linking fragment is an antibody or a portion thereof. In some embodiments, the antibody, or a portion thereof, is fused to the secondary member, for example, SpyCatcher. In some embodiments, the antibody or a portion thereof is fused at its C-terminus to a linker, optionally a linker comprising a sequence established as Petition 870260072813, dated 07 / 22 / 2026, p. 71 / 407 / 240 SEQ ID NO:49 (GSGESG), and the linker is fused to the second member, for example, SpyCatcher, at the C-terminal of the linker.

[0075] In some embodiments, a capsid protein of the invention may comprise a detectable marker, which detectable marker may optionally act as a first member of a protein:protein binding pair and / or for detection and / or isolation of the capsid protein. In some embodiments, the detectable marker is c-myc. In some embodiments, the detectable marker comprises the AAV B1 epitope, for example, the amino acid sequence IGTRYLTR (SEQ ID NO: 45).

[0076] An AAV capsid protein of the invention may comprise an amino acid sequence selected from the group consisting of (a) an amino acid sequence established as SEQ ID NO: 2, (b) an amino acid sequence established as SEQ ID NO: 4, (c) an amino acid sequence established as SEQ ID NO: 6, (d) an amino acid sequence established as SEQ ID NO: 8, (e) an amino acid sequence established as SEQ ID NO: 10, (f) an amino acid sequence established as SEQ ID NO: 12, (g) an amino acid sequence established as SEQ ID NO: 14, (h) an amino acid sequence established as SEQ ID NO: 16, (i) an amino acid sequence established as SEQ ID NO: 18, (j) an amino acid sequence established as SEQ ID NO: 20, (k) an amino acid sequence established as SEQ ID NO: 22, (l) an amino acid sequence established as SEQ ID NO: 24, (m) a sequence amino acid sequence established as SEQ ID NO: 26,(n) an amino acid sequence established as SEQ ID NO: 28, (o) an amino acid sequence established as SEQ ID NO: 30, (p) an amino acid sequence established as SEQ ID NO: 32, (q) an amino acid sequence established as SEQ ID NO: 34, (r) an amino acid sequence established as SEQ ID NO: 36, (s) the sequence of, Petition 870260072813, dated 07 / 22 / 2026, p. 72 / 407 / 240 amino acids established as SEQ ID NO: 53, (t) the amino acid sequence established as SEQ ID NO: 55, (u) the amino acid sequence established as SEQ ID NO: 57, (v) the amino acid sequence established as SEQ ID NO: 59, (w) the amino acid sequence established as SEQ ID NO: 61, (x) the amino acid sequence established as SEQ ID NO: 63, (y) the amino acid sequence established as SEQ ID NO: 65, (z) the amino acid sequence established as SEQ ID NO: 67, (aa) the amino acid sequence established as SEQ ID NO: 69, (bb) the amino acid sequence established as SEQ ID NO: 71, (cc) an amino acid sequence with significant sequence identity, for example, at least 95% identity, for SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22,SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, or SEQ ID NO: 71 and (dd) an amino acid sequence from any portion of VP2 and / or VP3 of the amino acid sequences set forth in any one of (a)-(cc).

[0077] In some embodiments, a capsid protein of the invention is encoded by a nucleic acid molecule of the invention. Nucleic acid molecules encoding the capsid proteins of the invention are also provided in this document.

[0078] This document describes nucleic acid molecules comprising an AAV cap gene encoding an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV cap gene, or a portion thereof,Petition 870260072813, dated 22 / 07 / 2026, p. 73 / 407 / 240 comprises a nucleic acid sequence with significant sequence identity, for example, at least 95% identity, with the nucleic acid sequence of a cap gene of a non-primate animal AAV or portion thereof, or a remote AAV or portion thereof, and wherein the AAV cap gene is further modified to comprise (a) a nucleotide sequence encoding a first member of a protein:protein linking pair, (b) a nucleotide sequence encoding a detectable marker, (c) a point mutation, (d) a chimeric nucleotide sequence, or (e) any combination of (a), (b), (c), and (d).In some embodiments of nucleic acid molecules, the nucleic acid comprises an AAV rep gene and an AAV cap gene, wherein the entire AAV cap gene comprises a first nucleic acid sequence with significant sequence identity, for example, at least 95% identity, with the nucleic acid sequence of a cap gene of a non-primate animal AAV or a remote AAV, and wherein the AAV rep gene, or portion thereof, comprises a second nucleic acid sequence with significant sequence identity, for example, at least 95% identity, with the nucleic acid sequence of a rep gene of a second AAV, or portion thereof, wherein the non-primate animal AAV is not identical to the second AAV.In some embodiments, a nucleic acid molecule of the invention comprises an AAV cap gene encoding an AAV capsid protein, wherein the AAV cap gene comprises a nucleotide sequence identical to, or with significant identity to, for example, at least 95% sequence identity, at least a portion of the nucleotide sequence of a cap gene selected from the group consisting of (i) a cap gene from a non-primate animal AAV, (ii) a cap gene from a remote AAV, or (iii) a combination thereof, wherein said AAV cap gene is further modified to comprise (a) a nucleotide sequence encoding a first member of a protein:protein linking pair, (b) a nucleotide sequence that... Petition 870260072813, dated 22 / 07 / 2026, p. 74 / 407 / 240 encodes a detectable marker, (c) a point mutation, (d) a chimeric nucleotide sequence comprising a portion of a nucleotide sequence of another, for example, second, AAV cap gene that is operationally linked to said nucleotide sequence of the AAV cap gene selected from the group consisting of the non-primate animal AAV cap gene, a remote AAV, or a combination thereof, (e) any combination of (a), (b), (c), and (d).

[0079] In some embodiments, a nucleic acid molecule of the invention comprises an AAV cap gene encoding an AAV capsid protein, wherein the AAV cap gene comprises a nucleotide sequence identical to, or with significant identity to, for example, at least 95% sequence identity, at least a portion of the nucleotide sequence of a non-primate animal AAV cap gene, wherein said AAV cap gene is further modified to comprise (a) a nucleotide sequence encoding a first member of a protein:protein linkage pair, (b) a nucleotide sequence encoding a detectable marker, (c) a point mutation, (d) a chimeric nucleotide sequence comprising a portion of a nucleotide sequence of another, for example, second, AAV cap gene that is operationally linked to said non-primate animal AAV cap gene nucleotide sequence, (e) any combination of (a), (b), (c), and (d).

[0080] In some embodiments, a nucleic acid molecule of the invention comprises an AAV cap gene encoding an AAV capsid protein, wherein the AAV cap gene comprises a nucleotide sequence identical to, or with significant identity to, for example, at least 95% sequence identity, at least a portion of the nucleotide sequence of a cap gene from a remote animal AAV, wherein said AAV cap gene is further modified to comprise (a) a nucleotide sequence encoding a first member of a linking pair Petition 870260072813, dated 07 / 22 / 2026, p. 75 / 407 / 240 protein: protein, (b) a nucleotide sequence encoding a detectable marker, (c) a point mutation, (d) a chimeric nucleotide sequence comprising a portion of a nucleotide sequence from another AAV cap gene that is operationally linked to said nucleotide sequence from the remote animal AAV cap gene, (e) any combination of (a), (b), (c), and (d).

[0081] In some embodiments, a nucleic acid molecule of the invention comprises an AAV rep gene and an AAV cap gene, wherein the AAV cap gene comprises a first nucleotide sequence identical to, or with significant identity to, for example, at least 95% sequence identity, a nucleotide sequence of a cap gene selected from the group consisting of (i) a cap gene from a non-primate animal AAV, (ii) a cap gene from a distant primate AAV, and (iv) a combination thereof, wherein the AAV rep gene comprises a second nucleotide sequence of an AAV rep gene from another, for example, AAV.

[0082] In some embodiments, a nucleic acid molecule of the invention comprises an AAV rep gene and an AAV cap gene, wherein the AAV cap gene comprises a first nucleotide sequence that is identical to, or significantly identical to, for example, at least 95% sequence identity, with a nucleotide sequence of a cap gene of a non-primate animal AAV, wherein the AAV rep gene comprises a second nucleotide sequence that is identical to, or significantly identical to, for example, at least 95% sequence identity, with a nucleotide sequence of an AAV rep gene of another, for example, second AAV.

[0083] In some embodiments, a nucleic acid molecule of the invention comprises an AAV rep gene and an AAV cap gene, wherein the AAV cap gene comprises a nucleotide sequence identical to or with Petition 870260072813, dated 22 / 07 / 2026, p. 76 / 407 / 240 significant identity, for example, at least 95% sequence identity, with a first nucleotide sequence of a cap gene of a remote animal AAV, wherein the AAV rep gene comprises a nucleotide sequence identical to or with significant identity, for example, at least 95% sequence identity, with a second nucleotide sequence of an AAV rep gene of another, for example, second AAV.

[0084] In some embodiments of the nucleic acid molecule of the invention, a cap gene nucleotide sequence comprising a nucleotide sequence identical to or with significant identity, for example, at least 95% sequence identity, with a non-primate animal AAV nucleotide sequence, the cap gene of a nucleotide sequence identical to or with significant identity, for example, at least 95% sequence identity, with a remote AAV nucleotide sequence, or a combination thereof, is modified to comprise (a) a nucleotide sequence encoding at least one first member of a protein:protein linking pair, (b) a nucleotide sequence encoding a detectable marker, and / or (c) a nucleotide sequence encoding a point mutation.

[0085] In some nucleic acid embodiments, the protein:protein binding pair can be selected from SpyTag:SpyCatcher, SpyTag:SpyCatcher, SpyTag:KTag, Isopeptag:pilin-C, SnoopTag:SnoopCatcher and SpyTag002:SpyCatcher002. In some embodiments, the first member of a protein:protein linkage pair comprises a detectable marker, for example, c-myc comprising a sequence established as SEQ ID NO:44.

[0086] In some nucleic acid embodiments, a nucleotide sequence of a non-primate animal AAV cap gene, the remote AAV cap gene, or a combination thereof, is modified to comprise the B1 epitope comprising an IGTRYLTR amino acid sequence. Petition 870260072813, dated 07 / 22 / 2026, p. 77 / 407 / 240 (SEQ ID NO: 45).

[0087] In some embodiments of the nucleic acid molecule of the invention, a nucleotide sequence of a non-primate animal AAV cap gene, the remote AAV cap gene, or a combination thereof, comprises a nucleotide sequence encoding a VP3 capsid protein, or portion thereof, comprising an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity, an amino acid sequence of a non-primate animal AAV VP3 capsid protein and / or an amino acid sequence of a remote AAV VP3 capsid protein.In some embodiments, a nucleotide sequence of a non-primate animal AAV cap gene, the remote AAV cap gene, or a combination thereof, comprises a nucleotide sequence encoding a VP2 capsid protein, or a portion thereof, comprising an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity, an amino acid sequence of a non-primate animal AAV VP2 capsid protein and / or an amino acid sequence of a remote AAV VP2 capsid protein.In some embodiments, a nucleotide sequence of a non-primate animal AAV cap gene, the remote AAV cap gene, or a combination thereof, comprises a nucleotide sequence encoding a VP1 capsid protein, or a portion thereof, comprising an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity, an amino acid sequence of a non-primate animal AAV VP1 capsid protein and / or an amino acid sequence of a remote AAV VP1 capsid protein.

[0088] In some embodiments, a nucleic acid molecule of the invention comprises a nucleotide sequence encoding a non-primate animal VP3 capsid protein of the invention. In some embodiments, Petition 870260072813, dated 07 / 22 / 2026, page 78 / 407 / 240, a nucleic acid molecule of the invention comprises a nucleotide sequence encoding a non-primate animal VP3 capsid protein of the invention and a non-primate animal VP2 capsid protein of the invention. In some embodiments, a nucleic acid molecule of the invention comprises a nucleotide sequence encoding a non-primate animal VP3 capsid protein of the invention, a VP2 capsid protein of the invention, and a VP1 capsid protein of the invention.

[0089] In some embodiments, the cap gene of a nucleic acid molecule of the invention encodes (i) a VP1 capsid protein that is (a) a chimeric AAV VP1 capsid protein, optionally wherein the chimeric VP1 capsid protein comprises a VP1-u-exclusive region comprising an amino acid sequence identical to, or significantly identical to, for example, at least 95% sequence identity, an amino acid sequence of another, for example, second, AAV operationally linked to a common VP1 / VP2 region and a VP3 region comprising an amino acid sequence identical to, or significantly identical to, for example, at least 95% sequence identity, an amino acid sequence of the non-primate animal AAV or the remote AAV, or (b) a VP1 capsid protein comprising an amino acid sequence identical to, or significantly identical to, for example, at least 95% sequence identity,with an amino acid sequence from a VP1 capsid protein of a non-primate animal AAV or a remote AAV, (ii) a VP2 capsid protein that is (a) a chimeric AAV VP2 capsid protein, optionally wherein the chimeric VP2 capsid protein comprises a common VP1 / VP2 region comprising an amino acid sequence identical or with significant identity, for example, at least 95% sequence identity, to an amino acid sequence of another, for example, second, AAV operationally linked to a VP3 region comprising an amino acid sequence, Petition 870260072813, dated 22 / 07 / 2026, p. 79 / 407 / 240 identical to or with significant identity, for example, at least 95% sequence identity, with an amino acid sequence of the non-primate animal AAV or (b) a VP2 capsid protein comprising an amino acid sequence identical or with significant identity, for example, at least 95% sequence identity, with an amino acid sequence of a VP2 capsid protein of the non-primate animal AAV and / or (iii) a VP3 capsid protein comprising an amino acid sequence identical or with significant identity, for example, at least 95% sequence identity, with an amino acid sequence of a VP3 capsid protein of the non-primate animal AAV or the remote AAV.

[0090] In some embodiments, a cap gene of a nucleic acid molecule of the invention encodes (i) a chimeric AAV VP1 capsid protein,optionally wherein the chimeric VP1 capsid protein comprises a VP1-exclusive (VP1-u) region comprising an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity, with an amino acid sequence of another, for example, AAV operationally linked to a common VP1 / VP2 region and a VP3 region comprising an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity, with an amino acid sequence of the non-primate animal AAV or the remote AAV, (ii) a chimeric AAV VP2 capsid protein, optionally wherein the chimeric VP2 capsid protein comprises a common VP1 / VP2 region comprising an amino acid sequence identical to, or with significant identity to, for example, at least 95% sequence identity, with an amino acid sequence of another, for example,AAV operationally linked to a VP3 region of non-primate animal AAV or remote AAV, and / or (iii) the VP3 capsid protein comprising an identical or significantly identical amino acid sequence, for example, at least 95% of, Petition 870260072813, dated 07 / 22 / 2026, p. 80 / 407 / 240 sequence identity, with an amino acid sequence from a non-primate animal AAV or a remote AAV.

[0091] In some embodiments, the cap gene of a nucleic acid molecule of the invention encodes (i) a chimeric AAV VP1 capsid protein, optionally wherein the chimeric VP1 capsid protein comprises a VP1-u exclusive region comprising an amino acid sequence identical to, or significantly identical to, for example, at least 95% sequence identity, an amino acid sequence of another AAV operationally linked to a common VP1 / VP2 region and a VP3 region comprising an amino acid sequence identical to, or significantly identical to, for example, at least 95% sequence identity, an amino acid sequence of the non-primate animal AAV or the remote AAV, (ii) a VP2 capsid protein comprising an amino acid sequence identical to, or significantly identical to, for example, at least 95% sequence identity, an amino acid sequence of the non-primate animal AAV or the remote AAV,and (iii) the VP3 capsid protein comprising an amino acid sequence identical or with significant identity, for example, at least 95% sequence identity, to an amino acid sequence of the non-primate animal AAV or the remote AAV.

[0092] In some embodiments, the cap gene of a nucleic acid molecule of the invention encodes (i) a VP1 capsid protein comprising an amino acid sequence identical or with significant identity, for example, at least 95% sequence identity, to an amino acid sequence of the non-primate AAV or the remote AAV, (ii) a VP2 capsid protein comprising an amino acid sequence identical or with significant identity, for example, at least 95% sequence identity, to an amino acid sequence of the non-primate animal AAV or the remote AAV, and / or (iii) a capsid protein Petition 870260072813, dated 07 / 22 / 2026, p. 81 / 407 / 240 VP3 comprising an amino acid sequence that is identical or significantly identical, for example, with at least 95% sequence identity, to an amino acid sequence of a non-primate animal AAV or a remote AAV.

[0093] In some embodiments of the nucleic acid molecule of the invention, the other, second, AAV is a primate AAV or a combination of primate AAVs. In some embodiments, the other AAV is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13 and a combination thereof. In some embodiments, the other AAV is AAV2.

[0094] In some embodiments of the nucleic acid molecule of the invention, the non-primate animal AAV is a non-primate animal AAV listed in Table 2. In some embodiments, the non-primate AAV is an avian AAV (AAAV), a sea lion AAV, or a bearded dragon AAV. In some embodiments, the non-primate animal AAV is an AAAV and, optionally, a nucleotide sequence of an AAAV capsid protein comprises a modification at position I444 or I580 of an AAAV VP1 capsid protein. In some embodiments, the non-primate animal AAV is a scale AAV, for example, a bearded dragon AAV, and optionally, a nucleotide sequence of a bearded dragon AAV comprises a modification at position I573 or I436 of a bearded dragon VP1 capsid protein.In some embodiments, the non-primate animal AAV is a mammalian AAV, for example, a sea lion AAV, and optionally, a nucleotide sequence of a sea lion AAV comprises a modification at the selected position of the group consisting of I429, I430, I431, I432, I433, I434, I436, I437 and A565 of a VP1 capsid protein from a sea lion AAV.

[0095] The nucleic acid molecule embodiments of the invention may comprise a nucleotide sequence selected from the group Petition 870260072813, dated 07 / 22 / 2026, page. 82 / 407 / 240 consisting of (a) the nucleotide sequence established as SEQ ID NO: 1, (b) the nucleotide sequence established as SEQ ID NO: 3, (c) the nucleotide sequence established as SEQ ID NO: 5, (d) the nucleotide sequence established as SEQ ID NO: 7, (e) the nucleotide sequence established as SEQ ID NO: 9, (f) the nucleotide sequence established as SEQ ID NO: 11, (g) the nucleotide sequence established as SEQ ID NO: 13, (h) the nucleotide sequence established as SEQ ID NO: 15, (i) the nucleotide sequence established as SEQ ID NO: 17, (j) the nucleotide sequence established as SEQ ID NO: 19, (k) the nucleotide sequence established as SEQ ID NO: 21, (l) the sequence nucleotide sequence established as SEQ ID NO: 23, (m) nucleotide sequence established as SEQ ID NO: 25, (n) nucleotide sequence established as SEQ ID NO: 27, (o) nucleotide sequence established as SEQ ID NO: 29,(p) the nucleotide sequence established as SEQ ID NO: 31, (q) the nucleotide sequence established as SEQ ID NO: 33, (r) the nucleotide sequence established as SEQ ID NO: 35, (s) the nucleotide sequence established as SEQ ID NO: 52, (t) the nucleotide sequence established as SEQ ID NO: 54, (u) the nucleotide sequence established as SEQ ID NO: 56, (v) the nucleotide sequence established as SEQ ID NO: 58, (w) the nucleotide sequence established as SEQ ID NO: 60, (x) the nucleotide sequence established as SEQ ID NO: 62, (y) the nucleotide sequence established as SEQ ID NO: 64, (z) the nucleotide sequence established as SEQ ID NO: 66, (aa) the nucleotide sequence established as SEQ ID NO: 68, (bb) the nucleotide sequence established as SEQ ID NO: 70, (cc) a nucleotide sequence with at least 95% identity to the nucleotide sequence established as SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 52,54, 56, 58, 60, 62, 64, 66, 68, or 70, (dd) any portion of the (a)-(cc) nucleotide sequence that encodes a VP2 capsid protein and / or a VP3 capsid protein., Petition 870260072813, dated 07 / 22 / 2026, p. 83 / 407 / 240

[0096] In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:1, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:3, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:5, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:7, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof.In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:9, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:11, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:13, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:15, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof.In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:17, a portion of which codes for a... Petition 870260072813, dated 07 / 22 / 2026, p. 84 / 407 / 240 capsid protein VP2 and / or VP3 and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:19, a portion thereof encoding a capsid protein VP2 and / or VP3 and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:21, a portion thereof encoding a capsid protein VP2 and / or VP3 and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:23, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof.In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:25, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:27, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:29, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:31, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof.In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:33, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence. Petition 870260072813, dated 07 / 22 / 2026, p. 85 / 407 / 240, established as SEQ ID NO:35, a portion thereof encoding a VP2 and / or VP3 capsid protein and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:52, a portion thereof encoding a VP2 and / or VP3 capsid protein and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:54, a portion thereof encoding a VP2 and / or VP3 capsid protein and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:56, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof.In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:58, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:60, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:62, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:64, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof.In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:66, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a... Petition 870260072813, dated 07 / 22 / 2026, p. 86 / 407 / 240, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:68, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof. In some embodiments, a nucleic acid molecule comprises a nucleotide sequence established as SEQ ID NO:70, a portion thereof encoding a VP2 and / or VP3 capsid protein, and degenerate variants thereof.

[0097] In some embodiments, the nucleotide sequence encoding a VP1 capsid protein of the invention and, optionally, a VP2 and / or VP3 capsid protein of the invention is operationally linked to a promoter. In some embodiments, the promoter is selected from a viral promoter, a bacterial promoter, a mammalian promoter (e.g., human or non-human), an avian promoter, a fish promoter, an insect promoter, and any combination thereof. In some embodiments, the promoter is selected from p40, SV40, EF, CMV, B19p6, and CAG. In some embodiments, the promoter is an AAV p40 promoter. In some embodiments, the promoter directs the expression of the capsid protein(s) in a packaging cell.

[0098] In some embodiments, the cap gene of a nucleic acid molecule of the invention comprises is operationally linked to a promoter. In some embodiments, the promoter directs the expression of the capsid protein(s) in a packaging cell. In some embodiments, the promoter is selected from p40, SV40, EF, for example, EF1a CMV, B19p6 and CAG.

[0099] In some embodiments, a nucleic acid molecule of the invention further comprises a second nucleotide sequence encoding one or more AAV Rep proteins, optionally wherein the second nucleotide sequence is operationally linked to a promoter. In some embodiments, one or more Rep proteins are AAV Rep proteins. Petition 870260072813, dated 07 / 22 / 2026, page 87 / 407 / 240 of primate animals. In some embodiments, one or more Rep proteins are Rep proteins from non-primate animal AAVs. In some embodiments, one or more Rep proteins are selected from Rep78, Rep68, Rep52, and Rep40; optionally, one or more Rep proteins comprise Rep78. In some embodiments, the promoter operationally linked to the second nucleotide sequence encoding one or more Rep AAV proteins is selected from a viral promoter, a bacterial promoter, a mammalian promoter (e.g., human or non-human), an avian promoter, a fish promoter, an insect promoter, and any combination thereof. In some embodiments, the promoter operationally linked to the second nucleotide sequence encoding one or more AAV Rep proteins is selected from p19, p5, p40, SV40, EF, for example, EF1a CMV, B19p6 and CAG.In some embodiments, the promoter directs the expression of the capsid protein(s) in a packaging cell. In some embodiments, the promoter operationally linked to the second nucleotide sequence encoding one or more AAV Rep proteins is selected from p19 and / or p5.

[00100] Compositions and packaging cells comprising, and capsid proteins encoded from the nucleic acid molecules of the invention, are also part of the invention. Viral particles expressed by packaging cells of the invention are also described.

[00101] Compositions and packaging cells for producing AAV viral particles of the invention, in some embodiments, comprise a nucleic acid molecule of the invention, for example, comprising a cap gene of the invention encoding an AAV capsid protein of the invention. In some embodiments, a composition and / or packaging cell of the invention comprises a nucleic acid molecule of the invention. In some embodiments, the cap gene comprises a nucleotide sequence selected from the group consisting of the established nucleotide sequence as Petition 870260072813, dated 07 / 22 / 2026, page 88 / 407 / 240 SEQ ID NO: 1, nucleotide sequence established as SEQ ID NO: 3, nucleotide sequence established as SEQ ID NO: 5, nucleotide sequence established as SEQ ID NO: 7, nucleotide sequence established as SEQ ID NO: 9, nucleotide sequence established as SEQ ID NO: 11, nucleotide sequence established as SEQ ID NO: 13, nucleotide sequence established as SEQ ID NO: 15, nucleotide sequence established as SEQ ID NO: 17, nucleotide sequence established as SEQ ID NO: 19, nucleotide sequence established as SEQ ID NO: 21, nucleotide sequence established as SEQ ID NO: 23, nucleotide sequence established as SEQ ID NO: 25, nucleotide sequence established as SEQ ID NO: 27, nucleotide sequence established as SEQ ID NO: 29, sequence nucleotide sequence established as SEQ ID NO: 31, nucleotide sequence established as SEQ ID NO: 33, nucleotide sequence established as SEQ ID NO: 35,nucleotide sequence established as SEQ ID NO: 52, nucleotide sequence established as SEQ ID NO: 54, nucleotide sequence established as SEQ ID NO: 56, nucleotide sequence established as SEQ ID NO: 58, nucleotide sequence established as SEQ ID NO: 60, nucleotide sequence established as SEQ ID NO: 62, nucleotide sequence established as SEQ ID NO: 64, nucleotide sequence established as SEQ ID NO: 66, nucleotide sequence established as SEQ ID NO: 68, nucleotide sequence established as SEQ ID NO: 70, any portion of the nucleotide sequence established as SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 52, 54, 56, 58, 60, 62, 64, 66, 68, or 70, which encodes a VP2 capsid; any portion of the nucleotide sequence established as SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 52, 54, 56, 58, 60, 62, 64, 66, 68, or 70 which encodes a VP3 capsid.and any combination thereof.

[00102] In some forms, compositions and cells Petition 870260072813, dated 22 / 07 / 2026, p. 89 / 407 / 240 packagers further comprise a nucleic acid molecule comprising a rep gene encoding one or more AAV rep proteins, wherein said rep gene is operationally linked to a promoter, optionally wherein the rep gene and the cap gene are from two different AAVs. In some embodiments, the promoter operationally linked to the rep gene directs the expression of the Rep protein(s) in the packager cell, for example, the promoter is selected from p5, p19 SV40, EF, CMV, B19p6 and CAG. In some embodiments, one or more Rep proteins are selected from Rep78, Rep68, Rep52 and Rep40, optionally one or more Rep proteins comprise Rep78. In some embodiments, one or more Rep proteins are Rep proteins from primate AAVs. In some other embodiments, one or more Rep proteins are Rep proteins from non-primate animal AAVs. In some embodiments, one or more Rep proteins comprise both.

[00103] In some embodiments, compositions and packaging cells of the invention further comprise a nucleic acid molecule comprising a nucleotide sequence of a nucleotide of interest flanked on at least one side by at least one terminal inverted repeat of an AAV (ITR) that is recognized by one or more Rep proteins. In some embodiments, the nucleotide of interest is flanked on the other side by a second ITR of the same AAV as at least one ITR. In some embodiments, the nucleotide of interest is flanked on the other side by a second ITR, wherein the second ITR and the at least one ITR are of different AAVs.

[00104] In some embodiments, a composition and / or packaging cell of the invention further comprises a nucleic acid molecule comprising a nucleotide of interest (e.g., nucleotide sequence of a transgene) flanked by 5' and 3' AAV inverted terminal repeats (ITRs) such that the viral particles of interest Petition 870260072813, dated 07 / 22 / 2026, page 90 / 407 / 240 also includes a genome comprising the nucleotide of interest flanked by 5' and 3' AAV ITRs.

[00105] In some embodiments, a composition and / or packaging cell of the invention further comprises a nucleotide sequence encoding a reference capsid protein.

[00106] Consequently, in some embodiments, a composition, packaging cell and / or viral particle of the invention further comprises a genome comprising from 5' to 3': a 5' ITR, a nucleotide of interest and a 3' ITR. In some embodiments, the genome further comprises a promoter operationally linked to the nucleotide of interest. In some embodiments, the 5' and 3' ITRs are from AAVs of the same species. In some embodiments, the 5' and 3' ITRs are from AAVs of two different species.

[00107] In some embodiments, the nucleotide of interest is a reporter gene. In some embodiments, the reporter gene encodes β-galactosidase, green fluorescent protein (GFP), enhanced green fluorescent protein (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), Emerald, CyPet, cyan fluorescent protein (CFP), Cerulean, T-Sapphire, luciferase, alkaline phosphatase, or a combination thereof.

[00108] In some embodiments, the nucleotide of interest encodes a therapeutic protein, a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or portion(s) thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA.

[00109] This document describes a method for producing an AAV viral particle of the invention, the method comprising growing a packaging cell under conditions sufficient for particle production. Petition 870260072813, dated 07 / 22 / 2026, page. 91 / 407 / 240 viral, the packaging cell comprising (1) at least one nucleotide sequence encoding one or more AAV Rep proteins, for example, a rep gene, and (2) a first nucleotide sequence encoding an AAV capsid protein VP1, optionally a second nucleotide sequence encoding an AAV capsid protein VP2, and a third nucleotide sequence encoding a non-primate animal AAV capsid protein VP3 (for example, a first, second, and third nucleotide molecules of the invention) and optionally (3) a nucleotide of interest flanked by a first and / or second ITR of a second AAV, wherein one or more AAV Rep proteins recognize a recognition site of the first and / or second ITR of the second AAV, wherein the third nucleotide sequence encodes a non-primate animal AAV capsid protein VP3. invention,and optionally, wherein the first nucleotide sequence encodes an AAV capsid protein VP1 of the invention and / or the second nucleotide sequence encodes an AAV capsid protein VP2 of the invention. In some embodiments, a single cap gene of the invention comprises the first, second, and third nucleotide sequences. In some embodiments, a single-packaging plasmid comprises at least one nucleotide sequence encoding one or more AAV Rep proteins and any combination of the first, second, and third nucleotides, respectively, encoding an AAV capsid protein VP1, an AAV capsid protein VP2, and an AAV capsid protein VP3 from a non-primate animal.

[00110] In some embodiments, the method comprises cultivating a packaging cell of the invention. In some embodiments, the method comprises cultivating a packaging cell of the invention comprising a nucleic acid molecule of the invention, wherein the packaging cell optionally further comprises an auxiliary plasmid and / or a transfer plasmid comprising a nucleotide of interest. Petition 870260072813, dated 07 / 22 / 2026, page 92 / 407 / 240

[00111] Some method modalities further comprise isolating self-complementary adeno-associated viral particles from the culture supernatant and / or cell lysate. Some method modalities further comprise lysing the packaging cell and isolating single-stranded adeno-associated viral particles from the culture supernatant and / or cell lysate. Some modalities further comprise a. removal of cellular debris, b. treatment of the supernatant containing viral particles with Benzonase or DNase I and MgCl2, c. concentration of viral particles, d. purification of viral particles, and e. any combination of a.-d.

[00112] In some embodiments, mosaic viral particles are generated by transfecting mixtures of a first cap gene encoding a VP capsid protein comprising a first member of a protein:protein linkage pair and at least one reference cap gene encoding a reference VP capsid protein in packaging cells at a specified ratio. In some embodiments, a mosaic viral particle of the invention can be generated with mixtures of a modified cap gene:reference cap gene(s). In some embodiments, the modified cap gene encodes at least one of the AAV capsid proteins VP1, VP2, and VP3 comprising a modification, for example, a first member of a protein:protein linkage pair, and the reference cap gene encodes a reference capsid protein corresponding to at least one of the modified AAV capsid proteins VP1, VP2, and VP3, except for the modification.In some embodiments, a modified cap gene encodes a VP1 capsid protein modified with a first member of a protein:protein linkage pair, and a reference cap gene encodes an unmodified reference VP1 capsid protein. In some embodiments, a modified cap gene encodes a VP2 capsid protein modified with a first member of a protein:protein linkage pair, and a reference cap gene encodes an unmodified reference VP2 capsid protein. Petition 870260072813, dated 07 / 22 / 2026, page 93 / 407 / 240 modification. In some embodiments, a modified cap gene encodes a modified VP3 capsid protein with a first member of a protein:protein linkage pair and a reference cap gene encodes an unmodified reference VP3 capsid protein.

[00113] Generally, viral particles, as described in this document, comprise a viral capsid comprising a viral capsid protein, as described in this document, including mosaic viral capsids, wherein the viral capsid encapsulates a nucleotide of interest. In some embodiments, the nucleotide of interest is under the control of a promoter selected from the group consisting of a viral promoter, a bacterial promoter, a mammalian promoter, an avian promoter, a fish promoter, an insect promoter, and any combination thereof. In some embodiments, the nucleotide of interest is under the control of a non-human promoter. In some embodiments, the promoter is a cytomegalovirus (CMV) promoter. In some embodiments, the promoter is an EF1α promoter. In some embodiments, the promoter is a CAGG promoter. In some embodiments, the promoter is a Ubiquitin C (UbC) promoter.

[00114] Generally, a nucleotide of interest may be one or more genes, which may encode a detectable marker, for example, a reporter gene, or a therapeutic polypeptide. In some embodiments, the nucleotide of interest is a reporter gene. In some embodiments, the nucleotide of interest is a reporter gene that encodes a detectable marker selected from the group consisting of green fluorescent protein, luciferase, β-galactosidase, etc. In some embodiments, the detectable marker is green fluorescent protein. In other embodiments, the nucleotide of interest is selected from the group consisting of a suicide gene, a nucleotide encoding an antibody or fragment thereof, a nucleotide encoding a CRISPR / Cas system or portion(s) thereof, a nucleotide that Petition 870260072813, dated 07 / 22 / 2026, page 94 / 407 / 240 encodes antisense RNA, a nucleotide encoding siRNA, a secreted enzyme, a gene encoding a therapeutic protein, etc. In one embodiment, the nucleotide of interest encodes a multidomain therapeutic, for example, a protein comprising at least two domains that provide two distinct functions.

[00115] The compositions described in this document generally comprise a viral vector comprising a recombinant viral capsid protein, as described in this document, for example, comprising a capsid comprising recombinant viral capsid protein (including a mosaic capsid), wherein the capsid encapsulates a nucleotide of interest. In some embodiments, a composition described in this document comprises (1) a viral particle with a capsid comprising a viral capsid protein described in this document, and (2) a pharmaceutically acceptable carrier.

[00116] Methods for using viral capsid proteins, viral particles comprising them, compositions, etc., are also described in this document. In some embodiments, the methods comprise contacting a target cell (which may be in vitro (e.g., ex vivo) or in vivo, e.g., in a human) with a viral particle comprising a viral capsid protein, as described in this document, wherein the viral capsid or viral particle comprises a targeting ligand that specifically binds to a protein expressed on the surface of the target cell.

[00117] The viral particles as described in this document are particularly suitable for the targeted introduction of a nucleotide of interest into a specific cell, since the viral capsid protein(s) described in this document comprise a first member of a protein:protein linking pair to its cognate second member, optionally linked to a targeting linker. In some embodiments, the targeting linker is operationally linked to the protein (second member), Petition 870260072813, dated 07 / 22 / 2026, page 95 / 407 / 240, for example, fused to the protein, optionally through a ligand. In some embodiments, a targeting ligand may be a binding fragment, for example, a natural ligand, antibody, a multispecific binding molecule, etc. In some embodiments, the targeting ligand is an antibody or portion thereof. In some embodiments, the targeting ligand is an antibody comprising a variable domain that binds to a cell surface protein on a target cell and a constant heavy chain domain. In some embodiments, the targeting ligand is an antibody comprising a variable domain that binds to a cell surface protein on a target cell and a constant heavy chain domain of IgG.In some embodiments, the targeting ligand is an antibody comprising a variable domain that binds to a cell surface protein on a target cell and a constant IgG heavy chain domain, wherein the constant IgG heavy chain domain is operationally linked, for example, via a ligand, to a protein (e.g., the second member of a protein:protein linkage pair) that forms a covalent isopeptide bond with the first member.In some embodiments, a recombinant capsid protein described in this document comprises a SpyTag operationally linked to the viral capsid protein and covalently linked to SpyTag, an adapter polypeptide comprising SpyCatcher linked to a targeting linker comprising a variable antibody domain and an IgG heavy chain domain, wherein the SpyCatcher and the IgG heavy chain domain are linked via an amino acid linker, for example, GSGESG (SEQ ID NO:49). In some embodiments, the second member comprises the sequence established as SEQ ID NO:47, which comprises a portion of a human IgG4 heavy chain, said IgG4 portion with a sequence established as SEQ ID NO:51, linked via linker (SEQ ID NO:49) to SpyCatcher (SEQ ID NO:43). Petition 870260072813, dated 07 / 22 / 2026, p. 96 / 407 / 240

[00118] Generally, a targeting ligand binds specifically to a cell surface molecule, for example, an oligosaccharide, a receptor, a cell surface marker, etc., expressed on the surface of a eukaryotic (e.g., human) mammalian cell, for example, a target cell. BRIEF DESCRIPTION OF THE FIGURES

[00119] Figure 1 provides an illustrative (not to scale), non-limiting, and exemplary embodiment of a Rep-Cap expression plasmid of the invention that can be used to generate a chimeric AAV viral particle. Primate AAV sequences are shown as unfilled boxes and non-primate animal AAV sequences are shown in filled boxes. Also shown for illustrative purposes only are non-limiting exemplary (not to scale) positions for insertion of (1) a first member of a protein:protein linking pair to target the tropism of the assembled capsid comprising the encoded VP1, VP2, and VP3 proteins (solid line within the non-primate animal AAV capsid sequences) and (2) a detectable marker for detection of the encoded VP1, VP2, and VP3 proteins (dashed line within the non-primate animal AAV capsid sequences).A Rep-Cap expression plasmid, as shown in Figure 1, can be used to produce AAV viral particles comprising a nucleotide of interest that is flanked by the 5' and 3' inverted terminal repeat (ITR) sequences of primate AAV.

[00120] Figure 2A provides western blots using antibody B1, which recognizes a B1 epitope inserted into a chimeric cap gene of AAV2 / avian AAV (see Figure 1), to analyze the resulting chimeric VP1, VP2, and VP3 proteins of AAV2 / avian AAV. The western blots analyzed protein samples collected during various stages of AAV particle purification by affinity chromatography, including the input sample, the direct flow fraction (TF), and the elution fraction from the affinity chromatography column. Petition 870260072813, dated 07 / 22 / 2026, page 97 / 407 / 240

[00121] Figure 2B provides western blots using antibody B1, which recognizes a B1 epitope inserted into a chimeric cap gene of sea lion AAV2 / AAV (see Figure 1), to analyze the resulting chimeric VP1, VP2, and VP3 proteins of sea lion AAV2 / AAV. The western blots analyzed protein samples collected during various stages of AAV particle purification by affinity chromatography, including the input sample, the direct flow (TF) fraction, and the elution fraction from the affinity chromatography column.

[00122] Figure 2C provides western blots using antibody B1, which recognizes a B1 epitope inserted into a chimeric cap gene of bearded dragon AAV2 / AAV (see Figure 1), to analyze the resulting chimeric VP1, VP2, and VP3 proteins of bearded dragon AAV2 / AAV. The western blots analyzed protein samples collected during various stages of AAV particle purification by affinity chromatography, including the input sample, the direct flow (TF) fraction, and the elution fraction from the affinity chromatography column.

[00123] Figure 3A provides a predicted non-limiting avian AAV VP3 ribbon structure highlighting K580 and G444 as non-limiting insertion sites for a first member of a protein:protein binding pair.

[00124] Figure 3B provides the qPCR quantification of the virus titer obtained from crude virus preparations of a panel of chimeric AAV2 / avian AAV viral particles, without SpyTag or with a SpyTag insertion at the indicated position, or mosaic particles composed of AAV2 / avian AAV particles without SpyTag mixed with AAV2 / avian AAV particles with a SpyTag peptide insertion at the indicated position.

[00125] Figure 3C provides a western blot using antibody B1, which recognizes a linear epitope converted into chimeric VP1, VP2, and VP3 capsid proteins of avian AAV2 / AAV, analyzing the reaction between a Petition 870260072813, dated 07 / 22 / 2026, page 98 / 407 / 240 anti-ASGR1 antibody fused with the SpyCatcher “SpyC-mAb anti-ASGR1”, and a panel of chimeric viral particles of AAV2 / avian AAV without or with a SpyTag insertion at the indicated position, or mosaic particles comprising chimeric particles of AAV2 / avian AAV without SpyTag mixed with chimeric particles of AAV2 / avian AAV with a SpyTag peptide insertion at the indicated position.

[00126] Figure 4A provides a predicted non-limiting VP3 ribbon structure of sea lion AAV highlighting A565 and G432 as non-limiting insertion sites for a first member of a protein:protein binding pair.

[00127] Figure 4B provides the qPCR quantification of the virus titer obtained from crude virus preparations of a panel of chimeric sea lion AAV2 / AAV viral particles, without SpyTag or with a SpyTag insertion at the indicated position, or mosaic particles composed of sea lion AAV2 / AAV particles without SpyTag mixed with sea lion AAV2 / AAV particles with a SpyTag peptide insertion at the indicated position.

[00128] Figure 4C provides a western blot using antibody B1, which recognizes a linear epitope converted into chimeric capsid proteins VP1, VP2, and VP3 of sea lion AAV2 / AAV, analyzing the reaction between an anti-HER2 antibody (HERCEPTIN®) fused with the SpyCatcher SpyC-mAb anti-HER2, and a panel of sea lion AAV2 / AAV viral particles with or without SpyTag insertion at the indicated position, or mosaic sea lion AAV2 / AAV particles comprising chimeric sea lion AAV2 / AAV particles without SpyTag mixed with chimeric sea lion AAV2 / AAV particles with a SpyTag peptide insertion at the indicated position.

[00129] Figure 5A provides qPCR quantification of the virus titer obtained from crude viral preparations of a viral particle panel. Petition 870260072813, dated 07 / 22 / 2026, page 99 / 407 / 240 AAV2 / AAV sea lion, without SpyTag or with a SpyTag inserted in the indicated position and

[00130] Figure 5B provides a western blot using antibody B1, which recognizes a linear epitope converted into chimeric VP1, VP2, and VP3 capsid proteins of sea lion AAV2 / AAV, analyzing the reaction between an anti-HER2 antibody (HERCEPTIN®) fused with the SpyCatcher “SpyCmAb”, and a panel of sea lion AAV viral particles, without SpyTag or with a SpyTag insertion at the indicated position.

[00131] Figure 6A provides a predicted non-limiting bearded dragon AAV VP3 ribbon structure highlighting T573 and G436 as non-limiting insertion sites for a first member of a protein:protein binding pair.

[00132] Figure 6B provides qPCR quantification of virus titer obtained from crude virus preparations of a panel of AAV2 / AAV bearded dragon viral particles, without SpyTag or with a SpyTag insertion at the indicated position, or mosaic particles composed of AAV2 / AAV bearded dragon particles without SpyTag mixed with AAV2 / AAV bearded dragon particles with a SpyTag peptide insertion at the indicated position.

[00133] Figure 6C provides a western blot using antibody B1, which recognizes a linear epitope converted into chimeric VP1, VP2, and VP3 capsid proteins of bearded dragon AAV2 / AAV, analyzing the reaction between an anti-HER2 antibody (HERCEPTIN®) fused with the SpyCatcher “SpyCmAb anti-HER2”, and a panel of bearded dragon AAV2 / AAV viral particles with or without a SpyTag insertion at the indicated position, or bearded dragon AAV2 / AAV mosaic particles comprising chimeric bearded dragon AAV2 / AAV particles without SpyTag mixed with chimeric bearded dragon AAV2 / AAV particles with a SpyTag peptide insertion at the indicated position. Petition 870260072813, dated 07 / 22 / 2026, page 100 / 407 / 240

[00134] Figure 7A provides scatter plots obtained from flow cytometry evaluating the expression of green fluorescent protein (GFP) by 293 hErbB2 HER2-positive (+) cells infected with chimeric AAV2 / AAAV particles without SpyTag, chimeric particles of AAV2 / AAAV G444 Linker6 SpyTag or chimeric particles AAV2 / AAAV K580 Linker6 SpyTag. The chimeric particles AAV2 / AAAV G444 Linker6 SpyTag and chimeric particles AAV2 / AAAV K580 Linker6 SpyTag were conjugated to an isotype-irrelevant control antibody against GLP1R or an anti-HER2 antibody (HERCEPTIN®) fused with SpyCatcher (SEQ ID NO:43) via SpyTag (SEQ ID NO:42). Viruses express GFP as a transduction marker.

[00135] Figure 7B provides scatter plots obtained from flow cytometry evaluating green fluorescent protein (GFP) expression by 293 ASGR1-negative (-) or 293 hASGR1 ASGR1-positive (+) parental cells infected with AAV2 / AAAV chimeric particles without SpyTag or AAV2 / AAAV K580 Linker6 SpyTag chimeric particles. The AAV2 / AAAV K580 Linker6 SpyTag chimeric particles were conjugated to an isotype-irrelevant control antibody against GLP1R fused with SpyCatcher via SpyTag, or conjugated to a SpyCatcher-fused antibody that specifically binds to ASGR1 via SpyTag. Viruses express GFP as a transduction marker.

[00136] Figure 8A provides scatter plots obtained from flow cytometry evaluating green fluorescent protein (GFP) expression by HER2-positive (+) or HER2-negative (-) 293 hErbB2 parental cells infected with non-SpyTag AAV2 / sea lion chimeric particles or G432 Linker6 SpyTag AAV2 / sea lion chimeric particles. The G432 SpyTag AAV2 / sea lion chimeric particles were conjugated to an isotype-irrelevant control antibody against GLP1R fused with SpyCatcher via SpyTag, or conjugated to an anti-GLP1R antibody. Petition 870260072813, dated 07 / 22 / 2026, page 101 / 407 / 240 HER2 (HERCEPTIN®) fused with SpyCatcher (SEQ ID NO:43) via SpyTag. Viruses express GFP as a transduction marker.

[00137] Figure 8B provides scatter plots obtained from flow cytometry evaluating green fluorescent protein (GFP) expression by 293 hASGR1 ASGR1-positive (+) or 293 ASGR1-negative (-) parental cells infected with AAV2 / sea lion chimeric particles without SpyTag or cells infected with AAV2 / sea lion G432 Linker6 SpyTag chimeric particles. The AAV2 / sea lion G432 Linker6 SpyTag chimeric particles were conjugated to an isotype-irrelevant control antibody against GLP1R fused with SpyCatcher via SpyTag, or conjugated to a SpyCatcher-fused antibody that specifically binds to ASGR1 via SpyTag. Viruses express GFP as a transduction marker.

[00138] Figure 9 provides scatter plots obtained from flow cytometry evaluating the expression of green fluorescent protein (GFP) by 293 HER2-positive (+) cells infected with a panel of chimeric AAV2 / sea lion AAV viral particles, either chimeric AAV2 / sea lion AAV particles without SpyTag or with a SpyTag insertion at the indicated position. The SpyTag inserted into the chimeric AAV2 / sea lion particles was conjugated to an anti-HER2 antibody (HERCEPTIN®) fused with SpyCatcher (SEQ ID NO:43) via SpyTag. Viruses express GFP as a transduction marker.

[00139] Figure 10A provides scatter plots obtained from flow cytometry evaluating green fluorescent protein (GFP) expression by 293 hErbB2 HER2-positive (+) cells that are either “uninfected” or infected with AAV2 / bearded dragon chimeric particles without SpyTag, AAV2 / bearded dragon chimeric particles in Mosaic T573 Linker6 SpyTag, or AAV2 / bearded dragon chimeric particles in Mosaic G436 Linker6 SpyTag. The AAV2 / bearded dragon chimeric particles in Petition 870260072813, dated 07 / 22 / 2026, page 102 / 407 / 240 Mosaico T573 Linkeró SpyTag and AAV2 / bearded dragon chimeric particles in Mosaico G436 Linkeró SpyTag were conjugated to an anti-HER2 antibody (HERCEPTIN®) fused with SpyCatcher (SEQ ID NO: 43) via SpyTag. Viruses express GFP as a transduction marker.

[00140] Figure 10B provides scatter plots obtained from flow cytometry evaluating green fluorescent protein (GFP) expression by 293 hASGR1 ASGR1-positive (+) or 293 ASGR1-negative (-) parental cells infected with AAV2 / bearded dragon chimeric particles without SpyTag, AAV2 / bearded dragon T573 Linker6 SpyTag chimeric particles, or AAV2 / bearded dragon anti-ASGR1 T573 Linker6 SpyTag chimeric particles. The AAV2 / bearded dragon anti-ASGR1 T573 Linker6 SpyTag chimeric particles were conjugated to a SpyCatcher-fused antibody that specifically binds to ASGR1 via SpyTag. Viruses express GFP as a transduction marker.

[00141] Figure 11A provides the results of a Nanoluc luciferase assay evaluating the expression of Nanoluc reporter by hASGR1-positive (+) cells after infection with “AAV2 anti-ASGR1” particles, AAV2 / AAAV chimeric anti-ASGR1 particles, or AAV2 / AAV chimeric anti-ASGR1 particles from sea lions in the presence of the indicated concentration of purified human IgG. All particles were conjugated to a SpyCatcher-fused antibody that specifically binds to ASGR1 via SpyTag. Viruses express Nanoluc as a transduction marker.

[00142] Figure 11B provides a quantification of the graphs in Figure 11A, but normalized to the “PBS only” condition.

[00143] Figure 11C provides a table of IC50 values ​​for the IgG concentration required to neutralize the indicated viruses at 50%.

[00144] Figure 12A provides luminescence images of genetically modified mice expressing human ASGR1 in liver cells (ASGR1 humanized mice) 33 days after injection. Petition 870260072813, dated 07 / 22 / 2026, page 103 / 407 / 240 intravenous with phosphate-buffered saline (PBS) or with 5.0x1011 viral genomes (vg) / animal of SpyTag-labeled AAV2 / AAAV chimeric particles carrying firefly luciferase nucleotides of interest and modified by (1) SpyCatcher-anti-human ASGR1 antibody or (2) SpyCatcher-anti-human GLP1R antibody (control mAb). Viruses express firefly luciferase as a transduction marker. Mice were anesthetized using isoflurane, injected with a Luciferin substrate, and imaged 10 minutes later using the IVIS Spectrum In Vivo Imaging System (PerkinElmer).

[00145] Figure 12B provides a quantification of the average radiance of individual animals within the luminescence images represented in Panel A.

[00146] Figure 12C provides a quantification of the average radiance of the dissected organs (liver and lung) of the animals depicted in Panel A.

[00147] Figure 13A provides luminescence images of genetically modified mice expressing human ASGR1 in liver cells (ASGR1 humanized mice) 33 days after intravenous injection with phosphate-buffered saline (PBS) or with 5.0x1011 viral genomes (vg) / animal chimeric particles of AAV2 / sea lion AAV labeled with SpyTag carrying firefly luciferase nucleotides of interest and modified by (1) SpyCatcher-anti-human ASGR1 antibody or (2) SpyCatcher-anti-human GLP1R antibody (control mAb). Viruses express firefly luciferase as a transduction marker. Mice were anesthetized using isoflurane, injected with a Luciferin substrate, and imaged 10 minutes later using the IVIS Spectrum In Vivo Imaging System (PerkinElmer).

[00148] Figure 13B provides quantification of the average radiance of individual animals within the luminescence images depicted in panel A. Petition 870260072813, dated 07 / 22 / 2026, p. 104 / 407 / 240

[00149] Figure 13C provides quantification of the mean radiance of the dissected organs (liver and lung) of the animals depicted in panel A.

[00150] Figure 14 provides an immunofluorescence image of an organ of Corti explant culture from the inner ear of a neonatal mouse 3 days after infection with non-SpyTag sea lion AAV2 / AAV particles. The virus expresses GFP as a transduction marker (green) and the hair cells are labeled with an antibody that detects Myo7a (red).

[00151] Figure 15A provides an alignment of 16 C-terminal amino acids of chimeric AAV2 or AAV2 / sea lion sequences with a modification of the B1 epitope to replace it entirely or only at residue 730 with a homologous AAV sea lion sequence. The monoclonal antibody epitope B1 is illustrated.

[00152] Figure 15B provides qPCR quantification of virus titer obtained from purified virus preparations of chimeric sea lion AAV2 / AAV particles without SpyTag or without SpyTag and with a modification of the B1 epitope to replace it entirely or only at residue 730 with a homologous sea lion AAV sequence.

[00153] Figure 15C provides a protein gel staining using SYPRO Ruby analyzing the expression of capsid proteins VP1, VP2, and VP3 from chimeric sea lion AAV2 / AAV particles without SpyTag or without SpyTag and with a modification of the B1 epitope to replace it entirely or only at residue 730 with a homologous sea lion AAV sequence.

[00154] Figure 15D provides an XY plot obtained from the luminescence assessment of NanoLuc Luciferase expression from HEK293T cell lysates infected at various multiplicities of infection (MOIs) with chimeric sea lion AAV2 / AAV particles without SpyTag or without SpyTag and with a modification of the B1 epitope to replace it. Petition 870260072813, dated 22 / 07 / 2026, page 105 / 407 / 240 entirely or only at residue 730 by a homologous AAV sequence from sea lion. Viruses express NanoLuc Luciferase as a transduction marker.

[00155] Figure 16 provides the quantification of mean radiance of dissected mouse organs 34 days after intravenous injection with phosphate-buffered saline (PBS) or 5.0x1011 viral genomes (vg) / animal chimeric particles of AAV2 / sea lion AAV with a firefly luciferase nucleotide of interest and modified to be SpyTag-free or SpyTag-free and by a B1 epitope modification to replace it entirely or only at residue 730 with a homologous sequence of sea lion AAV. Viruses express firefly luciferase as a transduction marker. Mice were anesthetized using isoflurane, injected with a luciferin substrate, and imaged 10 minutes later using the IVIS Spectrum In Vivo Imaging System (PerkinElmer).

[00156] Figure 17 provides an illustrative (not to scale), non-limiting, and exemplary embodiment of a RepCap expression plasmid of the invention that can be used to generate a chimeric AAV viral particle. Primate AAV sequences are shown as unfilled boxes and sea lion AAV sequences are shown in filled boxes. Also shown for illustrative purposes only are only non-limiting exemplary positions (not to scale) for (1) alternative interface sites between primate and sea lion capsid sequences (dashed black lines within the primate animal AAV capsid sequence) and (2) a detectable marker for detection of the encoded VP1, VP2, and VP3 proteins (dashed line within the non-primate animal AAV capsid sequences).A Rep-Cap expression plasmid, as shown in Figure 17, can be used to produce AAV viral particles comprising a nucleotide of interest that is flanked by the sequences. Petition 870260072813, dated 07 / 22 / 2026, page 106 / 407 / 240 regarding inverted terminal repetition (ITR) 5' and 3' of the primate AAV.

[00157] Figure 18A provides qPCR quantification of viral titer obtained from purified virus preparations of chimeric AAV2 / sea lion AAV particles without SpyTag and with alternative interface sites between AAV2 and sea lion capsid sequences. The preparations were purified from Cell Lysate (v2 - v4) or Cell Lysate and Medium (v5).

[00158] Figure 18B provides an XY plot obtained from luminescence assessment of NanoLuc Luciferase expression from HEK293T cell lysates infected at various multiplicities of infection (MOIs) with SpyTag-free sea lion AAV2 / AAV particles and alternative interface sites between AAV2 and sea lion capsid sequences (Cell Lysate (v2 - v4)). A historical dataset for SpyTag-free sea lion AAV2 / AAV is used as a reference. Viruses express NanoLuc Luciferase as a transduction marker.

[00159] Figure 18C provides XY plots obtained from luminescence assessment of NanoLuc Luciferase expression from HEK293T cell lysates infected at various multiplicities of infection (MOIs) with SpyTag-free sea lion AAV2 / AAV particles and alternative interface sites between AAV2 and sea lion capsid sequences (Lysate and Cell Medium (v5)). A historical dataset for SpyTag-free sea lion AAV2 / AAV is used as a reference. Viruses express NanoLuc Luciferase as a transduction marker.

[00160] Figure 18D provides the quantification of mean radiance of dissected mouse organs 56 days after intravenous injection with phosphate-buffered saline (PBS) or 5.0x1011 viral (vg) / animal genomes of sea lion AAV2 / AAV particles with a firefly luciferase nucleotide of interest and modified to be SpyTag-free or SpyTag-free and the B1 epitope entirely replaced by a sequence Petition 870260072813, dated 07 / 22 / 2026, page 107 / 407 / 240 homologous sea lion AAV with or without alternative interface sites between AAV2 and sea lion capsid sequences. Viruses express firefly luciferase as a transduction marker. Mice were anesthetized using isoflurane, injected with a luciferin substrate, and imaged 10 minutes later using the IVIS Spectrum In Vivo Imaging System (PerkinElmer). DETAILED DESCRIPTION

[00161] Although recombinatorial approaches to targeting specific cells through gene therapy with AAVs have seen improvement in recent years, current recombinant approaches used to develop AAVs that evade detection and / or neutralization by pre-existing antibodies, presumably developed early in life, remain problematic. This paper describes an approach that leverages (1) the natural abilities of non-primate animal AAVs or remote AAVs to infect primate cells, (2) the lack of NAbs in humans for non-primate animal AAV capsid proteins, and, if desired or necessary, (3) the adaptability of a first member of a protein:protein linkage pair converted into AAV capsid proteins for the production of AAV viral particles useful for targeted gene therapy, e.g., the introduction of a nucleotide of interest to a specific cell of interest.This document describes a nucleotide molecule comprising at least one AAV cap gene harnessed according to its desired function. A nucleotide molecule of the invention comprises a cap gene or portion thereof from a non-primate animal and / or remote AAV (for the production of viral capsids that are not readily recognized by pre-existing Nabs). The cap gene or portion thereof from a non-primate animal AAV can be modified with a first member of a protein:protein linkage pair to which a second member comprising a targeting ligand can bind and direct the tropism of viral particles. Petition 870260072813, dated 07 / 22 / 2026, p. 108 / 407 / 240 resulting AAVs.

[00162] For those non-primate animal AAVs or remote AAVs that are unable to infect primate cells, the cap gene can be designed as a chimeric cap gene that encodes at least the phospholipase A2 (PLA2) domain of a VP1 capsid protein from a primate AAV and at least a portion of the VP3 capsid protein from a non-human primate AAV or remote AAV. The PLA2 domain is carried by a VP1 capsid protein (more particularly the VP1-exclusive (VP1-u) region of the VP1 capsid) and is believed to be important during AAV infection by mediating the transfer of the viral genome from late endosomes / lysosomes to the nucleus to initiate replication (Zadori et al., 2001, Dev Cell, 1(2):291-302).The VP3 capsid protein is the major surface capsid protein of an AAV virus particle and, as such, a virus capsid comprising at least a portion of a VP3 capsid protein from a non-primate animal AAV or a remote AAV is unlikely to be recognized by Nabs triggered against AAV serovars isolated from primates during the course of infection with the primate AAV.

[00163] A non-limiting representation of a nucleic acid molecule comprising a rep gene from a primate AAV and a chimeric cap gene is provided in Figure 1. For non-human primate AAVs and remote AAVs that are capable of infecting primate cells, the rep gene from a primate AAV may be operationally linked to a chimeric cap gene as described in this document or a cap gene from a non-primate animal AAV. The examples in this document show that such a nucleic acid molecule, when expressed in a packaging cell line with a helper plasmid and a primate AAV genome with a nucleotide of interest, is capable of encoding the appropriate replication and capsid proteins that function to replicate and encapsulate, respectively, the primate AAV genome into a viral particle capable of infecting cells in vivo. Furthermore, Petition 870260072813, dated 22 / 07 / 2026, p. 109 / 407 / 240 examples show that the tropism of such an AAV viral particle is easily adapted through the use of first and second members of a protein:protein linking pair and, moreover, the insertion of a first and second member of a protein:protein linking pair does not increase the probability of recognition of raised Nabs against primate AAV infection. As such, genetically modified viral particles, compositions comprising them, and respective methods of manufacture and use are provided herein.

[00164] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning commonly understood by a person skilled in the art to which this invention pertains.

[00165] Singular forms “a”, “an”, and “the” include plural references unless the context clearly indicates otherwise. Thus, for example, a reference to “a method” includes one or more methods and / or steps of the type described in this document and / or that will become apparent to those skilled in the art after reading this disclosure.

[00166] The “percentage (%) of identity” or similar can be readily determined for amino acid or nucleotide sequences along the entire length of a protein, or a portion thereof. A portion may be at least about 5 amino acids or 24 nucleotides, respectively, in length, and may be up to about 700 amino acids or 2100 nucleotides, respectively. Generally, when referring to “identity,” “homology,” or “similarity” between two different adeno-associated viruses, “identity,” “homology,” or “similarity” is determined in reference to “aligned” sequences. “Aligned” sequences or “alignments” refer to multiple nucleic acid sequences or protein (amino acid) sequences, often containing corrections for missing or additional bases or amino acids compared to a reference sequence.

[00167] Alignments can be performed using any of a variety of Multi-Sequence Alignment Programs. Petition 870260072813, dated 22 / 07 / 2026, p. 110 / 407 / 240 publicly or commercially available. Sequence alignment programs are available for amino acid sequences, for example, the programs “Clustal X”, “MAP”, “PIMA”, “MSA”, “BLOCKMAKER”, “MEME” and “Match-Box”. Generally, any of these programs is used in default settings, although one skilled in the art may alter these settings as needed. Alternatively, one skilled in the art may use another algorithm or computer program that provides at least the level of identity or alignment as that provided by the referenced algorithms and programs. See, for example, JD Thomson et al, Nucl. Acids. Res., “A comprehensive comparison of multiple sequence alignments”, 27(13):2682-2690 (1999).

[00168] Multi-sequence alignment programs are also available for nucleic acid sequences. Examples of such programs include “Clustal W”, “CAP Sequence Assembly”, “MAP”, and “MEME”, which are accessible via web servers on the internet. Other sources for such programs are known to those skilled in the art. Alternatively, Vector NTI utilities are also used. There are also a number of algorithms known in the art that can be used to measure nucleotide sequence identity, including those contained in the programs described above. As another example, polynucleotide sequences can be compared using FASTA™, a program in GCG Version 6.1. Fasta™ provides alignments and percent sequence identity of the regions of best overlap between search and fetch sequences.For example, the percentage of sequence identity between nucleic acid sequences can be determined using FASTA™ with its standard parameters (a word size of 6 and the NOPAM factor for the scoring matrix), as provided in GCG Version 6.1, incorporated into this document by reference.

[00169] “Meaningful identity” encompasses alignments of amino acid or nucleic acid sequences that are at least 90%, for example, Petition 870260072813, dated 07 / 22 / 2026, page 111 / 407 / 240 at least 93%, for example, at least 95%, for example, at least 96%, for example, at least 97%, for example, at least 98%, for example, at least 99%, or for example, at least 100% identical.

[00170] The term “chimeric” encompasses a functional gene or polypeptide comprising nucleic acid sequences or amino acid sequences, respectively, from at least two different organisms, for example, portions of a gene or polypeptide from at least one first and one second AAV, wherein the at least first and second portions are operationally linked. Unless specified as chimeric, nucleotide sequences, genes, polypeptides, and amino acids are considered non-chimeric, for example, comprising a nucleic acid sequence or amino acid sequence from only a single organism, for example, a single AAV.

[00171] The term “antibody” includes immunoglobulin molecules comprising four polypeptide chains, two heavy chains (H) and two light chains (L) interconnected by disulfide bonds. Each heavy chain comprises a variable heavy chain domain (VH) and a constant heavy chain region (CH). The constant heavy chain region comprises at least three domains, CH1, CH2, CH3 and, optionally, CH4. Each light chain comprises a variable light chain domain (CH) and a constant light chain region (CL). The variable heavy chain and light chain domains can be further subdivided into hypervariable regions, called complementarity-determining regions (CDRs), interspaced with non-conserved regions, called framework regions (FRs).Each variable heavy and light chain domain comprises three CDRs and four FRs, arranged from the amino terminal to the carboxy terminal in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (heavy chain CDRs can be abbreviated as HCDR1, HCDR2 and HCDR3; light chain CDRs can be abbreviated as LCDR1, LCDR2 and LCDR3). Petition 870260072813, dated 07 / 22 / 2026, page 112 / 407 / 240 Typical tetrameric antibody structures comprise two identical antigen-binding domains, each formed by the association of the Vh and Vl domains, and each of which, together with the respective CH and CL domains, forms the Fv region of the antibody. Single-domain antibodies comprise a single antigen-binding domain, for example, a Vh or a Vl. The antigen-binding domain of an antibody, for example, the part of an antibody that recognizes and binds to the first member of a specific antigen-binding pair, is also referred to as a "paratope". It is a small region (5 to 10 amino acids) of the Fv region of an antibody, part of the antigen-binding fragment (Fab region), and may contain parts of the antibody's heavy and / or light chains. A paratope binds specifically to a first member of a specific binding pair when the paratope binds to the first member of a specific binding pair with high affinity.The term “high-affinity” antibody refers to an antibody that has a KD relative to its first target member of a specific binding pair of approximately 10⁻⁹ M or lower (e.g., approximately 1 x 10⁻⁹ M, 1 x 10⁻¹⁰ M, 1 x 10⁻¹¹ M, or approximately 1 x 10⁻¹² M). In one embodiment, KD is measured by surface plasmon resonance, e.g., BIACORE™; in another embodiment, KD is measured by ELISA.

[00172] The phrase “complementarity-determining region,” or the term “CDR,” includes an amino acid sequence encoded by a nucleic acid sequence of an organism’s immunoglobulin genes that normally (i.e., in a wild-type animal) appears between two framework regions in a variable region of a light or heavy chain of an immunoglobulin molecule (e.g., an antibody or a T-cell receptor). A CDR may be encoded, for example, by a germline sequence or by a rearranged or non-rearranged sequence, and, for example, by a mature or unexposed B cell or T cell. A CDR may be a somatic mutant (e.g., varying from a sequence Petition 870260072813, dated 07 / 22 / 2026, p. 113 / 407 100 / 240 encoded in an animal's germline), humanized and / or modified with amino acid substitutions, additions, or deletions. In some circumstances (e.g., for a CDR3), CDRs may be encoded by two or more sequences (e.g., germline sequences) that are not contiguous (e.g., in an un-rearranged nucleic acid sequence) but are contiguous in a B-cell nucleic acid sequence, for example, as a result of splicing or ligation of the sequences (e.g., VDJ recombination to form a heavy-chain CDR3).

[00173] The term “light chain” includes an immunoglobulin light chain sequence from any organism and, unless otherwise specified, includes human κ and λ light chains, and a VpreB, as well as surrogate light chains. Variable light chain domains typically include three light chain CDRs and four framework (FR) regions, unless otherwise specified. Generally, a full-length light chain includes, from the amino terminus to the carboxyl terminus, a variable domain that includes FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 and a constant light chain region. A variable light chain domain is encoded by a variable light chain region gene sequence, which generally comprises V1 and J1 gene segments derived from a germline repertoire of V and J gene segments. Sequences, locations, and nomenclature for V and J light chain segments for various organisms can be found in the IMGT database, www.Light chains include those that, for example, do not selectively bind a first or second first member of a specific binding pair selectively bound by the first member of a binding protein to the specific binding pair in which they appear. Light chains also include those that bind and recognize, or assist the heavy chain or another light chain with binding and recognition, one or more first members of a pair. Petition 870260072813, dated 07 / 22 / 2026, p. 114 / 407 101 / 240 specific linker selectively linked to the first member of a specific linker-pair protein in which they appear. Common or universal light chains include those derived from a human Vk1-39Jk gene or a human Vk3-20Jk gene and include somatically mutated (e.g., affinity-matured) versions thereof. Exemplary human VL segments include a human Vk1-39 gene segment, a human Vk3-20 gene segment, a human VX1-40 gene segment, a human VX1-44 gene segment, a human VX2-8 gene segment, a human VX2-14 gene segment, and a human VX3-21 gene segment, and include somatically mutated (e.g., affinity-matured) versions thereof.Light chains can be made so that they comprise a variable domain of an organism (e.g., human or rodent, e.g., rat or mouse; or bird, e.g., chicken) and a constant region of the same organism or of a different organism (e.g., human or rodent, e.g., rat or mouse; or bird, e.g., chicken).

[00174] The term “about” or “approximately” includes being within a statistically significant range of a value. Such a range may be within an order of magnitude, preferably within 50%, more preferably within 20%, even more preferably within 10%, and even more preferably within 5% of a given value or range. The allowable variation encompassed by the term “about” or “approximately” depends on the particular system under study and can be readily appreciated by one skilled in the art.

[00175] The phrase “heavy chain” or “immunoglobulin heavy chain” includes an immunoglobulin heavy chain sequence, including a constant region immunoglobulin heavy chain sequence, from any organism. The variable heavy chain domains include three heavy chain CDRs and four FR regions, unless otherwise specified. The Petition 870260072813, dated 07 / 22 / 2026, page 115 / 407 102 / 240 Heavy chain fragments include CDRs, CDRs and FRs and their combinations. A typical heavy chain has, following the variable domain (from N-terminal to C-terminal), a CH1 domain, a hinge, a CH2 domain, and a CH3 domain. A functional fragment of a heavy chain includes a fragment that is capable of specifically recognizing a first member of a specific linking pair (e.g., recognizing the first member of a linking pair with a KD on the micromolar, nanomolar, or picomolar scale), that is capable of expression and secretion from a cell, and that comprises at least one CDR. Heavy chain variable domains are encoded by a variable region nucleotide sequence, which generally comprises Vh, Dh, and Jh segments derived from a repertoire of VH, DH, and JH segments present in the germline.The sequences, locations, and nomenclature for V, D, and J heavy chain segments for various organisms can be found in the IMGT database, which is accessible via the internet on the World Wide Web (www) at the URL “imgt.org”.

[00176] The term “heavy chain-only antibody”, “heavy chain-only antigen-binding protein”, “single-domain antigen-binding protein”, “single-domain binding protein”, or similar refers to a monomeric or homodimeric immunoglobulin molecule comprising an immunoglobulin-like chain comprising a variable domain operationally linked to a constant heavy chain region, which is unable to associate with a light chain because the constant heavy chain region typically lacks a functional CH1 domain.In this sense, the term “heavy chain-only antibody”, “heavy chain antigen-binding protein”, “single-domain antigen-binding protein”, “single-domain binding protein” or similar terms encompass (i) a monomeric single-domain antigen-binding protein comprising an immunoglobulin-like chain comprising a variable domain operationally linked to a constant chain region. Petition 870260072813, dated 07 / 22 / 2026, page 116 / 407 103 / 240 heavy without a functional Ch1 domain, or (ii) a homodimeric single-domain antigen-binding protein comprising two immunoglobulin-like chains, each comprising an operationally linked variable domain to a heavy chain constant region that lacks a functional Ch1 domain. In several respects, a homodimeric single-domain antigen-binding protein comprises two identical immunoglobulin-like chains, each comprising an identical operationally linked variable domain to an identical heavy chain constant region that lacks a functional Ch1 domain.Furthermore, each immunoglobulin-like chain of a single-domain antigen-binding protein comprises a variable domain, which may be derived from variable region heavy chain gene segments (e.g., Vh, Dh, Jh), light chain gene segments (e.g., Vl, JL), or a combination thereof, linked to a constant region heavy chain (Ch) gene sequence comprising a deletion or inactivating mutation in a Ch1 coding sequence (and optionally a hinged region) of a constant region heavy chain gene, e.g., IgG, IgA, IgE, IgD, or a combination thereof. A single-domain antigen-binding protein comprising a variable domain derived from heavy chain gene segments may be referred to as a “Vh-single-domain antibody” or “VH-single-domain antigen-binding protein,” see, for example, U.S. Patent No. 8,754,287, U.S. Patent Publications.Nos. 20140289876; 20150197553; 20150197554; 20150197555; 20150196015; 20150197556 and 20150197557, each of which is incorporated by reference in its entirety. A single-domain antigen-binding protein comprising a variable domain derived from light chain gene segments may be referred to as a “VL-single-domain antigen-binding protein,” see, for example, U.S. Publication No. 20150289489, incorporated in its entirety by reference. Petition 870260072813, dated 07 / 22 / 2026, page 117 / 407 104 / 240

[00177] The term “light chain” includes an immunoglobulin light chain sequence from any organism, and unless otherwise specified, includes kappa (κ) and lambda (λ) light chains and a VpreB, as well as surrogate light chains. Variable light chain domains typically include three light chain CDRs and four framework (FR) regions, unless otherwise specified. Generally, a complete light chain includes, from the amino terminus to the carboxyl terminus, a variable domain that includes FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 and a constant light chain region amino acid sequence. Variable light chain domains are encoded by the variable light chain region sequence, which generally comprises VL light chain and Jl light chain gene segments, derived from a germline repertoire of V and J light chain gene segments.The sequences, locations, and nomenclature for V and J light chain gene segments for various organisms can be found in the IMGT database, which is accessible via the internet on the World Wide Web (www) at the URL “imgt.org”. Light chains include those that, for example, do not selectively bind a first or second first member of a specific linking pair selectively linked by the first member of a specific linking pair-binding protein in which they appear. Light chains also include those that bind and recognize, or assist the heavy chain with binding and recognition of, one or more specific linking pairs selectively linked to the first member of a specific linking pair-binding protein in which they appear.Light chains also include those that bind and recognize, or assist the heavy chain with binding and recognition of one or more specific linkage pairs selectively attached to the first member of a specific linkage pair-binding protein in which they appear. Common or universal light chains include those derived from a human Vk1-39Jk5 gene or a human Vk3-20Jk1 gene and include somatically mutated versions (e.g., Petition 870260072813, dated 07 / 22 / 2026, p. 118 / 407 105 / 240 example, matured by affinity) of them.

[00178] The expression “operationally linked,” as used in this document, includes a physical juxtaposition (e.g., in three-dimensional space) of components or elements that interact, directly or indirectly with each other, or coordinate with each other to participate in a biological event, which juxtaposition achieves or enables such interaction and / or coordination. To give just one example, a control sequence (e.g., an expression control sequence) in a nucleic acid is referred to as being “operationally linked” to a coding sequence when it is located relative to the coding sequence in such a way that its presence or absence impacts the expression and / or activity of the coding sequence. In many embodiments, “operable linkage” involves covalent linkage of relevant components or elements to each other.Those skilled in the art will readily appreciate that, in some embodiments, covalent linkage is not required to achieve effective operable linkage. For example, in some embodiments, the nucleic acid control sequences that are operationally linked to the coding sequences they control are contiguous to the nucleotide of interest. Alternatively or additionally, in some embodiments, one or more of these control sequences act trans- or at a distance to control a coding sequence of interest. In some embodiments, the term “expression control sequence,” as used in this document, refers to polynucleotide sequences that are necessary and / or sufficient to effect the expression and processing of the coding sequences to which they are linked.In some embodiments, expression control sequences may be or comprise appropriate transcription initiation, termination, promoter and / or enhancer sequences; efficient RNA processing signals, such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that improve translation efficiency (e.g., sequence...). Petition 870260072813, dated 07 / 22 / 2026, page 119 / 407 106 / 240 Kozak consensus); sequences that improve protein stability; and / or, in some embodiments, sequences that increase protein secretion. In some embodiments, one or more control sequences are preferentially or exclusively active in a specific host cell or organism, or type thereof. To give an example, in prokaryotes, control sequences typically include promoter, ribosomal binding site, and transcription termination sequence; in eukaryotes, in many embodiments, these control sequences include promoters, enhancers, and / or transcription termination sequences.Those versed in the technique will appreciate from the context that, in many modalities, the term “control sequences” refers to components whose presence is essential for expression and processing, and in some modalities, it includes components whose presence is advantageous for expression (including, for example, leader sequences, targeting sequences, and / or fusion partner sequences).

[00179] “Redirection” or “re-direction” may include a scenario in which the wild-type particle targets multiple cells within a tissue and / or multiple organs within an organism, where the overall targeting to the tissue or organs is reduced to null by the insertion of the heterologous amino acid, and where redirection to a more specific cell in the tissue or a more specific organ in the organism is achieved with the targeting ligand (e.g., through a targeting ligand) that binds to a marker expressed by the specific cell. Such redirection or re-direction may also include a scenario in which the wild-type particle targets a tissue, where the targeting to the tissue is reduced to null by the insertion of the heterologous amino acid, and where redirection to a completely different tissue is achieved with the targeting ligand.

[00180] “Specific linking pair”, “protein:protein linking pair” and the like include two proteins (e.g., a first member (e.g., a first polypeptide) and a second cognate member (e.g., a second polypeptide). Petition 870260072813, dated 07 / 22 / 2026, page 120 / 407 107 / 240 example, a second polypeptide)) that interact to form a linkage (e.g., a non-covalent linkage between an epitope of the first member and an antigen-binding portion of the second member of an antibody that recognizes the epitope) or a covalent isopeptide linkage under conditions that allow or facilitate linkage formation. In some embodiments, the term “cognate” refers to components that function together. Epitopes and antibodies cognate to them, particularly epitopes that can also act as a detectable marker (e.g., c-myc) are well known in the art. Protein:protein linkage pairs capable of interacting to form a covalent isopeptide linkage are analyzed in Veggiani et al. (2014) TrendsBiotechnol. 32:506 and include peptide:peptide linkage pairs such as SpyTag:SpyCatcher, SpyTag002:SpyCatcher002; SpyTag:Ktag; isopeptag:pilina C, SnoopTag:SnoopCatcher, etc.Generally, a first member of a protein:protein linkage pair refers to the member of a protein:protein linkage pair that is usually less than 30 amino acids long and forms a covalent isopeptide bond with the second cognate protein, where the second cognate protein is usually larger but may also be less than 30 amino acids long, as in the SpyTag:Ktag system.

[00181] The term “isopeptide linkage” refers to an amide linkage between a carboxyl or carboxamide group and an amino group, at least one of which is not derived from a protein backbone or, alternatively, is not part of the protein’s main structure. An isopeptide linkage can form within a single protein or it can occur between two peptides or a peptide and a protein. Thus, an isopeptide linkage can form intramolecularly within a single protein or intermolecularly, that is, between two peptide / protein molecules, for example, between two peptide linkers. Typically, an isopeptide linkage can occur between a lysine residue and an asparagine, an acid Petition 870260072813, dated 07 / 22 / 2026, page 121 / 407 108 / 240 aspartic, glutamine or glutamic acid residue or the terminal carboxyl group of the protein or peptide chain or may occur between the alpha terminal of the protein or peptide chain and an asparagine, aspartic acid, glutamine or glutamic acid. Each residue of the pair involved in the isopeptide linkage is referred to in this document as a reactive residue. In preferred embodiments of the invention, an isopeptide linkage may form between a lysine residue and an asparagine residue or between a lysine residue and an aspartic acid residue. In particular, isopeptide linkages may occur between the amine of the lysine side chain and the carboxamide group of asparagine or the carboxyl group of an aspartate.

[00182] The SpyTag:SpyCatcher system is described in U.S. Patent No. 9,547,003 and Zakeri et al. (2012) PNAS 109:E690-E697, each of which is incorporated herein in its entirety by reference, and is derived from the CnAb2 domain of the fibronectin-binding protein FbaB from Streptococcus pyogenes. By splitting the domain, Zakeri et al. obtained a “SpyTag” peptide with the sequence AHIVMVDAYKPTK (SEQ ID NO:42) that forms an amide linkage to its cognate protein “SpyCatcher”, a 112-amino acid polypeptide with the amino acid sequence established in SEQ ID NO:43. (Zakeri (2012), supra). An additional specific linkage pair derived from the CnAb2 domain is SpyTag:Ktag, which forms an isopeptide linkage in the presence of SpyLigase.(Fierer (2014) PNAS 111:E1176-1181) SpyLigase was manipulated by excision of the β-strand of SpyCatcher containing a reactive lysine, resulting in Ktag, the first member of a 10-residue protein:protein linkage pair, with the amino acid sequence ATHIKFSKRD (SEQ ID NO:72). The SpyTag002:SpyCatcher002 system is described in Keeble et al (2017) Angew Chem Int Ed Engl 56:16521-25, incorporated herein by reference. SpyTag002 has the amino acid sequence VPTIVMVDAYKRYK, established as SEQ ID NO:73, and binds SpyCatcher002. Petition 870260072813, dated 07 / 22 / 2026, p. 122 / 407 109 / 240

[00183] The SnoopTag:SnoopCatcher system is described in Veggiani (2016) PNAS 113:1202-07. The Ig D4-like domain of RrGa, an adhesion molecule of Streptococcus pneumoniae, was cleaved to form SnoopTag (residues 734-745) and SnoopCatcher (residues 749-860). Incubation of SnoopTag and SnoopCatcher results in a spontaneous isopeptide bond that is specific between the complementary proteins. Veggiani (2016)), supra.

[00184] The specific isopeptag:pilin-C binding pair was derived from the major pilin protein Spy0128 of Streptococcus pyogenes. (Zakeir and Howarth (2010) J. Am. Chem. Soc. 132:4526-27). Isopeptag has the amino acid sequence TDKDMTITFTNKKDAE, established as SEQ ID NO:75, and binds pilin-C (residues 18-299 of Spy0128). Incubation of SnoopTag and SnoopCatcher results in a spontaneous isopeptide binding that is specific between the complementary proteins. Zakeir and Howarth (2010), supra.

[00185] The term “detectable marker” includes a polypeptide sequence that is a member of a specific linkage pair, for example, that specifically binds to another polypeptide sequence, for example, an antibody paratope, with high affinity.Exemplary and non-limiting detectable markers include hexahistidine marker, FLAG marker, Strep II marker, streptavidin-binding peptide (SBP) marker, calmodulin-binding peptide (CBP), glutione Transferaminase (GST), maltose-binding protein (MBP), S-tag, HA tag, and c-myc (SEQ ID NO: 44). (Reviewed in Zhao et al. (2013) J. Analytical Meth. Chem. 1-8; incorporated herein by reference). A common detectable marker for primate AAVs is the B1 epitope (SEQ ID NO: 45). The non-primate animal AAV capsid proteins of the invention, which do not naturally comprise the B1 epitope, can be modified herein to comprise a B1 epitope. Generally, capsid proteins of non-primate animal AAVs may comprise a sequence with substantial homology to the B1 epitope within the last 10 amino acids of the protein. Petition 870260072813, dated 07 / 22 / 2026, p. 123 / 407 110 / 240 capsid. Consequently, in some embodiments, a non-primate animal AAV capsid protein of the invention may be modified with one, but less than five, point mutations within the last 10 amino acids of the capsid protein such that the AAV capsid protein comprises a B1 epitope.

[00186] The term “target cells” includes any cells in which the expression of a nucleotide of interest is desired. Preferably, target cells exhibit a receptor on their surface that allows the cell to be targeted with a targeting ligand, as described below.

[00187] The term “transduction” or “infection” or similar refers to the introduction of a nucleic acid into a target cell nucleus by a viral particle. The term efficiency in relation to transduction or similar, e.g., “transduction efficiency,” refers to the fraction (e.g., percentage) of cells that express a nucleotide of interest after incubation with a defined number of viral particles comprising the nucleotide of interest. Well-known methods for determining transduction efficiency include flow cytometry of transduced cells with a fluorescent reporter gene, RT-PCR for expression of the nucleotide of interest, etc.

[00188] Generally, a “reference” viral capsid protein / capsid / particle is identical to the test viral capsid protein / capsid / particle except for the change for which the effect is to be tested. For example, to determine the effect, for example, on transduction efficiency, of inserting a first member of a specific linking pair into a test viral particle, the transduction efficiencies of the test viral particle (in the absence or presence of an appropriate targeting ligand) can be compared with the transduction efficiencies of a reference viral particle (in the absence or presence of an appropriate targeting ligand, if necessary) that is identical to the test viral particle in all instances (by Petition 870260072813, dated 07 / 22 / 2026, page 124 / 407 111 / 240 example, additional point mutations, nucleotide of interest, numbers of viral particles and target cells, etc.) except for the presence of a first member of a specific linkage pair. In some embodiments, a reference viral capsid protein is capable of forming a capsid with a second viral capsid protein modified to comprise at least a first member of a protein:protein linkage pair, wherein the reference viral capsid protein does not comprise the first member of a protein:protein linkage pair, preferably wherein the capsid formed by the reference viral capsid protein and the modified viral capsid protein is a mosaic capsid. Adeno-associated viruses (AAV)

[00189] “AAV” is an abbreviation for adeno-associated virus and can be used to refer to the virus itself or its derivatives. AAVs are small, non-enveloped, single-stranded DNA viruses. Typically, a wild-type AAV genome is 4.7 kb and is characterized by two inverted terminal repeats (ITRs) and two open reading frames (ORFs), rep and cap. The wild-type rep reading frame encodes four proteins with molecular weights of 78 kD (“Rep78”), 68 kD (“Rep68”), 52 kD (“Rep52”), and 40 kD (“Rep40”). Rep78 and Rep68 are transcribed from the p5 promoter, and Rep52 and Rep40 are transcribed from the p19 promoter. These proteins function primarily in regulating the transcription and replication of the AAV genome. The wild-type cap reading frame encodes three structural viral proteins (VPs) (capsids) with molecular weights of 83-85 kD (VP1), 72-73 kD (VP2), and 61-62 kD (VP3).More than 80% of the total proteins in an AAV virion (capsid) comprise VP3; in mature virions VP1, VP2, and VP3 are found in relative abundances of approximately 1:1:10, although ratios of 1:1:8 have also been reported. Padron et al. (2005) J. Virology 79:5047-58.

[00190] The genomic sequences of several AAV serotypes, as well Petition 870260072813, dated 07 / 22 / 2026, page 125 / 407 112 / 240 as the sequences of native inverted terminal repeats (ITRs), Rep proteins, and capsid subunits are known in the art. Such sequences can be found in the literature or in public databases such as GenBank. See, for example, GenBank Accession Numbers NC_002077 (AAV1), AF063497 (AAV1), NC001401 (AAV-2), AF043303 (AAV2), NC_001729 (AAV3), NC_001829 (AAV4), U89790 (AAV4), NC_006152 (AAV5), AF513851 (AAV7), AF513852 (AAV8), and NC_006261 (AAV8); whose disclosures are incorporated into this document by reference for teaching about AAV amino acid and nucleic acid sequences. See also, for example, Srivistava et al. (1983) J. Virology 45:555; Chiorini et al. (1998) J. Virology 71:6823; Chiorini et al. (1999) J. Virology 73: 1309; Bantel-Schaal et al. (1999) J. Virology 73:939; Xiao et al. (1999) J. Virology 73:3994; Muramatsu et al. (1996) Virology 221:208; Shade et al., (1986) J. Virol. 58:921; Gao et al. (2002) Proc. Nat. Acad. Sci.USA 99: 11854; Moris et al. (2004) Virology 33:375-383; US Patent Publication 20170130245; international patent publications WO 00 / 28061, WO 99 / 61601, WO 98 / 11244; and US Patent No. 6,156,303, each of which is incorporated herein by reference in its entirety. Table 2 in this document provides sequences of several AAVs from non-primate animals.

[00191] “AAV” encompasses all naturally occurring and modified subtypes and forms, except where otherwise required.AAV includes primate AAVs (e.g., AAV type 1 (AAV1), AAV type 2 (AAV2), AAV type 3 (AAV3), AAV type 4 (AAV4), AAV type 5 (AAV5), AAV type 6 (AAV6), AAV type 7 (AAV7), AAV type 8 (AAV8), AAVs of non-primate animals (e.g., avian AAV (AAAV)), and other AAVs of non-primate animals, such as AAVs of mammals (e.g., bat AAV, sea lion AAV, bovine AAV, canine AAV, equine AAV, caprine AAV, and ovine AAV, etc.), AAVs of squamates (e.g., snake AAV, a... Petition 870260072813, dated 07 / 22 / 2026, p. 126 / 407 113 / 240 bearded dragon), etc., and remote AAV, etc. “Primate AAV” refers to AAV generally isolated from primates. Similarly, “Non-primate animal AAV” refers to AAV isolated from non-primate animals. “Remote AAV”, as used in this document, encompasses: Isolated AAVs from primate or non-primate animals, generally with limited contact with the general human population. A wild-type capsid protein (AAV) isolated from primate animals, for example, an AAV from a primate, comprising a wild-type VP1 capsid protein comprising an amino acid sequence with less than 99%, for example, less than 95%, for example, less than 90%, for example, less than 85% amino acid sequence identity with each of the following: the VP1 capsid protein of AAV1, the VP1 capsid protein of AAV2, the VP1 capsid protein of AAV3, the VP1 capsid protein of AAV4, the VP1 capsid protein of AAV5, the VP1 capsid protein of AAV6, the VP1 capsid protein of AAV7, the VP1 capsid protein of AAV8, the VP1 capsid protein of AAV9, the VP1 capsid protein of AAV10, the VP1 capsid protein of AAV11, the capsid protein of AAV12 capsid VP1, and AAV13 capsid VP1 protein and / or AAV isolated from non-primate animals, for example, a non-primate animal AAV comprising a wild-type capsid protein comprising an amino acid sequence with less than 99%, for example, less than 95%, for example, less than 90%, for example, less than 85% amino acid sequence identity for each of the AAVs listed in Table 2.

[00192] Seropositivity can be assessed using well-known methods. For example, the absence of IgG can be determined by enzyme-linked immunosorbent assay (ELISA) or other well-known immune system-based assays. To detect neutralizing antibodies, a neutralization assay can be conducted in which Petition 870260072813, dated 07 / 22 / 2026, page 127 / 407 114 / 240 AAV particles are incubated with increasing amounts (serial dilutions) of (i) serum from a specific subject or mixed serum from multiple subjects or (ii) purified immunoglobulins (IVIG or IgG) prepared from an individual sample or pooled serum samples (e.g., from tens to thousands of donors representing a cross-section of immunoglobulins in a given population), followed by detection of cellular infection, e.g., following reporter gene expression (e.g., a luciferase gene, GFP, etc.). The level of infection is then compared to the level in a control sample not exposed to serum / IVIG / IgG. See, for example, Example 8. The neutralizing titer can be defined, for example, as the IVIG / IgG concentration or the highest serum dilution factor that results in 50% or more inhibition of reporter gene expression compared to the control.In one embodiment, a serum dilution in which more than a 70% reduction in the number of infected cells is observed compared to the control is considered positive for neutralizing activity. Interactions with known specific neutralizing antibodies can be studied using, for example, an immunoblot assay.

[00193] As used in this document, “of a [specified] AAV” with respect to a gene (e.g., rep, cap, etc.), capsid protein (e.g., a VP1 capsid protein, a VP2 capsid protein, a VP3 capsid protein, etc.), region of a capsid protein of a specified AAV (e.g., PLA2 region, VP1u region, VP1 / VP2 common region, VP3 region), nucleotide sequence (e.g., ITR sequence), for example, a cap gene or capsid protein of AAV2, etc., encompasses, in addition to the gene or polypeptide comprising, respectively, a nucleic acid sequence or amino acid sequence established in this document for the specified AAV, also variants of the gene or polypeptide, including variants comprising the smallest number of nucleotides or amino acids necessary to retain one or more Petition 870260072813, dated 07 / 22 / 2026, page 128 / 407 115 / 240 biological functions. As used in this document, a variant gene or variant polypeptide comprises a nucleic acid sequence or amino acid sequence that differs from the nucleic acid sequence or amino acid sequence established in this document for the gene or polypeptide of a specified AAV, wherein the difference(s) generally do not alter at least one biological function of the gene or polypeptide, and / or the phylogenetic characterization of the gene or polypeptide, for example, wherein the difference(s) may be due to degeneracy of the genetic code, isolate variations, sequence length, etc. For example, the rep gene and the cap gene, as used in this document, may encompass rep and cap genes that differ from the wild-type gene in that the genes may encode one or more Rep proteins and Cap proteins, respectively. In some embodiments, a Rep gene encodes at least Rep78 and / or Rep68.In some embodiments, the cap gene includes those that may differ from the wild type in that one or more alternative initiation codons or sequences between one or more alternative initiation codons are removed so that the cap gene encodes only a single cap protein, for example, where the initiation codons VP2 and / or VP3 are removed or replaced so that the cap gene encodes a functional VP1 capsid protein, but not a VP2 capsid protein or a VP3 capsid protein. Consequently, as used in this document, a rep gene encompasses any sequence that encodes a functional Rep protein. A cap gene encompasses any sequence that encodes at least one functional cap gene.

[00194] It is well known that the wild-type cap gene expresses all three capsid proteins VP1, VP2, and VP3 from a single open reading frame of the cap gene under the control of the p40 promoter found in the rep ORF.The term "capsid protein," "Cap protein," and similar terms refer to a protein that is part of the viral capsid. For adeno-associated viruses, capsid proteins are generally referred to as VP1, VP2, and / or VP3, etc. Petition 870260072813, dated 07 / 22 / 2026, page 129 / 407 116 / 240 can be encoded by the single cap gene. For AAV, the three AAV capsid proteins are produced in nature in an overlapping fashion from the use of the alternative translational initiation codon of the cap open reading frame (ORF), although all three proteins use a common stop codon. The ORF of a wild-type cap gene encodes three alternative initiation codons from 5' to 3': “initiation codon VP1”, “initiation codon VP2”, and “initiation codon VP3”; and a “common stop codon”. The largest viral protein, VP1, is generally encoded from initiation codon VP1 to the “common stop codon”. VP2 is generally encoded from initiation codon VP2 to the common stop codon. VP3 is generally encoded from initiation codon VP3 to the common stop codon. Consequently, VP1 comprises an N-terminal sequence that it does not share with VP2 or VP3, referred to as the VP1-exclusive region (VP1-u).The VP1-u region is generally encoded by the sequence of a wild-type cap gene from the VP1 start codon to the VP2 start codon. VP1-u comprises a phospholipase A2 (PLA2) domain, which may be important for infection, as well as nuclear localization signals that may assist the virus in targeting the nucleus for uncoating and genome release. The VP1, VP2, and VP3 capsid proteins share the same C-terminal sequence that makes up the entire VP3, which may also be referred to in this document as the VP3 region. The VP3 region is encoded from the VP3 start codon to the common stop codon. VP2 has an additional ~60 amino acids that it shares with VP1. This region is called the VP1 / VP2 common region.

[00195] In some embodiments, one or more of the Cap proteins of the invention may be encoded by one or more cap genes with one or more ORFs. In some embodiments, the VP proteins of the invention may be expressed from more than one ORF comprising a nucleotide sequence encoding any combination of VP1, VP2 and / or VP3 by the use of Petition 870260072813, dated 07 / 22 / 2026, p. 130 / 407 117 / 240 separate nucleotide sequences operationally linked to at least one expression control sequence for expression in a packaging cell, each producing one or more VP1, VP2, and / or VP3 capsid proteins of the invention. In some embodiments, a VP capsid protein of the invention can be individually expressed from an ORF comprising a nucleotide sequence encoding any one of VP1, VP2, or VP3 by using separate nucleotide sequences operationally linked to an expression control sequence for expression in a viral replication cell, each producing only one of the VP1, VP2, or VP3 capsid proteins.In another embodiment, VP proteins can be expressed from an ORF comprising nucleotide sequences encoding VP1, VP2, and VP3 capsid proteins operationally linked to at least one expression control sequence for expression in a viral replication cell, each producing VP1, VP2, and VP3 capsid proteins. Consequently, although the amino acid positions provided in this document may be given relative to the VP1 capsid protein of the referenced AAV, one skilled in the art would be able to respectively and easily determine the position of that same amino acid within the VP2 and / or VP3 capsid protein of the AAV and the corresponding amino acid positions among different AAVs.

[00196] The phrase “Inverted Terminal Repeat” or “ITR” includes symmetrical nucleic acid sequences in the genome of adeno-associated viruses necessary for efficient replication. ITR sequences are located at each end of the AAV DNA genome. ITRs serve as the origins of replication for viral DNA synthesis and are essential cis components for generating AAV particles, for example, by packaging into AAV particles.

[00197] The AAV ITR comprises recognition sites for Rep78 or Rep68 replication proteins. A “D” region of the ITR comprises Petition 870260072813, dated 07 / 22 / 2026, page 131 / 407 118 / 240 is the DNA nick site where DNA replication begins and provides directionality for the nucleic acid replication step. An AAV replicating in a mammalian cell typically comprises two ITR sequences.

[00198] A single ITR can be manipulated with Rep binding sites on both strands of the “A” regions and two symmetrical D regions on each side of the ITR palindrome. Such a manipulated construct in a double-stranded circular DNA template allows nucleic acid replication initiated by Rep78 or Rep68 that proceeds in both directions. A single ITR is sufficient for AAV replication of a circular particle. In methods of producing an AAV viral particle of the invention, the rep coding sequence encodes a Rep protein or Rep protein equivalent that is capable of binding to an ITR comprised in the transfer plasmid.

[00199] The Cap proteins of the invention, when expressed with appropriate Rep proteins by a packaging cell, can encapsulate a transfer plasmid comprising a nucleotide of interest and an even number of two or more ITR sequences. In some embodiments, a transfer plasmid comprises one ITR sequence. In some embodiments, a transfer plasmid comprises two ITR sequences.

[00200] Rep78 and / or Rep68 bind to unique and known sites in the ITR hairpin sequence and act to disrupt and unwind the hairpin structures at the end of an AAV genome, thus providing access to the replication mechanism of the viral replication cell. As is well known, Rep proteins can be expressed from more than one ORF comprising nucleotide sequence encoding any combination of Rep78, Rep68, Rep52 and / or Rep40 by using separate nucleotide sequences operationally linked to at least one expression control sequence for expression in a viral replication cell, each Petition 870260072813, dated 07 / 22 / 2026, page 132 / 407 119 / 240 producing one or more of the Rep78, Rep68, Rep52, and / or Rep40 proteins. Alternatively, Rep proteins can be individually expressed from an ORF comprising a nucleotide sequence encoding any one of Rep78, Rep68, Rep52, or Rep40 by using separate nucleotide sequences operationally linked to an expression control sequence for expression in a packaging cell, each producing only one Rep78, Rep68, Rep52, or Rep40 protein. In another embodiment, Rep proteins can be expressed from an ORF comprising nucleotide sequences encoding Rep78 and Rep52 proteins operationally linked to at least one expression control sequence for expression in a viral replication cell, each producing Rep78 and Rep52 proteins.

[00201] In a method for producing an AAV virion, for example, a viral particle, of the invention, a rep coding sequence and a cap gene of the invention can be provided in a simple packaging plasmid (see, for example, Figure 1). However, one skilled in the art will recognize that such a condition is not necessary. Such viral particles may or may not include a genome.

[00202] A “chimeric AAV capsid protein” includes an AAV capsid protein comprising amino acid sequences, for example, portions, of two or more different AAVs and which is capable of forming and / or does form a viral capsid / AAV viral particle. A chimeric AAV capsid protein is encoded by a chimeric AAV capsid gene, for example, a chimeric nucleotide comprising a plurality, for example, at least two, of nucleic acid sequences, each plurality being identical to a portion of a capsid gene encoding a distinct AAV capsid protein, and the pluralities together encoding a functional chimeric AAV capsid protein. The association of a chimeric capsid protein with a specific AAV Petition 870260072813, dated 07 / 22 / 2026, page 133 / 407 120 / 240 indicates that the capsid protein comprises one or more portions of a capsid protein from that AAV and one or more portions of a capsid protein from a different AAV. For example, a chimeric capsid protein of AAV2 includes a capsid protein comprising one or more portions of a VP1, VP2, and / or VP3 capsid protein from AAV2 and one or more portions of a VP1, VP2, and / or VP3 capsid protein from a different AAV.

[00203] The term “portion” refers to at least 5 amino acids or at least 15 nucleotides, but less than the full-length polypeptide or nucleic acid molecule, with 100% identity to a sequence from which the portion is derived, see Penzes (2015) J. General Virol. 2769. A “portion” encompasses any contiguous segment of amino acids or nucleotides sufficient to determine that the polypeptide or nucleic acid molecule form from which the portion is derived is “of a [specified] AAV” or has “significant identity” with a specific AAV, for example, a non-primate animal AAV or remote AAV. In some embodiments, a portion comprises at least 5 amino acids or 15 nucleotides with 100% identity to a sequence associated with the specified AAV. In some embodiments, a moiety comprises at least 10 amino acids or 30 nucleotides with 100% identity to a sequence associated with the specified AAV.In some embodiments, a moiety comprises at least 15 amino acids or 45 nucleotides with 100% identity to a sequence associated with the specified AAV. In some embodiments, a moiety comprises at least 20 amino acids or 60 nucleotides with 100% identity to a sequence associated with the specified AAV. In some embodiments, a moiety comprises at least 25 amino acids or 75 nucleotides with 100% identity to a sequence associated with the specified AAV. In some embodiments, a moiety comprises at least 30 amino acids or 90 nucleotides with 100% identity. Petition 870260072813, dated 07 / 22 / 2026, p. 134 / 407 121 / 240 identity with a sequence associated with the specified AAV. In some embodiments, a portion comprises at least 35 amino acids or 105 nucleotides with 100% identity with a sequence associated with the specified AAV. In some embodiments, a portion comprises at least 40 amino acids or 120 nucleotides with 100% identity with a sequence associated with the specified AAV. In some embodiments, a portion comprises at least 45 amino acids or 135 nucleotides with 100% identity with a sequence associated with the specified AAV. In some embodiments, a portion comprises at least 50 amino acids or 150 nucleotides with 100% identity with a sequence associated with the specified AAV. In some embodiments, a portion comprises at least 60 amino acids or 180 nucleotides with 100% identity with a sequence associated with the specified AAV.In some embodiments, a portion comprises at least 70 amino acids or 210 nucleotides with 100% identity to a sequence associated with the specified AAV. In some embodiments, a portion comprises at least 80 amino acids or 240 nucleotides with 100% identity to a sequence associated with the specified AAV. In some embodiments, a portion comprises at least 90 amino acids or 270 nucleotides with 100% identity to a sequence associated with the specified AAV. In some embodiments, a portion comprises at least 100 amino acids or 300 nucleotides with 100% identity to a sequence associated with the specified AAV. Viral capsid proteins, viral particles, modified nucleic acids

[00204] In some embodiments, a Cap protein of the invention, for example, a VP1 capsid protein as described in this document, a VP2 capsid protein as described in this document, and / or a VP3 capsid protein as described in this document, is modified to comprise, for example, a first member of a protein:protein linkage pair, a detectable marker, point mutation, etc. Petition 870260072813, dated 07 / 22 / 2026, page 135 / 407 122 / 240

[00205] Chimerism is a type of modification, as described in this document. Generally, modification of the gene or polypeptide of a specified AAV, or variants thereof, results in a nucleic acid sequence or amino acid sequence that differs from the nucleic acid sequence or amino acid sequence established in this document for the specified AAV, wherein the modification alters, confers, or removes one or more biological functions, but does not alter the phylogenetic characterization of the gene or polypeptide. A modification may include an insertion of, for example, a first member of a protein:protein linkage pair and a point mutation, for example, so that the natural tropism of the capsid protein is reduced to nullified and / or so that the capsid protein comprises a detectable marker.Preferred modifications include those that do not alter and preferentially decrease the low or non-existent recognition of the modified capsid by pre-existing antibodies found in the general population that were produced during the course of infection with another AAV, for example, infection with serotypes such as AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAVDJ, Anc80L65, AAV2G9, AAV-LK03, virions based on such serotypes, virions of currently used AAV gene therapy modalities, or a combination thereof. Other modifications as described in this document include the modification of a capsid protein so that it comprises a first member of a protein:protein linking pair, a detectable marker, etc., which modifications generally result from modifications at the genetic level, for example, through the modification of a cap gene.

[00206] In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, is a mosaic capsid, for example, comprising at least two sets of VP1, VP2 and / or VP3 proteins, each of which is Petition 870260072813, dated 07 / 22 / 2026, page 136 / 407 123 / 240 encoded by a different cap gene. A mosaic capsid in this document generally refers to a mosaic of a first viral capsid protein modified to comprise a first member of a protein:protein linking pair and a corresponding second viral capsid protein lacking the first member of a protein:protein linking pair. In relation to a mosaic capsid, the second viral capsid protein lacking the first member of a protein:protein linking pair may be referred to as a reference capsid protein encoded by a reference cap gene.In some mosaic capsid embodiments, preferably when the VP1, VP2, and / or VP3 capsid proteins modified with a first member of the protein:protein pair are not chimeric capsid proteins, a reference VP1, VP2, and / or VP3 capsid protein may comprise an amino acid sequence identical to that of the viral VP1, VP2, and / or VP3 capsid protein modified with a first member of a protein:protein linkage pair, except that the reference capsid protein does not possess the first member of a protein:protein linkage pair. In some mosaic capsid embodiments, a reference VP1, VP2, and / or VP3 capsid protein corresponds to the viral VP1, VP2, and / or VP3 capsid protein modified with a first member of a protein:protein linkage pair, except that the reference capsid protein does not possess the first member of a protein:protein linkage pair.In some embodiments, a reference capsid protein VP1 corresponds to a viral capsid protein VP1 modified with a first member of a protein:protein linkage pair, except that the reference capsid protein lacks the first member of a protein:protein linkage pair. In some embodiments, a reference capsid protein VP2 corresponds to a viral capsid protein VP2 modified with a first member of a protein:protein linkage pair, except that the reference capsid protein lacks the first member of a pair. Petition 870260072813, dated 07 / 22 / 2026, page 137 / 407 124 / 240 protein:protein linkage. In some embodiments, a reference capsid protein VP3 corresponds to a viral capsid protein VP3 modified with a first member of a protein:protein linkage pair, except that the reference capsid protein does not possess the first member of a protein:protein linkage pair. In some embodiments of the mosaic capsid comprising a chimeric capsid protein VP1, VP2 and / or VP3 modified further to comprise a first member of a protein:protein linkage pair, a reference protein may be a corresponding capsid protein from which portions thereof form part of the chimeric capsid protein.As a non-limiting example in some embodiments, the mosaic capsid comprising a chimeric AAV2 / AAAV VP1 capsid protein modified to comprise a first member of a protein:protein linkage pair may further comprise as a reference capsid protein: an AAV2 VP1 capsid protein without the first member, an AAAV VP1 capsid protein without the first member, a chimeric AAV2 / AAAV VP1 capsid protein without the first member. Similarly, in some embodiments, a mosaic capsid comprising a chimeric AAV2 / AAAV VP2 capsid protein modified to comprise a first member of a protein:protein linkage pair may further comprise, as a reference capsid protein: an AAV2 VP2 capsid protein without the first member, an AAAV VP1 capsid protein without the first member, or a chimeric AAV2 / AAAV VP2 capsid protein without the first member.In some embodiments, a mosaic capsid comprising a chimeric VP3 capsid protein of AAV2 / AAAV modified to comprise a first member of a protein:protein linkage pair may further comprise, as a reference capsid protein: an AAV2 VP2 capsid protein without the first member, or an AAAV VP1 capsid protein without the first member. Petition 870260072813, dated 07 / 22 / 2026, page 138 / 407 125 / 240 first member, a chimeric AAV2 / AAAV VP3 capsid protein lacking the first member. In some mosaic capsid embodiments, a reference capsid protein can be any capsid protein, provided it lacks the first member of the protein:protein linkage pair and is capable of forming a capsid with the first capsid protein modified with the first member of a protein:protein linkage pair.

[00207] Generally, mosaic particles can be generated by transfecting mixtures of modified and reference Cap genes in production cells at the indicated ratios. The protein subunit ratios, for example, modified VP protein:unmodified VP protein ratios, in the particle may, but not necessarily, stoichiometrically reflect the ratios of at least two Cap gene species encoding the first modified capsid protein with a first member of a protein:protein linkage pair and one or more reference Cap genes, for example, modified Cap gene:reference Cap gene packaged in transfected cells. In some embodiments, the protein subunit ratios in the particle do not stoichiometrically reflect the modified Cap gene:reference Cap gene(s) ratio transfected in packaging cells.

[00208] In some mosaic viral particle embodiments, the protein subunit ratio varies from about 1:59 to about 59:1. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:1 (e.g., the mosaic viral particle comprises about 30 modified capsid proteins and about 30 reference capsid proteins). In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:2 (e.g., the mosaic viral particle comprises about 20 modified capsid proteins and about 40 reference capsid proteins). In some mosaic viral particle embodiments, the protein subunit ratio is at least about 3:5. In some Petition 870260072813, dated 07 / 22 / 2026, page 139 / 407 In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:3 (e.g., the mosaic viral particle comprises about 15 modified capsid proteins and about 45 reference capsid proteins). In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:4 (e.g., the mosaic viral particle comprises about 12 modified capsid proteins and 48 reference capsid proteins). In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:5 (e.g., the mosaic viral particle comprises 10 modified capsid proteins and 50 reference capsid proteins). In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:6.In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:7. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:8. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:9 (e.g., the mosaic viral particle comprises about 6 modified capsid proteins and about 54 reference capsid proteins). In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:10. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:11 (e.g., the mosaic viral particle comprises about 5 modified capsid proteins and about 55 reference capsid proteins).In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:12. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:13. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 1:14 (per. Petition 870260072813, dated 07 / 22 / 2026, pp. 140 / 407 127 / 240 example, the mosaic viral particle comprises about 4 modified capsid proteins and about 56 reference capsid proteins). In some embodiments of mosaic viral particles, the protein subunit ratio is at least about 1:15. In some embodiments of mosaic viral particles, the protein subunit ratio is at least about 1:19 (for example, the mosaic viral particle comprises about 3 modified capsid proteins and about 57 reference capsid proteins). In some embodiments of mosaic viral particles, the protein subunit ratio is at least about 1:29 (for example, the mosaic viral particle comprises about 2 modified capsid proteins and about 58 reference capsid proteins). In some embodiments of mosaic viral particles, the protein subunit ratio is at least about 1:59.In some mosaic viral particle embodiments, the protein subunit ratio is at least about 2:1 (e.g., the mosaic viral particle comprises about 40 modified capsid proteins and about 20 reference capsid proteins). In some mosaic viral particle embodiments, the protein subunit ratio is at least about 5:3. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 3:1 (e.g., the mosaic viral particle comprises about 45 modified capsid proteins and about 15 reference capsid proteins). In some mosaic viral particle embodiments, the protein subunit ratio is at least about 4:1 (e.g., the mosaic viral particle comprises about 48 modified capsid proteins and 12 reference capsid proteins).In some mosaic viral particle embodiments, the protein subunit ratio is at least about 5:1 (for example, the mosaic viral particle comprises 50 modified capsid proteins and 10 reference capsid proteins). In some mosaic viral particle embodiments, the protein subunit ratio... Petition 870260072813, dated 07 / 22 / 2026, page 141 / 407 The ratio of 128 / 240 is at least about 6:1. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 7:1. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 8:1. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 9:1 (e.g., the mosaic viral particle comprises about 54 modified capsid proteins and about 6 reference capsid proteins). In some mosaic viral particle embodiments, the protein subunit ratio is at least about 10:1. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 11:1 (e.g., the mosaic viral particle comprises about 55 modified capsid proteins and about 5 reference capsid proteins).In some mosaic viral particle embodiments, the protein subunit ratio is at least about 12:1. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 13:1. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 14:1 (e.g., the mosaic viral particle comprises about 56 modified capsid proteins and about 4 reference capsid proteins). In some mosaic viral particle embodiments, the protein subunit ratio is at least about 15:1. In some mosaic viral particle embodiments, the protein subunit ratio is at least about 19:1 (e.g., the mosaic viral particle comprises about 57 modified capsid proteins and about 3 reference capsid proteins).In some mosaic viral particle embodiments, the protein subunit ratio is at least about 29:1 (e.g., the mosaic viral particle comprises about 58 modified capsid proteins and about 2 reference capsid proteins). In some particle embodiments... Petition 870260072813, dated 07 / 22 / 2026, page 142 / 407 In a 129 / 240 viral mosaic pattern, the protein subunit ratio is at least approximately 59:1.

[00209] In some non-mosaic viral particle embodiments, the protein subunit ratio may be 1:0 wherein each capsid protein of the non-mosaic viral particle is modified with a first member of a protein:protein linkage pair. In some non-mosaic viral particle embodiments, the protein subunit ratio may be 0:1 wherein each capsid protein of the non-mosaic viral particle is not modified with a first member of a protein:protein linkage pair.

[00210] In some embodiments, a capsid protein of the invention is modified to comprise a detectable marker. Many detectable markers are known in the art. (See, for example: Nilsson et al. (1997) “Affinity fusion strategies for detection, purification, and immobilization of modified proteins” Protein Expression and Purification 11: 1-16, Terpe et al.(2003) “Overview of tag protein fusions: From molecular and biochemical fundamentals to commercial systems” Applied Microbiology and Biotechnology 60:523-533 e referências destes).Detectable markers include, but are not limited to, a detectable polyhistidine marker (e.g., a His-6, His-8, or His-10 marker) that binds to immobilized divalent cations (e.g., Ni2+), a biotin moiety (e.g., in an in vivo biotinylated polypeptide sequence) that binds to immobilized avidin, a GST (glutathione S-transferase) sequence that binds to immobilized glutathione, an S marker that binds to immobilized protein S, an antigen that binds to an immobilized antibody or domain or fragment thereof (including, for example, T7, myc, FLAG, and B markers that bind to corresponding antibodies), a FLASH marker (a detectable marker that couples to specific arsenic-based moieties), a receptor or receptor domain that binds to an immobilized ligand (or vice versa), protein A or a derivative thereof (e.g., protein A). Petition 870260072813, dated 07 / 22 / 2026, p. 143 / 407 130 / 240 example, Z) that binds to immobilized IgG, maltose-binding protein (MBP) that binds to immobilized amylose, an albumin-binding protein that binds to immobilized albumin, a chitin-binding domain that binds to immobilized chitin, a calmodulin-binding peptide that binds to immobilized calmodulin, and a cellulose-binding domain that binds to immobilized cellulose. Another exemplary detectable marker is a SNAPtag, commercially available from Covalys (www.covalys.com). In some embodiments, a detectable marker disclosed in this document comprises a detectable marker recognized only by an antibody paratope. In some embodiments, a detectable marker disclosed in this document comprises a detectable marker recognized by an antibody paratope and other specific binding pairs.

[00211] In some embodiments, the detectable marker forms a binding pair with an immunoglobulin constant domain. In some embodiments, the detectable marker and / or detectable marker forms a binding pair with a metal ion, for example, Ni2+, Co2+, Cu2+, Zn2+, Fe3+, etc. In some embodiments, the detectable marker is selected from the group consisting of streptavidin, Strep II, HA, L14, 4C-RGD, LH, and Protein A.

[00212] In some embodiments, the detectable marker is selected from the group consisting of FLAG, HA, and c-myc (EQKLISEEDL; SEQ ID NO:44). In some embodiments, the detectable marker is c-myc (SEQ ID NO:44).

[00213] In some embodiments, a detectable marker is a B-cell epitope, for example, it is between about 1 amino acid and about 35 amino acids in length and forms a binding pair with an antibody paratope, for example, an immunoglobulin variable domain. In some embodiments, the detectable marker comprises a B1 epitope (SEQ ID NO:45). In some embodiments, a capsid protein is modified. Petition 870260072813, dated 07 / 22 / 2026, p. 144 / 407 131 / 240 to understand a B1 epitope in the VP3 region.

[00214] In some embodiments, a capsid protein of the invention comprises at least one first member of a peptide:peptide linkage pair.

[00215] In some embodiments, a capsid protein of the invention comprises a first member of a protein:protein linkage pair comprising a detectable marker, which can also be used for the detection and / or isolation of the Cap protein and / or as a first member of a protein:protein linkage pair. In some embodiments, a detectable marker acts as a first member of a protein:protein linkage pair for the binding of a targeting ligand comprising a multispecific binding protein that can bind to both the detectable marker and a target expressed by a cell of interest. In some embodiments, a Cap protein of the invention comprises a first member of a protein:protein linkage pair comprising cmyc (SEQ ID NO:44). The use of a detectable marker as a first member of a protein:protein linkage pair is described in, for example, WO2019006043, which is incorporated herein by reference in its entirety.

[00216] In some embodiments, a capsid protein comprises a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair forms a covalent isopeptide bond. In some embodiments, the first member of a peptide:peptide linkage pair is covalently linked via an isopeptide bond to a second cognate member of the peptide:peptide linkage pair, and optionally, wherein the second cognate member of the peptide:peptide linkage pair is fused with a targeting ligand, wherein the targeting ligand binds to a target expressed by a cell of interest. In some embodiments, the protein:protein linkage pair may be Petition 870260072813, dated 07 / 22 / 2026, page 145 / 407 132 / 240 selected from the group consisting of SpyTag:SpyCatcher, SpyTag002:SpyCatcher002, SpyTag:Ktag, Isopeptag:pilin-C and SnoopTag:SnoopCatcher. In some embodiments, the first member is SpyTag (or a biologically active portion thereof) and the protein (second cognate member) is SpyCatcher (or a biologically active portion thereof). In some embodiments, the first member is SpyTag (or a biologically active portion thereof) and the protein (second cognate member) is Ktag (or a biologically active portion thereof). In some embodiments, the first member is Ktag (or a biologically active portion thereof) and the protein (second cognate member) is SpyTag (or a biologically active portion thereof). In some embodiments, the first member is SnoopTag (or a biologically active portion thereof) and the protein (second cognate member) is SnoopCatcher (or a biologically active portion thereof).In some embodiments, the first member is Isopeptag (or a biologically active portion thereof) and the protein (second cognate member) is Pilin-C (or a biologically active portion thereof). In some embodiments, the first member is SpyTag002 (or a biologically active portion thereof) and the protein (second cognate member) is SpyCatcher002 (or a biologically active portion thereof). In some embodiments, a Cap protein of the invention comprises a SpyTag. The use of a first member of a protein:protein linkage pair is described in WO2019006046, incorporated herein in its entirety.

[00217] In some embodiments, the first member of a protein:protein linkage pair and / or detectable marker is operationally linked (represented in the structure with, chemically linked to and / or displayed by) to the Cap protein of the invention via a first or second linker, for example, an amino acid spacer with at least one amino acid in length. In some embodiments, the first member of a pair of Petition 870260072813, dated 07 / 22 / 2026, p. 146 / 407 133 / 240 protein linkage: protein is flanked by a first or second linker, for example, a first and / or second amino acid spacer, each spacer having at least one amino acid in length.

[00218] In some embodiments, the first and / or second ligands are not identical. In some embodiments, the first and / or second ligands each independently have one or two amino acids in length. In some embodiments, the first and / or second ligands each independently have one, two, or three amino acids in length. In some embodiments, the first and / or second ligands each independently have one, two, three, or four amino acids in length. In some embodiments, the first and / or second ligands each independently have one, two, three, four, or five amino acids in length. In some embodiments, the first and / or second ligands each independently have one, two, three, four, or five amino acids in length. In some embodiments, the first and / or second ligands each independently have one, two, three, four, five, or six amino acids in length.In some embodiments, the first and / or second ligands each independently have a length of one, two, three, four, five, six, or seven amino acids. In some embodiments, the first and / or second ligands each independently have a length of one, two, three, four, five, six, seven, or eight amino acids. In some embodiments, the first and / or second ligands each independently have a length of one, two, three, four, five, six, seven, eight, or nine amino acids. In some embodiments, the first and / or second ligands each independently have a length of one, two, three, four, five, six, seven, eight, nine, or ten amino acids. In some embodiments, the first and / or second ligands each independently have a length of one, two, three, four, five, six, seven, eight, nine, ten, or more amino acids. Petition 870260072813, dated 07 / 22 / 2026, page 147 / 407 134 / 240

[00219] In some embodiments, the first and second ligands are identical in sequence and / or length and each has one amino acid length. In some embodiments, the first and second ligands are identical in length and each has one amino acid length. In some embodiments, the first and second ligands are identical in length and each has two amino acids length. In some embodiments, the first and second ligands are identical in length and each has three amino acids length. In some embodiments, the first and second ligands are identical in length and each has four amino acids length, for example, the ligand is GLSG (SEQ ID NO:37). In some embodiments, the first and second ligands are identical in length and each has five amino acids length.In some embodiments, the first and second ligands are identical in length and each has six amino acids in length, for example, the first and second ligands each comprise a GLSGSG sequence (SEQ ID NO:38). In some embodiments, the first and second ligands are identical in length and have seven amino acids in length. In some embodiments, the first and second ligands are identical in length and each has eight amino acids in length, for example, the first and second ligands each comprise a GLSGLSGS sequence (SEQ ID NO:39). In some embodiments, the first and second ligands are identical in length and have nine amino acids in length. In some embodiments, the first and second ligands are identical in length and each has ten amino acids in length, for example, the first and second ligands each comprise a sequence of GLSGLSGLSG (SEQ ID NO:40) or GLSGGSGLSG (SEQ ID NO:41).In some embodiments, the first and second ligands are identical in length and each is more than ten amino acids long. Petition 870260072813, dated 07 / 22 / 2026, pp. 148 / 407 135 / 240

[00220] Generally, a first member of an amino acid sequence of a protein:protein linkage pair as described in this document, for example, comprising a first member of a specific linkage pair by itself or in combination with one or more linkers, is between about 5 amino acids and about 50 amino acids in length. In some embodiments, the first member of the amino acid sequence of a protein:protein linkage pair is at least 5 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein linkage pair is 6 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein linkage pair is 7 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein linkage pair is 8 amino acids long.In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 9 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 10 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 11 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 12 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 13 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 14 amino acids long.In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 15 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 16 amino acids long. Petition 870260072813, dated 07 / 22 / 2026, p. 149 / 407 136 / 240 length. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 17 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 18 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 19 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 20 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 21 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 22 amino acids long.In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 23 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 24 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 25 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 26 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 27 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 28 amino acids long.In some embodiments, the first amino acid sequence member of a protein:protein bonding pair is 29 amino acids long. In some embodiments, the first amino acid sequence member of a protein:protein bonding pair is 30 amino acids long. In some embodiments, the first sequence member... Petition 870260072813, dated 07 / 22 / 2026, p. 150 / 407 137 / 240 amino acids of a protein:protein bonding pair is 31 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 32 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 33 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 34 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 35 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 36 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 37 amino acids long.In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 38 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 39 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 40 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 41 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 42 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 43 amino acids long.In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 44 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 45 amino acids long. Petition 870260072813, dated 07 / 22 / 2026, p. 151 / 407 138 / 240 length. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 46 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 47 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 48 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 49 amino acids long. In some embodiments, the first member of the amino acid sequence of a protein:protein bonding pair is 50 amino acids long.

[00221] Due to the high conservation of at least large extents and the large number of close relatives, the corresponding insertion sites for AAVs other than the enumerated AAVs can be identified by performing an amino acid alignment or by comparing capsid structures. See, for example, Rutledge et al. (1998) J. Virol. 72:309-19; Mietzsch et al. (2019) Viruses 11, 362, 1-34, and US Patent No. 9,624,274 for examples of alignments of different AAV capsid proteins, each of which is incorporated into this document by reference in its entirety. For example, Mietzsch et al. (2019) provide a ribbon overlay of different dependentoparvoviruses in Figure 7, representing the variable regions from VR I to VR IX.Using such structural analysis, as described therein, and sequence analysis, a person skilled in the technique can determine which amino acids within the variable region correspond to the AAV amino acid sequence that can accommodate the insertion of a first member of a protein:protein binding pair and / or detectable marker.

[00222] Thus, in some embodiments, the first member of a protein:protein binding pair and / or detectable marker is inserted into a Petition 870260072813, dated 07 / 22 / 2026, p. 152 / 407 139 / 240 capsid protein VP1 of a non-primate animal AV after an amino acid position corresponding to an amino acid position selected from the group consisting of G453 of the capsid protein VP1 of AAV2, N587 of the capsid protein VP1 of AAV2, G453 of the capsid protein VP1 of AAV9 and A589 of the capsid protein VP1 of AAV9. In some embodiments, the first member of a protein:protein linkage pair and / or detectable marker is inserted into a capsid protein VP1 of a non-primate animal AAV between amino acids corresponding to N587 and R588 of a capsid VP1 of AAV2. Additional suitable insertion sites of a non-primate animal VP1 capsid protein include those corresponding to I-1, I-34, I-138, I-139, I-161, I-261, I-266, I-381, I-447, I-448, I-459, I-471, I-520, I-534, I-570, I-573, I-584, I-587, I-588, I-591, I-657, I-664, I-713 and I-716 of the AAV2 VP1 capsid protein (Wu et al. (2000) J. Virol. 74:8635-8647).A modified viral capsid protein, as described in this document, may be a non-primate animal capsid protein comprising a first member of a protein:protein linkage pair and / or detectable marker inserted at a position corresponding to a position of an AAV2 capsid protein selected from the group consisting of I-1, I-34, I-138, I-139, I-161, I-261, I-266, I-381, I-447, I-448, I-459, I-471, I-520, I-534, I-570, I-573, I-584, I-587, I-588, I-591, I-657, I-664, I-713, I-716 and a combination thereof. Additional suitable insertion sites for a non-primate animal AAV include those corresponding to AAV1 I-587, AAV1 I-589, AAV3 I-585, AAV4 I-585, and AAV5 I-585.In some embodiments, a modified viral capsid protein as described herein may be a non-primate animal capsid protein comprising a first member of a protein:protein linkage pair and / or detectable marker inserted at a position corresponding to a position selected from the group consisting of I-587 (AAV1), I-589 (AAV1), I-585 (AAV3). Petition 870260072813, dated 07 / 22 / 2026, p. 153 / 407 140 / 240 I-585 (AAV4), I-585 (AAV5) and a combination thereof.

[00223] In some embodiments, the first member of a protein:protein linkage pair and / or detectable marker is inserted into a VP1 capsid protein of a non-primate animal AAV after an amino acid position corresponding to an amino acid position selected from the group consisting of I444 of an avian AAV VP1 capsid protein, I580 of an avian AAV VP1 capsid protein, I573 of a bearded dragon AAV VP1 capsid protein, I436 of a bearded dragon AAV VP1 capsid protein, I429 of a sea lion AAV VP1 capsid protein, I430 of a sea lion AAV VP1 capsid protein, I431 of a sea lion AAV VP1 capsid protein, I432 of a VP1 capsid protein of AAV from sea lion, I433 of a capsid protein VP1 from AAV from sea lion, I434 of a capsid protein VP1 from AAV from sea lion, I436 of a capsid protein VP1 from AAV from sea lion,I437 of a VP1 capsid protein from sea lion AAV and I565 of a VP1 capsid protein from sea lion AAV.

[00224] The nomenclature I###, I# or similar refers in this document to the insertion site (I) with ### naming the number of amino acids relative to the VP1 protein of an AAV capsid protein; however, such insertion may be located directly at the N-terminus or C-terminus, preferably at the C-terminus of an amino acid in the 5-amino acid N- or C-terminal sequence of such amino acid, preferably 3, more preferably 2, especially 1 amino acid(s) N- or C-terminal of such amino acid. Furthermore, the positions referred to in this document are relative to the VP1 protein encoded by an AAV capsid gene, and corresponding positions (and point mutations thereof) can be easily identified for the VP2 and VP3 capsid proteins encoded by the capsid gene by performing a sequence alignment of the Petition 870260072813, dated 07 / 22 / 2026, p. 154 / 407 141 / 240 VP1, VP2 and VP3 proteins encoded by the appropriate AAV capsid gene.

[00225] Consequently, an insertion at the corresponding position of the coding nucleic acid of one of these cap gene sites leads to an insertion in VP1, VP2 and / or VP3, as capsid proteins are encoded by overlapping reading frames of the same gene with staggered initiation codons. Therefore, for AAV2, for example, according to this nomenclature, insertions between amino acids 1 and 138 are inserted only in VP1, insertions between 138 and 203 are inserted in VP1 and VP2, and insertions between 203 and the C-terminus are inserted in VP1, VP2 and VP3, which is obviously also the case for the I-587 insertion site. Therefore, the present invention encompasses AAV structural genes with corresponding insertions in the VP1, VP2 and / or VP3 proteins.

[00226] Nucleic acids encoding a VP3 capsid protein of the invention are also provided in this document. AAV capsid proteins may be, but are not necessarily, encoded by overlapping reading frames of the same gene with staggered initiation codons. In some embodiments, a nucleic acid encoding a VP3 capsid protein of the invention does not also encode a VP2 capsid protein or a VP1 capsid protein of the invention. In some embodiments, a nucleic acid encoding a VP3 capsid protein of the invention may also encode a VP2 capsid protein of the invention, but does not encode a VP1 capsid of the invention. In some embodiments, a nucleic acid encoding a VP3 capsid protein of the invention may also encode a VP2 capsid protein of the invention and a VP1 capsid of the invention.

[00227] In some embodiments, a viral capsid comprising the modified viral capsid protein comprising the first and second members of a protein:protein linkage pair (e.g., wherein the second member is operationally linked to a targeting linker, Petition 870260072813, dated 07 / 22 / 2026, page 155 / 407 142 / 240 comprises a multispecific binding protein, etc.) is capable of infecting a specific cell, for example, it has an enhanced ability to target and bind to a specific cell compared to that of a control viral capsid that is identical to the modified viral capsid protein, except that it lacks one or both of the first and second members of a protein:protein binding pair, for example, it comprises a control capsid protein. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand and exhibits detectable transduction efficiency compared to the undetectable transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is 10% higher than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is 20% higher than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein-protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is 30% greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to a first and a second member. Petition 870260072813, dated 07 / 22 / 2026, page 156 / 407 143 / 240 appropriate members of a protein:protein binding pair linked to a targeting ligand exhibits a transduction efficiency that is 40% higher than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described herein, binding to a first and a second appropriate members of a protein:protein binding pair linked to a targeting ligand exhibits a transduction efficiency that is 50% higher than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described herein, binding to a first and a second appropriate members of a protein:protein binding pair linked to a targeting ligand exhibits a transduction efficiency that is 60% higher than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is 70% greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is 75% greater than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand exhibiting a transduction efficiency that is 80% greater than the transduction efficiency of a control viral capsid. Petition 870260072813, dated 07 / 22 / 2026, page 157 / 407 144 / 240 In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is 85% higher than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is 90% higher than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is 95% greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is 99% greater than the transduction efficiency of a control viral capsid.

[00228] In some embodiments, a viral capsid comprising a modified viral capsid protein comprising the first and second members of a protein:protein binding pair (e.g., wherein the second member is operationally linked to a targeting ligand, comprises a multispecific binding protein, etc.) is capable of infecting a specific cell, i.e., has an enhanced ability to target and bind to a specific cell compared with that of a control viral capsid that is identical to the modified viral capsid protein, except Petition 870260072813, dated 07 / 22 / 2026, page 158 / 407 145 / 240 that it does not possess one or both of the first and second members of a protein:protein binding pair, for example, comprising a control capsid protein. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a detectable transduction efficiency compared to the undetectable transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is 10% greater than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is 20% higher than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is 30% higher than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is 40% greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a capsid protein... Petition 870260072813, dated 07 / 22 / 2026, page 159 / 407 A modified viral capsid, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is 50% higher than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is 60% higher than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is 70% greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is 75% greater than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is 80% greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits an efficiency. Petition 870260072813, dated 07 / 22 / 2026, page 160 / 407 147 / 240 transduction efficiency that is 85% higher than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand exhibiting a transduction efficiency that is 90% higher than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand exhibiting a transduction efficiency that is 95% higher than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is 99% greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is at least 1.5 times greater than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is at least 2 times greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, if... Petition 870260072813, dated 07 / 22 / 2026, page 161 / 407 148 / 240 binding to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand exhibits a transduction efficiency that is at least 3 times greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binding to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand exhibits a transduction efficiency that is at least 4 times greater than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is at least 5 times greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is at least 6 times greater than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is at least 7 times greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits... Petition 870260072813, dated 07 / 22 / 2026, page 162 / 407 149 / 240 a transduction efficiency that is at least 8 times greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand exhibits a transduction efficiency that is at least 9 times greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand exhibits a transduction efficiency that is at least 10 times greater than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is at least 20 times greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to an appropriate first and second member of a protein:protein binding pair linked to a targeting ligand and exhibits a transduction efficiency that is at least 30 times greater than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein-protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is at least 40 times greater than the transduction efficiency of a control viral capsid. Petition 870260072813, dated 07 / 22 / 2026, page 163 / 407 150 / 240 In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is at least 50 times greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is at least 60 times greater than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is at least 70 times greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein binding pair linked to a targeting ligand, exhibiting a transduction efficiency that is at least 80 times greater than the transduction efficiency of a control viral capsid.In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein-linked pair linked to a targeting ligand, exhibiting a transduction efficiency that is at least 90 times greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral capsid comprising a modified viral capsid protein, as described in this document, binds to the first and second members of a protein:protein-linked pair linked to... Petition 870260072813, dated 07 / 22 / 2026, page 164 / 407 151 / 240 A targeting ligand exhibits a transduction efficiency that is at least 100 times greater than the transduction efficiency of a control viral capsid. In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof, and optionally comprising a first and a second member of a protein:protein linkage pair (e.g., wherein the second member is operationally linked to a targeting ligand, comprises a multispecific linkage protein, etc.).) is more capable of avoiding neutralization by pre-existing antibodies in serum isolated from a human patient compared to an appropriate viral control particle (for example, comprising a viral capsid of an AAV serotype from which a portion is included in the viral capsid of the invention, for example, as part of the viral capsid protein comprising an amino acid sequence from a capsid protein of a non-primate animal AAV, a remote AAV, or a combination thereof), which also optionally comprises a first and a second member of a protein:protein linkage pair (for example, wherein the second member is operationally linked to a targeting linker, comprises a multispecific linkage protein, etc.).In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 2 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value of at least 2 times that of a control viral particle). Petition 870260072813, dated 07 / 22 / 2026, page 165 / 407 152 / 240

[00229] In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 3 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared with a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value of at least 3 times that of a control viral particle).In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 4 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value of at least 4 times that of a control viral particle).In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 5 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value at least 5 times that of a control viral particle). In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 6 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle. Petition 870260072813, dated 07 / 22 / 2026, p. 166 / 407 153 / 240 for example, (for example, a viral particle of the invention has an IC50 value of at least 6 times that of a control viral particle). In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 7 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared with a suitable control viral particle, for example, (for example, a viral particle of the invention has an IC50 value of at least 7 times that of a control viral particle).In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 8 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value of at least 8 times that of a control viral particle).In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence from a capsid protein of a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 9 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value at least 9 times that of a control viral particle). In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence from a capsid protein of a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 10 times more total IVIG or IgG. Petition 870260072813, dated 07 / 22 / 2026, page 167 / 407 154 / 240 for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value of at least 10 times that of a control viral particle). In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 20 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value of at least 20 times that of a control viral particle).In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 30 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value at least 30 times that of a control viral particle).In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 40 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value at least 40 times that of a control viral particle). In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a protein. Petition 870260072813, dated 07 / 22 / 2026, page 168 / 407 A viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 50 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value of at least 50 times that of a control viral particle). In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence from a capsid protein of a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 60 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value of at least 60 times that of a control viral particle).In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 70 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value at least 70 times that of a control viral particle).In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 80 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value at least 80 times that of a control viral particle). In some... Petition 870260072813, dated 07 / 22 / 2026, page 169 / 407 156 / 240 embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV or a combination thereof requires at least 90 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value of at least 90 times that of a control viral particle).In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof requires at least 100 times more total IVIG or IgG for neutralization (e.g., 50% or more inhibition of infection) compared to a suitable control viral particle, for example, (e.g., a viral particle of the invention has an IC50 value of at least 100 times that of a control viral particle). In some embodiments, a viral particle of the invention comprising a viral capsid protein comprising an amino acid sequence of a capsid protein from a non-primate animal AAV, a remote AAV, or a combination thereof has an undetectable IC50 when incubated with pooled human serum Ig of at least 100; 10,000; 20,000; 30,000; 40,000; 50,000 or more human donors. Targeting Ligands

[00230] A viral particle described in this document may further comprise a targeting ligand.

[00231] In some embodiments of the invention comprising a detectable marker, a targeting ligand comprises a multispecific binding molecule comprising (i) an antibody paratope that specifically binds to the detectable marker and (ii) a second binding domain that specifically binds to a receptor, which may be conjugated to Petition 870260072813, dated 07 / 22 / 2026, p. 170 / 407 157 / 240 surface of a sphere (e.g., for purification) or expressed by a target cell. Thus, a multispecific binding molecule comprising (i) an antibody paratope that specifically binds to the detectable marker and (ii) a second binding domain that specifically binds to a receptor targets the viral particle. Such “targeting” or “direction” may include a scenario where the wild-type viral particle targets multiple cells within a tissue and / or multiple organs within an organism, whose broad targeting to the tissue or organs is reduced to nullified by insertion of the detectable marker, and whose redirection to more specific cells in the most specific tissue or organ in the organism is achieved with the multispecific binding molecule.Such redirection or redirection may also include a scenario in which the wild-type viral particle targets a tissue, whose targeting to the tissue is reduced to nullified by the insertion of the detectable marker, and whose redirection to a completely different tissue is achieved with the multispecific binding molecule. An antibody paratope as described in this document generally comprises, at a minimum, a complementarity-determining region (CDR) that specifically recognizes the detectable marker, for example, a CDR3 region of a variable heavy and / or light chain domain. In some embodiments, a multispecific binding molecule comprises an antibody (or portion thereof) comprising the antibody paratope that specifically binds to the detectable marker.For example, a multispecific binding molecule may comprise a single-domain heavy chain variable region or a single-domain light chain variable region, wherein the single-domain heavy chain variable region or single-domain light chain variable region comprises an antibody paratope that specifically binds to the detectable marker. In some embodiments, a multispecific binding molecule may comprise an Fv region, for example, a multispecific binding molecule may... Petition 870260072813, dated 07 / 22 / 2026, page 171 / 407 158 / 240 comprise an scFv, which comprises an antibody paratope that specifically binds to the detectable marker. In some embodiments, a multispecific binding molecule as described in this document comprises an antibody paratope that specifically binds to c-myc (SEQ ID NO:44).

[00232] One embodiment of the present invention is a multimeric structure comprising a modified viral capsid protein of the present invention. A multimeric structure comprises at least 5, preferably at least 10, more preferably at least 30, most preferably at least 60 modified viral capsid proteins comprising a first member of a specific linking pair as described in this document. They can form regular viral capsids (empty viral particles) or viral particles (capsids encapsulating a nucleotide of interest). The formation of viral particles comprising a viral genome is a highly preferable feature for the use of the modified viral capsids described in this document.

[00233] A further embodiment of the present invention is the use of at least one modified viral capsid protein and / or a nucleic acid encoding the same, preferably at least one multimeric structure (e.g., viral particle) for the manufacture and use as in the transfer of a nucleotide of interest to a target cell. Methods of Use and Manufacturing

[00234] An additional embodiment of the modified viral capsid proteins described in this document is their use for the delivery of a nucleotide of interest, for example, a reporter gene or a therapeutic gene, to a target cell. Generally, a nucleotide of interest may be a transfer plasmid, which may generally comprise 5' and 3' inverted terminal repeat (ITR) sequences flanking the reporter gene(s) or therapeutic gene(s) (which may be under the control Petition 870260072813, dated 07 / 22 / 2026, page 172 / 407 159 / 240 of a viral or nonviral promoter, when enclosed within an AAV particle. In one embodiment, a nucleotide of interest is a transfer plasmid comprising from 5' to 3': a 5' ITR, a promoter, a gene (e.g., a reporter and / or therapeutic gene) and a 3' ITR.

[00235] Non-limiting examples of useful promoters include, for example, cytomegalovirus (CMV) promoter, spleen focus-forming virus (SFFV) promoter, elongation factor 1 alpha (EF1a) promoter (1.2 kb Efla promoter or 0.2 kb Efla promoter), chimeric EF1a / IF4 promoter, and phosphoroglycerate kinase (PGK) promoter. An internal enhancer may also be present in the viral construct to increase the expression of the gene of interest. For example, the CMV enhancer (Karasuyama et al. 1989. J. Exp. Med. 169:13, which is incorporated herein by reference in its entirety) may be used. In some embodiments, the CMV enhancer may be used in combination with the chicken β-actin promoter.

[00236] A variety of reporter genes (or detectable fractions) can be encapsulated in a multimeric structure comprising the modified viral capsid proteins described in this document. Examples of reporter genes include, for example, β-galactosidase (encoded lacZ gene), green fluorescent protein (GFP), enhanced green fluorescent protein (EgFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (EbFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, Ypet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (EyFP), Cerulean, T-Sapphire, luciferase, alkaline phosphatase, or a combination thereof.The methods described in this document demonstrate the construction of targeting particles employing the use of a lacZ reporter gene encoding galactosidase; however, those skilled in the art, upon reading this disclosure, will understand that the viral capsids described in this document... Petition 870260072813, dated 07 / 22 / 2026, page 173 / 407 160 / 240 can be generated in the absence of a reporter gene or with any reporter gene known in the art.

[00237] A variety of therapeutic genes can also be encapsulated in a multimeric structure comprising the modified viral capsid proteins described in this document, for example, as part of a transfer particle. Non-limiting examples of a therapeutic gene include those encoding a toxin (e.g., a suicide gene), a therapeutic antibody or fragment thereof, a CRISPR / Cas system or portions thereof, antisense RNA, siRNA, shRNA, etc.

[00238] A further embodiment of the present invention is a process for the preparation of a modified capsid protein, the method comprising the steps of: a) express a nucleic acid that encodes the modified capsid protein under suitable conditions, and b) Isolate the capsid protein expressed in step a).

[00239] In some embodiments, a viral particle as described in this document comprises a mosaic capsid, for example, a capsid comprising genetically modified capsid proteins as described in this document (in the absence or presence of a covalent linkage with a targeting ligand) in a certain ratio with reference capsid proteins. A method for manufacturing such a mosaic viral particle comprises a) express a nucleic acid encoding the modified capsid protein and a nucleotide encoding a reference capsid protein in a ratio (w / w) of at least about 60:1 to about 1:60, for example, 2:1, 1:1, 3:5, 1:2, 1:3, etc. under suitable conditions, and b) Isolate the capsid protein expressed in step a).

[00240] In some forms, a composition described in this Petition 870260072813, dated 07 / 22 / 2026, page 174 / 407 161 / 240 document comprises, or a method described in this document combines, a modified cap gene:reference cap gene (or combination of reference cap genes) in a ratio ranging from at least about 1:60 to about 60:1, for example, 2:1, 1:1, 3:5, 1:2, 1:3, etc. In some embodiments, the ratio is at least about 1:2. In some embodiments, the ratio is at least about 1:3. In some embodiments, the ratio is at least about 1:4. In some embodiments, the ratio is at least about 1:5. In some embodiments, the ratio is at least about 1:6. In some embodiments, the ratio is at least about 1:7. In some embodiments, the ratio is at least about 1:8. In some sports, the ratio is at least approximately 1:9. In some sports, the ratio is at least approximately 1:10. In some sports, the ratio is at least approximately 1:11. In some sports, the ratio is at least approximately 1:12.In some modalities, the ratio is at least approximately 1:13. In some modalities, the ratio is at least approximately 1:14. In some modalities, the ratio is at least approximately 1:15. In some modalities, the ratio is at least approximately 1:16. In some modalities, the ratio is at least approximately 1:17. In some modalities, the ratio is at least approximately 1:18. In some modalities, the ratio is at least approximately 1:19. In some modalities, the ratio is at least approximately 1:20. In some modalities, the ratio is at least approximately 1:25. In some modalities, the ratio is at least approximately 1:30. In some modalities, the ratio is at least approximately 1:35. In some modalities, the ratio is at least approximately 1:40. In some disciplines, the ratio is at least approximately 1:45. In some disciplines, the ratio is at least approximately 1:50. In some disciplines, the ratio is at least approximately 1:55.In some sports, the ratio is at least approximately 1:60. In some sports, the ratio is at least approximately 2:1. In some sports, the ratio is at least approximately 3:1. In some sports, the ratio is at least approximately 4:1. In some sports... Petition 870260072813, dated 07 / 22 / 2026, p. 175 / 407 162 / 240 the ratio is at least about 5:1. In some modalities, the ratio is at least about 6:1. In some modalities, the ratio is at least about 7:1. In some modalities, the ratio is at least about 8:1. In some modalities, the ratio is at least about 9:1. In some modalities, the ratio is at least about 10:1. In some modalities, the ratio is at least about 11:1. In some modalities, the ratio is at least about 12:1. In some modalities, the ratio is at least about 13:1. In some modalities, the ratio is at least about 14:1. In some modalities, the ratio is at least about 15:1. In some modalities, the ratio is at least about 16:1. In some modalities, the ratio is at least approximately 17:1. In some modalities, the ratio is at least approximately 18:1. In some modalities, the ratio is at least approximately 19:1. In some modalities, the ratio is at least approximately 20:1.In some disciplines, the ratio is at least approximately 25:1. In some disciplines, the ratio is at least approximately 30:1. In some disciplines, the ratio is at least approximately 35:1. In some disciplines, the ratio is at least approximately 40:1. In some disciplines, the ratio is at least approximately 45:1. In some disciplines, the ratio is at least approximately 50:1. In some disciplines, the ratio is at least approximately 55:1. In some disciplines, the ratio is at least approximately 60:1.

[00241] In some embodiments, the VP protein subunit ratios in the mosaic viral particle may, but do not necessarily, stoichiometrically reflect the ratios of the modified cap gene:reference cap gene. Generally, a mosaic capsid formed according to the method will be considered to have a modified capsid protein:reference capsid protein ratio similar to the (p:p) ratio of nucleic acids encoding the same used to produce the mosaic capsid. In some embodiments, a mosaic capsid comprises a protein subunit ratio of about 1:59 to about 59:1. Petition 870260072813, dated 07 / 22 / 2026, page 176 / 407 163 / 240

[00242] Other embodiments of the present invention include a method for altering the tropism of a virus, the method comprising the steps of: (a) inserting a nucleic acid encoding a heterologous amino acid sequence into a nucleic acid sequence encoding a viral capsid protein to form a nucleotide sequence encoding a genetically modified capsid protein comprising the heterologous amino acid sequence and / or (b) growing a packaging cell under conditions sufficient for the production of viral vectors, wherein the packaging cell comprises the nucleic acid. A further embodiment of the present invention is a method for displaying a targeting ligand on the surface of a capsid protein, the method comprising the steps of: (a) expressing a nucleic acid encoding a recombinant viral capsid protein, as described herein (and optionally,(a) with a nucleotide encoding a reference capsid protein) under suitable conditions, wherein the nucleic acid encodes a capsid protein comprising a first member of a specific linking pair, (b) isolate the expressed capsid protein comprising a first member of a specific linking pair from step (a) or capsid comprising the same, and (c) incubate the capsid protein or capsid with a second cognate member of the specific linking pair under suitable conditions to allow the formation of an isopeptide linkage between the first and second members, wherein the second cognate member of the specific linking pair is fused to a targeting ligand.

[00243] In some embodiments, the packaging cell further comprises an auxiliary plasmid and / or a transfer plasmid compr...

Claims

1. Chimeric recombinant particle in adeno-associated virus (AAV) mosaic, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein, and (iii) packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein: (A) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2, and / or an AAV capsid protein VP3, wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2, or the AAV capsid protein VP3 comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids of a protein of capsid of an AAV from a non-primate animal,and (ii) at least 5 amino acids exhibiting 100% identity with a primate animal AAV; and wherein the first AAV capsid protein comprises a selected modification of the group consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, (d) any combination of (a), (b) and (c); and (B) the second reference AAV capsid protein is the same as the first AAV capsid protein, except for the absence of Petition 870260072813, dated 22 / 07 / 2026, p. 255 / 407 2 / 52 referred modification, in which the mosaic chimeric recombinant particle of AAV is capable of infecting a mammalian host,and optionally in which the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:

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2. Chimeric recombinant particle in AAV mosaic according to claim 1, characterized in that: (a) the protein:protein linkage pair is selected from SpyTag:SpyCatcher, SpyTag:KTag, Isopeptag:pilin C, SnoopTag:SnoopCatcher and SpyTag002:SpyCatcher002, optionally wherein the first member of the protein:protein linkage pair is flanked by a first and / or second linker that links the first member of the protein:protein linkage pair to the first AAV capsid protein, and wherein the first and / or second linker each independently has at least one amino acid in length, optionally wherein the first and second linkers are not identical or the first and second linkers are identical and have 10 amino acids in length, and optionally wherein the first AAV capsid protein additionally comprises a second cognate member of the linkage pair. protein:protein,optionally wherein the first and second members are linked by a covalent bond, optionally an isopeptide bond, optionally wherein: (i) the first member is SpyTag and the second cognate member is SpyCatcher or KTag, (ii) the first member is KTag and the second cognate member is SpyTag, Petition 870260072813, dated 22 / 07 / 2026, p. 256 / 407 3 / 52 (iii) the first member is SnoopTag and the second cognate member is SnoopCatcher, (iv) the first member is isopeptag and the second cognate member is Pilin-C, or (v) the first member is SpyTag002 and the second cognate member is SpyCatcher002, optionally wherein SpyTag comprises an amino acid sequence established in SEQ ID NO:42, (b) the first member of the protein:protein linking pair comprises c-myc comprising a sequence established in SEQ ID NO:44; or (c) the detectable label comprises a B1 epitope comprising an IGTRYLTR amino acid sequence (SEQ ID NO:45).

3. Chimeric recombinant particle mosaic of AAV according to claim 1 or 2, characterized in that: (a) the primate animal AAV is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9 and a combination thereof; and / or (b) the non-primate animal AAV is an avian AAV (AAAV), a sea lion AAV or a bearded dragon AAV, optionally wherein: (i) the non-primate animal AAV is an AAAV, and the modification is at position I-444 or I-580 of a VP1 capsid protein of the AAAV; (ii) the non-primate animal AAV is a bearded dragon AAV, and the modification is at position I-573 or I-436 of a VP1 capsid protein of the bearded dragon AAV; or (iii) the non-primate animal AAV is a sea lion AAV, and the modification is at a selected position of the group consisting of I429, I-430, I-431, I-432, I-433, I-434, I-436, I-437 and A-565 of a protein from Petition 870260072813, dated 22 / 07 / 2026, p.257 / 407 4 / 52 capsid VP1 of the sea lion AAV.

4. Recombinant mosaic particle of non-primate animal AAV, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein, and (iii) packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein: (A) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, non-primate animal AAV capsid proteins VP1, VP2 and VP3, and wherein at least one of the AAV VP1 capsid protein,The AAV capsid protein VP2 and the AAV capsid protein VP3 comprise a selected modification of the group consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b) and (c); and (B) the second reference AAV capsid protein is the same as the first AAV capsid protein except for the absence of said modification, wherein the recombinant mosaic AAV particle of animal Petition 870260072813, dated 22 / 07 / 2026, p. 258 / 407 5 / 52 non-primate is capable of infecting a mammalian host, and optionally in which the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15., 5. Recombinant mosaic particle of non-primate animal AAV according to claim 4, characterized in that: (a) the protein:protein linkage pair is selected from SpyTag:SpyCatcher, SpyTag:KTag, Isopeptag:pilin C, SnoopTag:SnoopCatcher and SpyTag002:SpyCatcher002, optionally wherein the first member of the protein:protein linkage pair is flanked by a first and / or second linker that links the first member of the protein:protein linkage pair to the first AAV capsid protein, and wherein the first and / or second linker each independently has at least one amino acid in length, optionally wherein the first and second linkers are not identical or the first and second linkers are identical and have 10 amino acids in length, and optionally wherein the first AAV capsid protein additionally comprises a second cognate member of the pair. protein:protein linkage,optionally wherein the first and second members are linked by a covalent bond, optionally an isopeptide bond, optionally wherein: (i) the first member is SpyTag and the second cognate member is SpyCatcher or KTag, (ii) the first member is KTag and the second cognate member is SpyTag, (iii) the first member is SnoopTag and the second cognate member is SnoopCatcher, Petition 870260072813, dated 07 / 22 / 2026, p. 259 / 407 6 / 52 (iv) the first member is isopeptag and the second cognate member is Pilin-C, or (v) the first member is SpyTag002 and the second cognate member is SpyCatcher002, optionally wherein SpyTag comprises an amino acid sequence established in SEQ ID NO:42, (b) the first member of the protein:protein linking pair comprises c-myc comprising a sequence established in SEQ ID NO:44; or (c) the detectable label comprises a B1 epitope comprising an IGTRYLTR amino acid sequence (SEQ ID NO:45).

6. Recombinant mosaic particle of non-primate animal AAV according to claim 4 or 5, characterized in that the non-primate animal AAV is an avian AAV (AAAV), a sea lion AAV or a bearded dragon AAV, optionally wherein: (i) the non-primate animal AAV is an AAAV, and the modification is at position I-444 or I-580 of a VP1 capsid protein of the AAAV; (ii) the non-primate animal AAV is a bearded dragon AAV, and the modification is at position I-573 or I-436 of a VP1 capsid protein of the bearded dragon AAV; or (iii) the non-primate animal AAV is a sea lion AAV, and the modification is at a selected position of the group consisting of I429, I-430, I-431, I-432, I-433, I-434, I-436, I-437 and A-565 of a VP1 capsid protein of the sea lion AAV.

7. Recombinant mosaic particle of non-primate animal AAV, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein, and (iii) packaged within the AAV capsid, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein: (A) the AAV ITR sequence comprises at least 15 nucleotides exhibiting at least 90% identity with at least 15 nucleotides of the AAV ITR sequence from a primate animal AAV; (B) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and an AAV capsid protein VP3, wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are AAV capsid proteins VP1, VP2 and VP3 from a non-primate animal,wherein the first AAV capsid protein comprises a selected group modification consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a)-(c), (C) the second reference AAV capsid protein is the same as the first AAV capsid protein except for the absence of said modification, wherein the non-primate animal AAV mosaic recombinant particle is capable of infecting a mammalian host, and optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:

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8. Recombinant mosaic particle of non-animal AAV. Petition 870260072813, dated 07 / 22 / 2026, page 1. 261 / 407 8 / 52 primate according to claim 7, characterized in that: (a) the protein:protein linkage pair is selected from SpyTag:SpyCatcher, SpyTag:KTag, Isopeptag:pilin C, SnoopTag:SnoopCatcher and SpyTag002:SpyCatcher002, optionally wherein the first member of the protein:protein linkage pair is flanked by a first and / or second linker that links the first member of the protein:protein linkage pair to the first AAV capsid protein, and wherein the first and / or second linker each independently has at least one amino acid in length, optionally wherein the first and second linkers are not identical or the first and second linkers are identical and have 10 amino acids in length,and optionally wherein the first AAV capsid protein additionally comprises a second cognate member of the protein:protein linkage pair, optionally wherein the first and second members are linked by a covalent bond, optionally an isopeptide bond, optionally wherein: (i) the first member is SpyTag and the second cognate member is SpyCatcher or KTag, (ii) the first member is KTag and the second cognate member is SpyTag, (iii) the first member is SnoopTag and the second cognate member is SnoopCatcher, (iv) the first member is isopeptag and the second cognate member is Pilin-C, or (v) the first member is SpyTag002 and the second cognate member is SpyCatcher002, optionally wherein SpyTag comprises a sequence of Petition 870260072813, dated 22 / 07 / 2026, p. 262 / 407 9 / 52 amino acids established in SEQ ID NO:42,(b) the first member of the protein:protein linkage pair comprises c-myc comprising a sequence established in SEQ ID NO:44; or (c) the detectable label comprises a B1 epitope comprising an IGTRYLTR amino acid sequence (SEQ ID NO:45).

9. Recombinant mosaic particle of non-primate animal AAV according to claim 7 or 8, characterized in that: (a) the primate animal AAV is selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9 and a combination thereof; and / or (b) the non-primate animal AAV is an avian AAV (AAAV), a sea lion AAV or a bearded dragon AAV, optionally wherein: (i) the non-primate animal AAV is an AAAV, and the modification is at position I-444 or I-580 of a VP1 capsid protein of the AAAV; (ii) the non-primate animal AAV is a bearded dragon AAV, and the modification is at position I-573 or I-436 of a VP1 capsid protein of the bearded dragon AAV; or (iii) the non-primate animal AAV is a sea lion AAV, and the modification is at a selected position of the group consisting of I429, I-430, I-431, I-432, I-433, I-434, I-436, I-437 and A-565 of a VP1 capsid protein of the sea lion AAV.

10. Recombinant mosaic capsid of non-primate animal AAV, characterized in that it comprises: (i) a first AAV capsid protein, wherein the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, Petition 870260072813, dated 22 / 07 / 2026, p. 263 / 407 10 / 52 wherein AAV capsid protein VP1, AAV capsid protein VP2, and AAV capsid protein VP3 are, respectively, AAV capsid proteins VP1, VP2, and VP3 from non-primate animals, and wherein at least one of AAV capsid protein VP1, AAV capsid protein VP2, and AAV capsid protein VP3 comprises a selected group modification consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV capsid, (b) a detectable label, (c) a point mutation,wherein the point mutation reduces the natural tropism of the AAV capsid and / or creates a detectable label, and (d) any combination of (a), (b) and (c); and (ii) a second reference AAV capsid protein, wherein the second reference AAV capsid protein does not have the modification of the first AAV capsid protein, optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:

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11. Chimeric recombinant AAV mosaic capsid, characterized in that it comprises: (i) a first AAV capsid protein, wherein the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, and wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2 or the AAV capsid protein VP3 comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids of a capsid protein of Petition 870260072813, dated 22 / 07 / 2026, page.264 / 407 11 / 52 a non-primate animal AAV, and (ii) at least 5 amino acids exhibiting 100% identity with a primate animal AAV; and wherein the first AAV capsid protein comprises a selected group modification consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV capsid, (b) a detectable label, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV capsid and / or creates a detectable label, (d) any combination of (a), (b) and (c); and (ii) a second reference AAV capsid protein, wherein the second reference AAV capsid protein does not have the modification of the first AAV capsid protein, optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:

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12. Composition for producing a recombinant mosaic capsid of non-primate animal AAV, characterized in that it comprises, in a given ratio: (i) a first nucleic acid molecule comprising a cap gene encoding a first AAV capsid protein, wherein the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, AAV capsid proteins VP1, VP2 and VP3 of animal AAV. Petition 870260072813, dated 22 / 07 / 2026, p.265 / 407 12 / 52 non-primate, and wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2, and the AAV capsid protein VP3 comprises a selected modification of the group consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV capsid, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV capsid and / or creates a detectable label, and (d) any combination of (a), (b), and (c); and (ii) a second nucleic acid molecule comprising a cap gene encoding a second reference AAV capsid protein, wherein the second reference AAV capsid protein does not have the modification of the first AAV capsid protein, optionally wherein the first nucleic acid molecule and the second nucleic acid molecule are present in a ratio between 1:1 and 1:

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13. Composition for producing a recombinant chimeric mosaic capsid of AAV, characterized in that it comprises, in a given ratio: (i) a first nucleic acid molecule comprising a cap gene encoding a first AAV capsid protein, wherein the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, and wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2 or the AAV capsid protein VP3 comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids of a capsid protein of Petition 870260072813, of 22 / 07 / 2026, p. 266 / 407 13 / 52 an AAV from a non-primate animal, and (ii) at least 5 amino acids showing 100% identity with an AAV from a primate animal;and wherein the first AAV capsid protein comprises a selected group modification consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV capsid, (b) a detectable label, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV capsid and / or creates a detectable label, (d) any combination of (a), (b) and (c); and (ii) a second nucleic acid molecule comprising a cap gene encoding a second reference AAV capsid protein, wherein the second reference AAV capsid protein does not possess the modification of the first AAV capsid protein, optionally wherein the first nucleic acid molecule and the second nucleic acid molecule are present in a ratio between 1:1 and 1:

15.

14. Packaging cell for producing recombinant mosaic particles of non-primate animal AAV, characterized in that it comprises: (i) a first nucleic acid molecule comprising a cap gene encoding a first AAV capsid protein, wherein the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, Petition 870260072813, dated 22 / 07 / 2026, p. 267 / 407 14 / 52 respectively, VP1, VP2 and VP3 capsid proteins of non-primate animal AAV, and wherein at least one of the VP1 capsid protein of AAV, the VP2 capsid protein of AAV and the VP3 capsid protein of AAV comprises a selected modification of the group consisting of: (a) a first member of a protein:protein linkage pair,wherein the protein:protein linkage pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b) and (c); (ii) a second nucleic acid molecule comprising a cap gene encoding a second reference AAV capsid protein, wherein the second reference AAV capsid protein does not possess the modification of the first AAV capsid protein, optionally wherein the first nucleic acid molecule and the second nucleic acid molecule are present in a ratio between 1:1 and 1:15; and (iii) a third nucleic acid molecule comprising a nucleotide sequence of interest flanked on at least one side by a first AAV ITR sequence that is recognized by one or more Rep proteins, 15. Packaging cell for producing mosaic chimeric recombinant AAV particles, characterized in that it comprises: (i) a first nucleic acid molecule comprising a cap gene encoding a first AAV capsid protein, wherein the first AAV capsid protein comprises a capsid protein Petition 870260072813, dated 22 / 07 / 2026, page 1. 268 / 407 15 / 52 VP1 of AAV, a VP2 capsid protein of AAV and / or a VP3 capsid protein of AAV, wherein at least one of the VP1 capsid protein of AAV, the VP2 capsid protein of AAV or the VP3 capsid protein of AAV comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids of a capsid protein of a non-primate animal AAV, and (ii) at least 5 amino acids exhibiting 100% identity with a primate animal AAV;and wherein the first AAV capsid protein comprises a selected group modification consisting of: (a) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, (d) any combination of (a), (b) and (c); (ii) a second nucleic acid molecule comprising a cap gene encoding a second reference AAV capsid protein, wherein the second reference AAV capsid protein does not possess the modification of the first AAV capsid protein, optionally wherein the first nucleic acid molecule and the second nucleic acid molecule are present in a ratio between 1:1 and 1:15;and (iii) a third nucleic acid molecule comprising a nucleotide sequence of interest flanked on at least one side by a first AAV ITR sequence that is recognized by one or more Rep proteins; 16. Packaging cell for producing particles Petition 870260072813, dated 07 / 22 / 2026, page. 269 / 407 16 / 52 recombinant mosaic AAVs from non-primate animals, characterized in that it comprises: (i) a first nucleic acid molecule comprising a cap gene encoding a first AAV capsid protein, wherein the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, non-primate animal AAV capsid proteins VP1, VP2 and VP3, and wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 comprises a selected modification of the group consisting of: (a) a first member of a protein:protein binding pair,wherein the protein:protein linkage pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b) and (c); (ii) a second nucleic acid molecule comprising a cap gene encoding a second reference AAV capsid protein, wherein the second reference AAV capsid protein does not have the modification of the first AAV capsid protein, optionally wherein the first nucleic acid molecule and the second nucleic acid molecule are present in a ratio between 1:1 and 1:15; and (iii) a third nucleic acid molecule comprising Petition 870260072813, dated 22 / 07 / 2026, p. 270 / 407 17 / 52 a nucleotide sequence of interest flanked on at least one side by a first ITR sequence of AAV that is recognized by one or more Rep proteins,where the first ITR sequence of AAV comprises at least 15 nucleotides exhibiting at least 90% identity with at least 15 nucleotides of an ITR sequence of AAV from a primate animal.

17. Method for producing a mosaic chimeric recombinant particle of AAV, characterized in that it comprises: (I) transfecting a packaging cell with: (a) a nucleic acid molecule comprising a cap gene encoding a first AAV capsid protein comprising an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2 or the AAV capsid protein VP3 comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids of a capsid protein from a non-primate animal AAV, and (ii) at least 5 amino acids exhibiting 100% identity with a primate animal AAV;and wherein the first AAV capsid protein comprises a selected group modification consisting of: (i) a first member of a protein:protein linkage pair, wherein the protein:protein linkage pair directs the tropism of the AAV particle, (ii) a detectable label, (iii) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, Petition 870260072813, 22 / 07 / 2026, p. 271 / 407 18 / 52 (iv) any combination of (i), (ii) and (iii); and (b) a nucleic acid molecule comprising a cap gene encoding a second reference AAV capsid protein, wherein the second reference AAV capsid protein does not possess the modification of the first AAV capsid protein;and (c) a nucleic acid molecule comprising a nucleotide sequence of interest flanked on at least one side by a first ITR sequence of AAV that is recognized by one or more Rep proteins; and (II) growing the packaging cell under conditions sufficient for the production of an AAV particle.

18. Method for producing a recombinant mosaic particle of non-primate animal AAV, characterized in that it comprises: (I) transfecting a packaging cell with: (a) a nucleic acid molecule comprising a cap gene encoding a first AAV capsid protein comprising an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, non-primate animal AAV capsid proteins VP1, VP2 and VP3, and wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 comprises a selected group modification consisting of: (i) a first member of a pair of protein:protein binding, wherein the protein:protein binding pair directs the tropism of the AAV particle, Petition 870260072813,(ii) a detectable label, (iii) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (iv) any combination of (i), (ii) and (iii); and (b) a nucleic acid molecule comprising a cap gene encoding a second reference AAV capsid protein, wherein the second reference AAV capsid protein does not possess the modification of the first AAV capsid protein; and (c) a nucleic acid molecule comprising a nucleotide sequence of interest flanked on at least one side by a first AAV ITR sequence that is recognized by one or more Rep proteins; and (II) cultivate the packaging cell under conditions sufficient for the production of an AAV particle.

19. Method for producing a recombinant mosaic particle of non-primate animal AAV, characterized in that it comprises: (I) transfecting a packaging cell with: (a) a nucleic acid molecule comprising a cap gene encoding a first AAV capsid protein comprising an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, non-primate animal AAV capsid proteins VP1, VP2 and VP3, and wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 comprises a selected modification of the group consisting of: Petition 870260072813, of 22 / 07 / 2026, page 273 / 407 20 / 52 (i) a first member of a protein-linking pair,(a) a nucleic acid molecule comprising a cap gene encoding a second reference AAV capsid protein, wherein the second reference AAV capsid protein does not possess the modification of the first AAV capsid protein; and (b) a nucleic acid molecule comprising a nucleotide sequence of interest flanked on at least one side by a first AAV ITR sequence that is recognized by one or more Rep proteins,wherein the first AAV ITR sequence comprises at least 15 nucleotides exhibiting at least 90% identity with at least 15 nucleotides of an AAV ITR sequence from a primate animal AAV; and (II) cultivate the packaging cell under conditions sufficient for the production of an AAV particle.

20. Method for producing a chimeric recombinant AAV particle that is resistant to neutralizing antibodies, characterized in that the method comprises: (I) transfecting a packaging cell with: (a) a nucleic acid molecule comprising a cap gene encoding a first AAV capsid protein comprising an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2 or the Petition 870260072813, dated 22 / 07 / 2026, p. 274 / 407 21 / 52 AAV capsid protein VP3 comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids from a capsid protein of a non-primate animal AAV, and (ii) at least 5 amino acids exhibiting 100% identity with a primate animal AAV;and wherein the first AAV capsid protein comprises a selected group modification consisting of: (i) a first member of a protein-binding pair, wherein the protein-binding pair directs the tropism of the AAV particle, (ii) a detectable label, (iii) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, (iv) any combination of (i), (ii) and (iii); and (b) a nucleic acid molecule comprising a nucleotide sequence of interest flanked on at least one side by an AAV first ITR that is recognized by one or more Rep proteins;and (II) cultivate the packaging cell under conditions sufficient for the production of a recombinant AAV particle, wherein the chimeric recombinant AAV particle requires at least 7 times more IgG for neutralization compared with a control AAV particle, wherein the control AAV particle is of the same serotype as the chimeric recombinant AAV particle but does not comprise an amino acid sequence from a non-primate animal AAV, and wherein neutralization is defined as an IgG concentration that results in 50% or more inhibition of transfection, as assessed by the expression of the nucleotide sequence of interest in a target cell Petition 870260072813, dated 22 / 07 / 2026, p. 275 / 407 22 / 52 transfected with the chimeric recombinant AAV particle.; 21. Use of a chimeric recombinant AAV particle that is resistant to neutralizing antibodies, characterized in that it is for delivering a nucleic acid molecule to a target cell, wherein a chimeric recombinant AAV capsid protein of the chimeric recombinant AAV particle comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2 or the AAV capsid protein VP3 comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids of a capsid protein of a non-primate animal AAV, and (ii) at least 5 amino acids exhibiting 100% identity with a primate animal AAV; and wherein the AAV chimeric recombinant capsid protein comprises a selected group modification consisting of: (a) a first member of a protein-linking pair,wherein the protein-binding pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, (d) any combination of (a), (b) and (c), wherein the chimeric recombinant AAV particle requires at least 7 times more IgG for neutralization compared with a control AAV particle, wherein the control AAV particle is of the same serotype as the chimeric recombinant AAV particle but does not comprise an amino acid sequence from a non-primate animal AAV, and Petition 870260072813, dated 22 / 07 / 2026, p. 276 / 407 23 / 52 where neutralization is defined as an IgG concentration that results in 50% or more inhibition of transfection, as assessed by the expression of a nucleotide of interest in a target cell transfected with the chimeric recombinant AAV particle,optionally, wherein the capsid of the chimeric recombinant AAV particle comprises a targeting linker that specifically binds to a protein expressed on the surface of the target cell, wherein the nucleic acid molecule comprises a nucleotide sequence encoding: (a) a reporter selected from the group consisting of: β-galactosidase, green fluorescent protein (GFP), enhanced green fluorescent protein (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), Emerald, CyPet, cyan fluorescent protein (CFP), Cerulean, TSapphire, luciferase, alkaline phosphatase and a combination thereof; or (b) a therapeutic protein, a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof,an antisense oligonucleotide, a ribozyme, an RNAi molecule, or a shRNA molecule.

22. In vitro method for redirecting, to a target cell, a chimeric recombinant AAV particle that is resistant to neutralizing antibodies and encapsulates a nucleic acid molecule, characterized in that the method comprises placing the target cell in contact with the chimeric recombinant AAV particle, wherein a chimeric recombinant AAV capsid of the chimeric recombinant AAV particle comprises a targeting ligand that specifically binds to a protein expressed in Petition 870260072813, dated 07 / 22 / 2026, p. 277 / 407 24 / 52 target cell surface, wherein the recombinant chimeric capsid protein of the recombinant chimeric AAV particle comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein at least one of the AAV capsid proteins VP1,The AAV capsid protein VP2 or the AAV capsid protein VP3 comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids from a non-primate animal AAV capsid protein, and (ii) at least 5 amino acids exhibiting 100% identity with a primate animal AAV; and wherein the chimeric recombinant AAV capsid protein comprises a selected group modification consisting of: (a) a first member of a protein-binding pair, wherein the protein-binding pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, (d) any combination of (a), (b) and (c), wherein the chimeric recombinant AAV particle requires at least 7 times more IgG for neutralization compared with a control AAV particle,wherein the control AAV particle is of the same serotype as the chimeric recombinant AAV particle, but does not comprise an amino acid sequence from a non-primate animal AAV, and wherein neutralization is defined as an IgG concentration that results in 50% or more inhibition of transfection, as assessed by the expression of a nucleotide of interest in a target cell transfected with Petition 870260072813, dated 07 / 22 / 2026, p. 278 / 407 25 / 52 the chimeric recombinant particle of AAV, wherein the nucleic acid molecule comprises a nucleotide sequence encoding: (a) a reporter selected from the group consisting of: βgalactosidase, green fluorescent protein (GFP), enhanced green fluorescent protein (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP),(a) enhanced yellow fluorescent protein (eYFP), Emerald, CyPet, cyan fluorescent protein (CFP), Cerulean, TSapphire, luciferase, alkaline phosphatase and a combination thereof; or (b) a therapeutic protein, a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

23. Use of a chimeric recombinant AAV particle that is resistant to neutralizing antibodies, characterized in that it is in the preparation of a medicament to treat a disease or disorder suitable for treatment with gene therapy, wherein a chimeric recombinant AAV capsid protein of the chimeric recombinant AAV particle comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2 or the AAV capsid protein VP3 comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids of a capsid protein of a non-primate animal AAV, and (ii) at least 5 amino acids exhibiting 100% identity with a primate animal AAV; and Petition 870260072813, dated 07 / 22 / 2026,page. 279 / 407 26 / 52 wherein the chimeric recombinant AAV capsid protein comprises a selected group modification consisting of: (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, (d) any combination of (a), (b) and (c), wherein the chimeric recombinant AAV particle requires at least 7 times more IgG for neutralization compared with a control AAV particle, wherein the control AAV particle is of the same serotype as the chimeric recombinant AAV particle but does not comprise an amino acid sequence from a non-primate animal AAV, and wherein neutralization is defined as an IgG concentration that results in 50% or more inhibition of transfection,as assessed by the expression of a nucleotide of interest in a target cell transfected with the chimeric recombinant AAV particle, optionally where the disease or disorder is a chronic or genetic disease, an enzyme deficiency, an immune deficiency, a pathogen infection and / or cancer.

24. Method for producing a recombinant non-human primate AAV particle that is resistant to neutralizing antibodies, characterized in that the method comprises: (I) transfecting a packaging cell with: (a) a nucleic acid molecule comprising a cap gene encoding a first AAV capsid protein comprising an AAV capsid protein VP1, an AAV capsid protein VP2 Petition 870260072813, dated 22 / 07 / 2026, page. 280 / 407 27 / 52 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, AAV capsid proteins VP1, VP2 and VP3 from non-primate animals, and wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 comprises a selected modification of the group consisting of: (i) a first member of a protein-linking pair,wherein the protein-binding pair directs the tropism of the AAV particle, (ii) a detectable label, (iii) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (iv) any combination of (a), (b) and (c); and (b) a nucleic acid molecule comprising a nucleotide sequence of interest flanked on at least one side by a first ITR sequence of AAV that is recognized by one or more Rep proteins; and (ii) cultivating the packaging cell under conditions sufficient for the production of a recombinant AAV particle, wherein the recombinant AAV particle requires at least 7 times more IgG for neutralization compared with a control AAV particle, wherein the control AAV particle is of the same serotype as the recombinant AAV particle but does not comprise an amino acid sequence of a non-primate animal AAV,and where neutralization is defined as an IgG concentration that results in 50% or more inhibition of transfection, as assessed by the expression of the nucleotide sequence of interest in a target cell transfected with the recombinant AAV particle.

25. Use of a recombinant non-primate animal AAV particle that is resistant to neutralizing antibodies, characterized in that it is for delivering a nucleic acid molecule to a target cell, wherein a recombinant non-primate animal AAV capsid protein of the recombinant non-primate animal AAV particle comprises a VP1 AAV capsid protein, a VP2 AAV capsid protein and / or a VP3 AAV capsid protein, wherein the VP1 AAV capsid protein, the VP2 AAV capsid protein and the VP3 AAV capsid protein are, respectively, VP1, VP2 and VP3 AAV capsid proteins, and wherein at least one of the VP1 AAV capsid protein, the VP2 AAV capsid protein and the VP3 AAV capsid protein comprises a selected modification of the group consisting of: (i) a first member of a protein-binding pair, where the protein-binding pair directs the tropism of the AAV particle,(ii) a detectable label, (iii) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (iv) any combination of (a), (b) and (c), wherein the recombinant non-primate animal AAV particle requires at least 7 times more IgG for neutralization compared with a control AAV particle, wherein the control AAV particle is of the same serotype as the recombinant non-primate animal AAV particle but does not comprise an amino acid sequence of a non-primate animal AAV, and wherein neutralization is defined as a concentration of IgG Petition 870260072813, dated 22 / 07 / 2026, p. 282 / 407 29 / 52 which results in 50% or more inhibition of transfection, as assessed by the expression of a nucleotide of interest in a target cell transfected with the recombinant non-primate animal AAV particle,optionally, wherein the recombinant non-primate animal AAV capsid of the recombinant non-primate animal AAV particle comprises a targeting linker that specifically binds to a protein expressed on the surface of the target cell, wherein the nucleic acid molecule comprises a nucleotide sequence encoding: (a) a reporter selected from the group consisting of: β-galactosidase, green fluorescent protein (GFP), enhanced green fluorescent protein (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), Emerald, CyPet, cyan fluorescent protein (CFP), Cerulean, TSapphire, luciferase, alkaline phosphatase and a combination thereof; or (b) a therapeutic protein, a suicide gene, an antibody or a fragment thereof,a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

26. In vitro method for redirecting, to a target cell, a recombinant non-primate animal AAV particle that is resistant to neutralizing antibodies and encapsulates a nucleic acid molecule, characterized in that the method comprises placing the target cell in contact with the recombinant non-primate animal AAV particle, wherein a recombinant non-primate animal AAV capsid of the recombinant non-primate animal AAV particle comprises a targeting linker that specifically binds to a protein. Petition 870260072813, dated 07 / 22 / 2026, p. 283 / 407 30 / 52 expressed on the target cell surface, wherein a recombinant non-primate animal AAV capsid protein of the recombinant non-primate animal AAV particle comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1,AAV capsid protein VP2 and AAV capsid protein VP3 are, respectively, AAV capsid proteins VP1, VP2, and VP3 from non-primate animals, wherein at least one of the AAV capsid protein VP1, AAV capsid protein VP2, and AAV capsid protein VP3 comprises a selected group modification consisting of: (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b), and (c); and wherein the recombinant non-primate animal AAV particle requires at least 7 times more IgG for neutralization compared to a control AAV particle, wherein the control AAV particle is of the same serotype as the recombinant non-primate animal AAV particle,but does not comprise an amino acid sequence of a non-primate animal AAV, and wherein neutralization is defined as an IgG concentration that results in 50% or more inhibition of transfection, as assessed by the expression of a nucleotide of interest in a target cell transfected with the recombinant non-primate animal AAV particle, Petition 870260072813, dated 07 / 22 / 2026, p. 284 / 407 31 / 52 wherein the nucleic acid molecule comprises a nucleotide sequence encoding: (a) a reporter selected from the group consisting of: βgalactosidase, green fluorescent protein (GFP), enhanced green fluorescent protein (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), Emerald, CyPet, cyan fluorescent protein (CFP), Cerulean, TSapphire,luciferase, alkaline phosphatase and a combination thereof; or (b) a therapeutic protein, a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

27. Use of a recombinant non-primate animal AAV particle that is resistant to neutralizing antibodies, characterized by being in the preparation of a medicament to treat a disease or disorder suitable for treatment with gene therapy, wherein a recombinant non-primate animal AAV capsid protein of the recombinant non-primate animal AAV particle comprises a VP1 AAV capsid protein, a VP2 AAV capsid protein and / or a VP3 AAV capsid protein, wherein the VP1 AAV capsid protein, the VP2 AAV capsid protein and the VP3 AAV capsid protein are, respectively, VP1, VP2 and VP3 AAV capsid proteins from non-primate animals, and wherein at least one of the VP1 AAV capsid protein, the VP2 AAV capsid protein and the VP3 AAV capsid protein comprises a selected modification of the group consisting in: Petition 870260072813, dated 07 / 22 / 2026,page. 285 / 407 32 / 52 (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b) and (c), wherein the recombinant non-primate animal AAV particle requires at least 7 times more IgG for neutralization compared with a control AAV particle, wherein the control AAV particle is of the same serotype as the recombinant non-primate animal AAV particle but does not comprise an amino acid sequence of a non-primate animal AAV, and wherein neutralization is defined as an IgG concentration that results in 50% or more inhibition of transfection, as assessed by the expression of a nucleotide of interest in a target cell transfected with the recombinant AAV particle from a non-primate animal,Optionally, the disease or disorder may be a chronic or genetic disease, an enzyme deficiency, an immune deficiency, a pathogen infection, and / or cancer.

28. Use of a chimeric recombinant AAV mosaic particle, characterized in that it is for delivering a nucleic acid molecule to a target cell, wherein the chimeric recombinant AAV mosaic particle comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid molecule comprising an AAV ITR sequence, wherein: (A) the first AAV capsid protein comprises a Petition 870260072813, dated 22 / 07 / 2026, page. 286 / 407 33 / 52 AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein at least one of the AAV capsid proteins VP1,The AAV capsid protein VP2 or the AAV capsid protein VP3 comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids of a non-primate animal AAV capsid protein, and (ii) at least 5 amino acids exhibiting 100% identity with a primate animal AAV capsid protein; and wherein the first AAV capsid protein comprises a selected group modification consisting of: (i) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (ii) a detectable label, (iii) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, (iv) any combination of (i), (ii) and (iii); and (B) the second reference AAV capsid protein is the same as the first AAV capsid protein, except for the absence of said modification,wherein the mosaic chimeric recombinant AAV particle is capable of infecting a mammalian host, and optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15, wherein the nucleic acid molecule comprises a nucleotide sequence encoding: (a) a reporter selected from the group consisting of: β-galactosidase, green fluorescent protein (GFP), green fluorescent protein Petition 870260072813, dated 22 / 07 / 2026, p. 287 / 407 34 / 52 enhanced (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), Emerald, CyPet, cyan fluorescent protein (CFP), Cerulean, TSapphire, luciferase,alkaline phosphatase and a combination thereof; or (b) a therapeutic protein, a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

29. Use of a non-primate animal AAV mosaic recombinant particle, characterized in that it is for delivering a nucleic acid molecule to a target cell, wherein the non-primate animal AAV mosaic recombinant particle comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid molecule comprising an AAV ITR sequence, wherein: (A) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, capsid proteins VP1, VP2 and VP3 of non-primate animal AAV,and wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2, and the AAV capsid protein VP3 comprises a selected modification from the group consisting of: Petition 870260072813, 22 / 07 / 2026, p. 288 / 407 35 / 52 (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b), and (c); and (B) the second reference AAV capsid protein is the same as the first AAV capsid protein, except for the absence of said modification, wherein the recombinant mosaic AAV particle from a non-primate animal is capable of infecting a mammalian host,and optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15, wherein the nucleic acid molecule comprises a nucleotide sequence encoding: (a) a reporter selected from the group consisting of: βgalactosidase, green fluorescent protein (GFP), enhanced green fluorescent protein (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), Emerald, CyPet, cyan fluorescent protein (CFP), Cerulean, TSapphire, luciferase, alkaline phosphatase and a combination thereof; or (b) a therapeutic protein, a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme,an RNAi molecule or a shRNA molecule.

30. Use of a recombinant particle in AAV mosaic Petition 870260072813, dated 07 / 22 / 2026, page. 289 / 407 36 / 52 non-primate animal, characterized in that it is for delivering a nucleic acid molecule to a target cell, wherein the non-primate animal AAV mosaic recombinant particle comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid molecule comprising an AAV ITR sequence, wherein: (A) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, VP1 capsid proteins, VP2 and VP3 of non-primate animal AAV,and wherein at least one of the AAV capsid protein VP1, the AAV capsid protein VP2, and the AAV capsid protein VP3 comprises a selected group modification consisting of: (a) a first member of a protein-binding pair, wherein the protein-binding pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b), and (c); and (B) the second reference AAV capsid protein is the same as the first AAV capsid protein, except for the absence of said modification, and (C) the AAV ITR sequence comprises at least 15 nucleotides exhibiting at least 90% identity with at least 15 nucleotides of an AAV ITR sequence from a primate animal AAV,wherein the recombinant mosaic AAV particle from a non-primate animal is capable of infecting a mammalian host, optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15, and wherein the nucleic acid molecule comprises a nucleotide sequence encoding: (a) a reporter selected from the group consisting of: βgalactosidase, green fluorescent protein (GFP), enhanced green fluorescent protein (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), Emerald, CyPet, cyan fluorescent protein (CFP), Cerulean, TSapphire, luciferase, phosphatase alkaline and a combination thereof; or (b) a therapeutic protein, a suicide gene,an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

31. Chimeric recombinant particle in AAV mosaic, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid sequence comprising an AAV ITR sequence, wherein: (A) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein at least one of the Petition 870260072813, dated 22 / 07 / 2026, p. 291 / 407 38 / 52 AAV capsid protein VP1, AAV capsid protein VP2 or AAV capsid protein VP3 comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids of an avian AAV capsid (AAAV),and (ii) at least 5 amino acids exhibiting 100% identity with a primate animal AAV; and wherein the first AAV capsid protein comprises a selected group modification consisting of: (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, (d) any combination of (a), (b) and (c); (B) the second reference AAV capsid protein is the same as the first AAV capsid protein, except for the absence of said modification, wherein the mosaic chimeric recombinant AAV particle is capable of infecting a mammalian host, and optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15,optionally wherein the first member of the protein-linking pair is linked to a second cognate member of the protein-linking pair by an isopeptide linkage, optionally wherein the second cognate member of the protein-linking pair is operationally linked to a targeting ligand that specifically binds to a protein expressed on the surface of a target cell; and Petition 870260072813, dated 22 / 07 / 2026, p. 292 / 407 39 / 52 (C) the nucleic acid molecule encodes a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule., 32. Recombinant mosaic particle of AAV, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid sequence comprising an AAV ITR sequence, wherein: (A) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, AAAV capsid proteins VP1, VP2 and VP3, and wherein at least one of the AAAV capsid proteins VP1,The AAAV capsid protein VP2 and the AAAV capsid protein VP3 comprise a selected modification of the group consisting of: (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b) and (c); (B) the second reference AAV capsid protein is the same as the first AAV capsid protein, except for the absence of said modification, wherein the recombinant mosaic AAV particle is capable Petition 870260072813, dated 22 / 07 / 2026, p. 293 / 407 40 / 52 of infecting a mammalian host, and optionally in which the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15,optionally wherein the first member of the protein-linking pair is linked to a second cognate member of the protein-linking pair by an isopeptide linkage, optionally wherein the second cognate member of the protein-linking pair is operationally linked to a targeting ligand that specifically binds to a protein expressed on the surface of a target cell; and (C) the nucleic acid molecule encodes a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

33. Recombinant mosaic particle of AAV, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid sequence comprising an AAV ITR sequence, wherein: (A) the AAV ITR sequence comprises at least 15 nucleotides exhibiting at least 90% identity with at least 15 nucleotides of an AAV ITR sequence from a primate animal AAV;and (B) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, Petition 870260072813, dated 22 / 07 / 2026, page. 294 / 407 41 / 52 respectively, AAAV capsid proteins VP1, VP2 and VP3, and wherein at least one of the AAAV capsid protein VP1, the AAAV capsid protein VP2 and the AAAV capsid protein VP3 comprises a selected modification of the group consisting of: (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b) and (c);(C) the second reference AAV capsid protein is the same as the first AAV capsid protein, except for the absence of said modification, wherein the recombinant mosaic AAV particle is capable of infecting a mammalian host, and optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15, optionally wherein the first member of the protein-linking pair is linked to a second cognate member of the protein-linking pair by an isopeptide linkage, optionally wherein the second cognate member of the protein-linking pair is operationally linked to a targeting linker that specifically binds to a protein expressed on the surface of a target cell;and (D) the nucleic acid molecule encodes a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule. Petition 870260072813, dated 22 / 07 / 2026, pp. 295 / 407 42 / 52; 34. Chimeric recombinant AAV mosaic particle, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein: (A) the first AAV capsid protein comprises an AAV VP1 capsid protein, an AAV VP2 capsid protein and / or an AAV VP3 capsid protein, wherein at least one of the AAV VP1 capsid protein, the AAV VP2 capsid protein or the AAV VP3 capsid protein comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids of a capsid protein of sea ​​lion, and (ii) at least 5 amino acids showing 100% identity with an AAV from a primate animal;and wherein the first AAV capsid protein comprises a selected group modification consisting of: (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, (d) any combination of (a), (b) and (c); and (B) the second reference AAV capsid protein is the same as the first AAV capsid protein except for the absence of said modification, wherein the mosaic chimeric recombinant AAV particle is capable of infecting a mammalian host, and Petition 870260072813, dated 22 / 07 / 2026, p. 296 / 407 43 / 52 optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15;and (C) the nucleic acid molecule encodes a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.; 35. Recombinant mosaic particle of AAV, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein: (A) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, VP1, VP2 and VP3 capsid proteins of sea lion AAV, and wherein at least one of the capsid proteins VP1 of AAV sea lion,The sea lion AAV capsid protein VP2 and the sea lion AAV capsid protein VP3 comprise a selected modification of the group consisting of: (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b) and (c); and (B) the second reference AAV capsid protein is the same as the first AAV capsid protein except for the absence of said modification, wherein the recombinant mosaic AAV particle is capable of infecting a mammalian host,and optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15; and (C) the nucleic acid molecule encodes a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

36. Recombinant mosaic particle of AAV, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein: (A) the AAV ITR sequence comprises at least 15 nucleotides exhibiting at least 90% identity with at least 15 nucleotides of the AAV ITR sequence from a primate animal AAV; (B) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, Petition 870260072813, dated 22 / 07 / 2026, page 298 / 407 45 / 52 respectively,capsid proteins VP1, VP2 and VP3 of sea lion AAV, wherein at least one of the sea lion AAV capsid protein VP1, the sea lion AAV capsid protein VP2 and the sea lion AAV capsid protein VP3 comprises a selected group modification consisting of: (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b) and (c); and (C) the second reference AAV capsid protein is the same as the first AAV capsid protein, except for the absence of said modification, wherein the recombinant mosaic AAV particle is capable of infecting a mammalian host,and optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15; and (D) the nucleic acid molecule encodes a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

37. Chimeric recombinant mosaic particle of AAV, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a sequence of Petition 870260072813, dated 07 / 22 / 2026, page 1. 299 / 407 46 / 52 nucleic acid comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein: (A) the first AAV capsid protein comprises an AAV VP1 capsid protein, an AAV VP2 capsid protein and / or an AAV VP3 capsid protein, wherein at least one of the AAV VP1 capsid protein, the AAV VP2 capsid protein or the AAV VP3 capsid protein comprises (i) at least 5 amino acids exhibiting 100% identity with at least 5 amino acids of a bearded dragon capsid protein,and (ii) at least 5 amino acids exhibiting 100% identity with a primate animal AAV; and wherein the first AAV capsid protein comprises a selected group modification consisting of: (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, preferably wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, (d) any combination of (a), (b) and (c); (B) the second reference AAV capsid protein is the same as the first AAV capsid protein except for the absence of said modification, wherein the mosaic chimeric recombinant AAV particle is capable of infecting a mammalian host,optionally wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15; and (C) the nucleic acid molecule encodes a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

38. Recombinant mosaic particle of AAV, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein: (A) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, AAV capsid proteins VP1, VP2 and VP3 of bearded dragon, and wherein at least one of the capsid proteins VP1 of AAV of bearded dragon,The bearded dragon AAV capsid protein VP2 and the bearded dragon AAV capsid protein VP3 comprise a selected group modification consisting of: (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b) and (c); and (B) the second reference AAV capsid protein is the same as the first AAV capsid protein except for the absence of said modification, Petition 870260072813, dated 22 / 07 / 2026, p. 301 / 407 48 / 52 in which the recombinant mosaic particle of AAV is capable of infecting a mammalian host,optionally, wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15; and (C) the nucleic acid molecule encodes a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

39. Recombinant mosaic particle of AAV, characterized in that it comprises (i) a first AAV capsid protein, (ii) a second reference AAV capsid protein and (iii), packaged within an AAV capsid comprising the first and second reference AAV capsid proteins, a nucleic acid sequence comprising an AAV Inverted Terminal Repeat (ITR) sequence, wherein: (A) the AAV ITR sequence comprises at least 15 nucleotides exhibiting at least 90% identity with at least 15 nucleotides of the AAV ITR sequence from a primate animal AAV; (B) the first AAV capsid protein comprises an AAV capsid protein VP1, an AAV capsid protein VP2 and / or an AAV capsid protein VP3, wherein the AAV capsid protein VP1, the AAV capsid protein VP2 and the AAV capsid protein VP3 are, respectively, AAV capsid proteins VP1, VP2 and VP3 from bearded dragon,and wherein at least one of the bearded dragon AAV capsid protein VP1, the bearded dragon AAV capsid protein VP2, and the bearded dragon AAV capsid protein VP3 comprises Petition 870260072813, dated 22 / 07 / 2026, pp. 302 / 407 49 / 52 a selected modification of the group consisting of: (a) a first member of a protein-linking pair, wherein the protein-linking pair directs the tropism of the AAV particle, (b) a detectable label, (c) a point mutation, wherein the point mutation reduces the natural tropism of the AAV particle and / or creates a detectable label, and (d) any combination of (a), (b), and (c); (C) the second reference AAV capsid protein is the same as the first AAV capsid protein, except for the absence of said modification, where the recombinant mosaic AAV particle is capable of infecting a mammalian host,optionally, wherein the first AAV capsid protein and the second reference AAV capsid protein are present in a ratio between 1:1 and 1:15; and (D) the nucleic acid molecule encodes a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

40. Use of a sea lion AAV particle, characterized in that it is for delivering a nucleic acid molecule to a target cell, comprising placing the target cell in contact with a non-chimeric sea lion AAV capsid encapsulating the nucleic acid molecule, wherein the non-chimeric sea lion AAV capsid is constituted entirely of non-chimeric sea lion AAV capsid proteins, and wherein the nucleic acid molecule comprises a nucleotide sequence encoding: Petition 870260072813, dated 07 / 22 / 2026, p.303 / 407 50 / 52 (a) a reporter selected from the group consisting of: β-galactosidase, green fluorescent protein (GFP), enhanced green fluorescent protein (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), Emerald, CyPet, cyan fluorescent protein (CFP), Cerulean, TSapphire, luciferase, alkaline phosphatase and a combination thereof; or (b) a therapeutic protein, a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

41. Use of an avian AAV particle (AAAV), characterized in that it is for delivering a nucleic acid molecule to a target cell, comprising bringing the target cell into contact with a non-chimeric AAAV capsid encapsulating the nucleic acid molecule, wherein the non-chimeric AAAV capsid is constituted entirely of non-chimeric AAAV capsid proteins, and wherein the nucleic acid molecule comprises a nucleotide sequence encoding: (a) a reporter selected from the group consisting of: β-galactosidase, green fluorescent protein (GFP), enhanced green fluorescent protein (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), Emerald, CyPet, cyan fluorescent protein (CFP), Cerulean, TSapphire, luciferase,alkaline phosphatase and a combination thereof; or (b) a therapeutic protein, a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

42. Use of a bearded dragon AAV particle, characterized in that it is for delivering a nucleic acid molecule to a target cell, comprising bringing the target cell into contact with a non-chimeric bearded dragon AAV capsid encapsulating the nucleic acid molecule, wherein the non-chimeric bearded dragon AAV capsid is constituted entirely of non-chimeric bearded dragon AAV capsid proteins, and wherein the nucleic acid molecule comprises a nucleotide sequence encoding: (a) a reporter selected from the group consisting of: β-galactosidase, green fluorescent protein (GFP), enhanced green fluorescent protein (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), Emerald, CyPet,(a) cyanofluorescent protein (CFP), Cerulean, TSapphire, luciferase, alkaline phosphatase and a combination thereof; or (b) a therapeutic protein, a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

43. Use of a chimeric particle of human / non-human animal AAV, characterized by the fact that it is for delivering a nucleic acid molecule to an inner ear cell, wherein the human AAV is AAV2, wherein the non-human animal AAV is sea lion AAV, and Petition 870260072813, dated 07 / 22 / 2026, p.305 / 407 52 / 52 wherein the nucleic acid molecule comprises a nucleotide sequence encoding: (a) a reporter selected from the group consisting of: βgalactosidase, green fluorescent protein (GFP), enhanced green fluorescent protein (eGFP), MmGFP, blue fluorescent protein (BFP), enhanced blue fluorescent protein (eBFP), mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, yellow fluorescent protein (YFP), enhanced yellow fluorescent protein (eYFP), Emerald, CyPet, cyan fluorescent protein (CFP), Cerulean, TSapphire, luciferase, alkaline phosphatase and a combination thereof; or (b) a therapeutic protein, a suicide gene, an antibody or a fragment thereof, a CRISPR / Cas system or a portion or portions thereof, an antisense oligonucleotide, a ribozyme, an RNAi molecule or a shRNA molecule.

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