Modified AAV capsid proteins for treating arthritis diseases

Abstract

The present invention relates to recombinant adeno-associated virus (rAAV) virions for gene therapy, wherein the rAAV virions comprise novel capsid proteins. In particular, the present invention relates to the use of such virions in gene therapy for the treatment of arthritic diseases, such as, for example, rheumatoid arthritis or symptoms thereof, preferably by intra-articular administration.

Description

Technical Field

[0001] The present invention relates to the field of gene therapy based on recombinant adeno-associated virus (rAAV), and in particular to the use of mutant capsid rAAV in treating or preventing arthritis diseases. Background Art

[0002] Recombinant adeno-associated virus (rAAV) vectors have been shown to have excellent safety and efficacy characteristics for delivering genes in humans. Therefore, rAAV vectors have been widely used in in vivo gene therapy and have shown safety and effectiveness in preclinical models and clinical trials. rAAV vectors have been successfully used in many gene therapy clinical trials for a range of diseases, including hemophilia B, hemophilia A, cystic fibrosis, α1 antitrypsin deficiency, spinal muscular atrophy (SMA), Parkinson's disease, Duchenne muscular dystrophy and Leber congenital amaurosis (Selot et al., Current Pharmaceutical Biotechnology, 2013, 14, 1072-1082). Alipoven (Alipogene tiparvovec, uniQure) has received marketing authorization in Europe as a gene therapy for the treatment of lipoprotein lipase deficiency (LPLD). Subsequently, Talimogene laherparepvec (T-Vec, a herpes virus-based gene therapy for the treatment of skin cancer) was approved. Amgen) and Strimvelis (GSK), an ex vivo stem cell-based retroviral gene therapy for the treatment of ADA-SCID, received approval for gene therapy drugs.

[0003] Gene therapy based on rAAV vectors has also been applied to rheumatoid arthritis (RA), a chronic inflammatory disease that affects approximately 1% of the population. The pathology of RA is widespread in the synovial joints. The localized nature of the joints makes in vivo gene therapy very attractive. Therapies that provide anti-inflammatory proteins designed to shift the balance in RA toward an anti-inflammatory state have been applied.

[0004] Much work has focused on developing AAV capsid proteins with desirable properties. Such properties may include higher transduction efficiency, tissue / organ tropism, off-targeting of unwanted tissues / organs, or avoidance of pre-existing neutralizing antibodies.

[0005] However, there is still a need in the art to further improve rAAV gene therapy vectors. Specifically, there is a need to improve the use of rAAV gene therapy vectors in arthritis diseases, and more precisely, there is a need to improve the efficiency of delivering genetic material to targeted tissues (such as synovial joints or specific cell types within synovial joints, preferably to fibroblast-like synoviocytes (FLS)). Summary of the Invention

[0006] In some aspects, the invention relates to the following numbered embodiments:

[0007] Embodiment 1. A recombinant adeno-associated virus (rAAV) virion comprising a modified capsid protein and a promoter operably linked to a nucleotide sequence encoding a gene product of interest, wherein the rAAV virion is used to treat or prevent an arthritis disease or for treating or preventing symptoms associated with an arthritis disease, wherein the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein, preferably wherein the product of interest is an immunosuppressant.

[0008] Embodiment 2. The rAAV virion for use according to embodiment 1, wherein the amino acid sequence Z is:

[0009] a. comprising or consisting of an amino acid residue sequence of formula I:

[0010] y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A

[0011] wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and

[0012] b. present at positions corresponding to amino acid residues at positions 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein.

[0013] Embodiment 3. The rAAV virion for use according to embodiment 1 or 2, wherein the gene product of interest is an IL-6 inhibitor.

[0014] Embodiment 4. The rAAV virion for use according to embodiment 1 or 2, wherein the gene product of interest is a TNFα inhibitor.

[0015] Embodiment 5. The rAAV virion for use according to embodiment 1 or 2, wherein the gene product of interest is an IL-1 inhibitor.

[0016] Embodiment 6. The rAAV virion for use according to embodiment 3, wherein the IL-6 inhibitor is selected from the group consisting of an IL-6 receptor antagonist, a humanized anti-IL-6 monoclonal antibody, a chimeric anti-IL-6 monoclonal antibody, a humanized rabbit anti-IL-6 monoclonal antibody and a soluble IL-6 receptor, preferably at least one of which

[0017] i) the IL-6 receptor antagonist is at least one of tocilizumab and sarilumab;

[0018] ii) the humanized anti-IL-6 monoclonal antibody is at least one of olokizumab and sirukumab;

[0019] iii) the chimeric anti-IL-6 monoclonal antibody is siltucimab; and

[0020] iv) The humanized rabbit anti-IL-6 monoclonal antibody is clazakizumab.

[0021] Embodiment 7. The rAAV virion for use according to embodiment 4, wherein the TNFα inhibitor is selected from the group consisting of etanercept, infliximab, adalimumab, certilizumab pegol and golimumab, preferably wherein the TNFα inhibitor is etanercept.

[0022] Embodiment 8. The rAAV virion for use according to embodiment 5, wherein the IL-1 inhibitor is selected from the group consisting of:

[0023] i) an IL-1 receptor antagonist, preferably a human IL-1 receptor antagonist, preferably the human IL-1 receptor antagonist anakinra;

[0024] ii) anti-IL-1 monoclonal antibodies, preferably human anti-IL-1 monoclonal antibodies, preferably human IL-1 monoclonal antibodies canakinumab or gevokizumab

[0025] iii) a human dimeric anti-IL-1 fusion protein, preferably a human dimeric anti-IL-1 fusion protein rilonacept; and

[0026] iv) a human dual variable domain anti-IL-1 immunoglobulin, preferably the human dual variable domain anti-IL-1 immunoglobulin lutikizumab.

[0027] Embodiment 9. The rAAV virion used according to any one of the preceding embodiments, wherein the promoter is a constitutive promoter or an inducible promoter, preferably the promoter is an NFκB-responsive promoter, preferably an NFκB-responsive CMV promoter, preferably an NFKB-responsive minimal CMV promoter.

[0028] Embodiment 10. The rAAV virion for use according to any one of the preceding embodiments, wherein the sequence Z is contained in the modified capsid protein at a position represented by formula II:

[0029] EEEIxxxxPVATExxGxxxxNxQy-Z-(x) n LPGMVWQxRDVYLQGPIWAKIPHTDG

[0030] a. wherein Z, x and y are as defined in Embodiment 2; and

[0031] b. wherein n is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0032] Embodiment 11. The rAAV virion for use according to any one of the preceding embodiments, wherein the capsid protein comprises an amino acid sequence selected from the group consisting of:

[0033] i) an amino acid sequence that has at least 70% sequence identity to the amino acid sequence having SEQ ID NO: 1, and wherein the amino acids at positions 588 to 602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11,

[0034] ii) an amino acid sequence that has at least 70% sequence identity to the amino acid sequence having SEQ ID NO: 2, and wherein the amino acids at positions 585 to 602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10,

[0035] iii) an amino acid sequence that has at least 70% sequence identity to the amino acid sequence having SEQ ID NO: 3, and wherein the amino acids at positions 587 to 601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9,

[0036] iv) an amino acid sequence that has at least 70% sequence identity to the amino acid sequence having SEQ ID NO: 4, and wherein the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8,

[0037] v) an amino acid sequence that has at least 70% sequence identity to the amino acid sequence having SEQ ID NO: 5, and wherein the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9,

[0038] vi) an amino acid sequence having at least 70% sequence identity to the amino acid sequence having SEQ ID NO: 6, and wherein the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8, and

[0039] vii) an amino acid sequence that has at least 70% sequence identity to the amino acid sequence having SEQ ID NO: 7, and wherein the amino acids at positions 587 to 604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12,

[0040] Wherein the modified capsid protein provides at least a two-fold increase in expression compared to an unmodified capsid protein having an amino acid sequence selected from the group consisting of SEQ ID NOs: 13-19 when tested under the same conditions, preferably in human FLS cells, wherein preferably the unmodified capsid protein has the amino acid sequence of SEQ ID NO: 19 or has the same serotype as the modified capsid protein.

[0041] Embodiment 12. The rAAV virion for use according to any one of the preceding embodiments, wherein the capsid protein comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-7, preferably wherein the capsid protein comprises or consists of SEQ ID NO: 4 or SEQ ID NO: 6.

[0042] Embodiment 13. An rAAV composition for use in treating or preventing an arthritic disease or for treating or preventing symptoms associated with an arthritic disease, wherein the rAAV composition comprises the rAAV virion as defined in any one of embodiments 1-12 and a pharmaceutically acceptable carrier.

[0043] Embodiment 14. An rAAV composition for use in treating or preventing an arthritic disease or for treating or preventing symptoms associated with an arthritic disease and an immunosuppressant, wherein the rAAV composition is as defined in embodiment 13, and wherein the treatment or prevention comprises administering the rAAV composition and administering the immunosuppressant to an individual.

[0044] Embodiment 15. The rAAV virion for use according to any one of embodiments 1 to 12, the rAAV composition for use according to embodiment 13, or the rAAV composition and an immunosuppressant for use according to embodiment 14, wherein the arthritis disease is selected from the group consisting of rheumatoid arthritis (RA), juvenile rheumatoid arthritis, osteoarthritis (OA), gout, pseudogout, spondyloarthritis (SpA), psoriatic arthritis, ankylosing spondylitis, septic arthritis, arthritis, juvenile idiopathic arthritis, blunt trauma, joint replacement, and Still's disease.

[0045] Embodiment 16. The rAAV virion for use according to any one of embodiments 1 to 12 or the rAAV composition for use according to embodiment 13, wherein the rAAV virion and / or the rAAV composition are administered systemically and / or locally.

[0046] Embodiment 17. The rAAV composition and immunosuppressant for use according to embodiment 14, wherein at least one of the rAAV composition and the immunosuppressant is administered topically.

[0047] Embodiment 18. The rAAV virion or rAAV composition for use according to embodiment 16 and / or the rAAV composition and an immunosuppressive agent for use according to embodiment 17, wherein the local administration is intra-articular administration. DETAILED DESCRIPTION

[0048] The present inventors have discovered that recombinant adeno-associated virus (rAAV) virions comprising modified capsid proteins are surprisingly efficient at transducing cells, and are particularly efficient at transducing cells of synovial joints.

[0049] In the treatment of arthritic diseases such as rheumatoid arthritis, the main target cells in the joints include, but are not limited to, fibroblast-like synoviocytes (FLS), cartilage cells, chondrocytes and chondroblasts. The object of the present invention is to provide capsid proteins that are improved in one or more of the following properties after rAAV administration compared to capsid proteins known in the art: i) higher expression levels in joint tissues, particularly in FLS; ii) improved joint tissue tropism, particularly improved tropism for FLS; and / or iii) improved off-targeting from non-desirable tissues / organs. In particular, these properties of rAAV virions comprising the modified capsid proteins of the present invention are improved compared to unmodified capsid proteins, preferably wild-type capsid proteins of the same serotype as the modified capsid protein and / or AAV5 capsid protein. It has been previously determined that AAV5 capsids produce the highest FLS expression levels when compared to other AAV serotypes (Adriaansen et al. (2005) Ann Rheum Dis 64:1677-1684; Apparailly et al. (2005) Hum. Gene Ther. 16:426-434). Due to the tissue / cell tropism conferred by the capsid, the modified capsids described in the present invention have the property of enhanced FLS transduction potential compared to unmodified AAV5. In particular, it is preferred that the capsid proteins of the present invention provide higher expression levels in synovial tissue, especially in FLS, preferably after intra-articular administration, compared to unmodified capsid protein (i.e., the same capsid protein but without the modification to be tested, preferably of the same serotype as the modified capsid protein), preferably wild-type unmodified capsid protein (preferably of the same serotype as the modified capsid protein), more preferably unmodified AAV5 or wtAAV5 capsid protein.

[0050] Thus, in a first aspect, the present invention relates to rAAV virions comprising a modified capsid protein.The rAAV virions as defined herein are particularly useful in gene therapy.

[0051] As used herein, "gene therapy" is the insertion of a nucleic acid sequence, such as a transgene as defined below (also referred to as a nucleotide sequence encoding a gene product of interest), into the cells and / or tissues of an individual to treat or prevent a disease or condition or to treat or prevent the symptoms of a disease or condition.

[0052] AAV can infect dividing cells and dormant cells, and the infection occurs through the interaction of capsid protein with cell membrane receptors, followed by the endocytosis of AAV virions. AAV belongs to the genus Dependovirus, which in turn belongs to the subfamily Parvovirinae, also known as Parvovirus, which can infect vertebrates. The subfamily Parvovirinae belongs to the small DNA animal virus family, i.e., the Parvoviridae. It can be inferred from their genus name that members of the Dependovirus genus are unique because they usually need to be co-infected with helper viruses such as adenovirus or herpesvirus to carry out productive infection in cell culture. The Dependovirus genus includes AAV that normally infects people and related viruses (such as cattle, dogs, horses and sheep adeno-associated viruses) that infect other warm-blooded animals. Further information about other members of Parvoviridae and Parvoviridae is described in Kenneth I. Berns, "Parvoviridae:The Viruses and Their Replication," Chapter 69 Fields Virology (3rd Edition 1996). For convenience, this article further illustrates and describes the present invention with reference to AAV. However, it should be understood that the present invention is not limited to AAV, but is equally applicable to other parvoviruses.

[0053] The genomic structure of all known AAV serotypes is very similar. The genome of AAV is a linear single-stranded DNA molecule with a length of less than about 5,000 nucleotides (nt). Inverted terminal repeats (ITRs) flank the unique coding nucleotide sequences of non-structural replication (Rep) proteins and structural (VP) proteins. VP proteins (VP1, VP2 and VP3) form capsids or protein shells (for some serotypes) with the help of assembly activation proteins (AAPs), which are encoded in alternative open reading frames that overlap with the open reading frames of VP2 / VP3. The terminal nucleotides are self-complementary and structured so that an energy-stable intramolecular duplex can be formed, thereby forming a T-shaped hairpin. The size of the terminal nucleotides depends on the serotype. For example, in the case of AAV2, 125nt of the terminal 145nt are self-complementary, while the remaining 20nt remain single-stranded. These hairpin structures serve as the starting point for viral DNA replication and are thus used as primers for the cellular DNA polymerase complex. Following infection of mammalian cells with wild-type AAV (wtAAV), Rep proteins (i.e., Rep78 and Rep52) are expressed from mRNA transcribed from the p5 promoter and the p19 promoter, respectively. Both Rep proteins function in the replication of the viral genome. Splicing events in the Rep ORF result in the expression of actually four Rep proteins (i.e., Rep78, Rep68, Rep52, and Rep40). However, it has been shown that Rep78 and Rep52 proteins encoded by unspliced ​​mRNA in mammalian cells are sufficient to produce AAV vectors. In addition, the production of wtAAV or rAAV in mammalian cells relies on a combination of alternating use of two splice acceptor sites and suboptimal use of the ACG start codon of VP2, which ensures the correct expression of all three capsid proteins in a ratio of approximately 1:1:10 (VP1:VP2:VP3).

[0054] As used herein, "rAAV virion" (also referred to herein as "rAAV vector" or "rAAV transgenic vector") refers to an AAV capsid comprising a non-natural nucleic acid sequence. Such sequences in rAAV are typically flanked by ITR sequences, preferably from wtAAV, and preferably encode a gene product of interest, such as, for example, a transgene or homology arms. In other words, rAAV virion means a rAAV genome wrapped by capsid protein, which comprises (i) a nucleotide sequence encoding a gene product of interest and (ii) at least one AAV ITR sequence. The rAAV genome may be missing one or preferably all wtAAV genes, but may still comprise a functional ITR nucleic acid sequence. Preferably, the rAAV virion does not comprise any nucleotide sequence encoding a viral protein, such as the rep (replication) or cap (capsid) genes of AAV. Thus, rAAV virions differ from wtAAV virions in that all or part of the viral genome has been replaced by a nucleotide sequence encoding a gene product of interest, which is a non-natural nucleic acid relative to the AAV nucleic acid sequence further defined herein.

[0055] In a preferred embodiment, the rAAV virion comprising the modified capsid protein of the present invention is used to treat or prevent arthritis disease or for treating or preventing symptoms associated with arthritis disease. The medical uses described herein (e.g., gene therapy for treating or preventing arthritis disease (symptoms associated with arthritis disease)) are rAAV virions according to the present invention that are customized for use as a drug for preventing or treating diseases and / or conditions defined herein, but can also be customized as (i) a method for preventing or treating diseases and / or conditions defined herein or their symptoms, the method comprising administering a sufficient amount or an effective amount of rAAV virions according to the present invention to a subject in need, and (ii) rAAV virions according to the present invention for preparing a drug for preventing or treating diseases and / or conditions defined herein, or (iii) rAAV virions according to the present invention for preventing or treating diseases and / or conditions defined herein. The present invention contemplates all such medical uses. Preferably, the modified capsid protein comprises the amino acid sequence Z at the C-terminal portion of the protein, and its residues are exposed on the surface of the capsid protein.

[0056] As used herein, the terms "treat," "treatment," or "treating" refer to the application or administration of the rAAV virions of the present invention to a subject suffering from an arthritis disease, wherein the purpose is to cure, partially or completely reverse, alleviate, ameliorate, inhibit, delay, contain, slow down, or stop the progression or severity of the arthritis disease or symptoms associated with the arthritis disease. The term "treat" includes alleviating or relieving at least one adverse effect or symptom of the arthritis disease. A treatment is generally "effective" if one or more symptoms or clinical markers are reduced. Alternatively, a treatment is "effective" if the progression of the arthritis disease is reduced or stopped. That is, "treatment" includes not only improvement of symptoms or markers, but also stopping or at least slowing the progression or worsening of symptoms that would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, relief of one or more symptoms, a reduction in the extent of the disease, a stable disease state (i.e., no worsening), a delay or slowing of disease progression, an improvement or alleviation of the disease state, and relief (whether partial or total relief), whether detectable or undetectable. The term "treatment" of an arthritis disease also includes providing relief of the symptoms or side effects of the arthritis disease (including palliative treatment). As used herein, the terms "prevent," "prevention," or "preventative" (also referred to as prophylactic) refer to the application or administration of a rAAV virion according to the present invention to a subject susceptible to an arthritis disease for the purpose of delaying or preventing the onset of, alleviating, ameliorating, alleviating, inhibiting the progression of, reducing the severity of, and / or reducing the incidence of one or more symptoms or features of the arthritis disease in the future. Thus, the rAAV virion according to the present invention can be administered to a subject who does not exhibit signs of an arthritis disease and / or to a subject who exhibits only early signs of an arthritis disease, preferably to reduce the risk of developing pathology associated with the arthritis disease.

[0057] As used herein, the term "cure" or "curing" means complete relief of one or more, preferably all, of the symptoms or features of an arthritis disease. As used herein, the term "delay" or "delaying" means delaying the onset and / or inhibiting the progression and / or reducing the severity of one or more of the symptoms or features of an arthritis disease.

[0058] In a preferred embodiment, when tested under the same conditions, the modified capsid protein of the present invention provides at least a two-fold increase in expression compared to the unmodified capsid protein. Preferably, the unmodified capsid protein is a capsid protein having the same serotype as the modified capsid protein but without the modification to be tested. More preferably, the unmodified capsid protein is a wild-type (wt) capsid protein having the same serotype as the modified capsid protein, wherein the wt capsid protein preferably has an amino acid sequence selected from the group consisting of SEQ ID NO: 13-19. Alternatively, it is preferred that the unmodified capsid protein has an amino acid sequence selected from the group consisting of SEQ ID NO: 13-19. Most preferably, the unmodified capsid protein has the amino acid sequence shown in SEQ ID NO: 19. The preferred unmodified capsid protein may depend on the tissue targeted by the rAAV virion. For example, rAAV with AAV5 capsid protein appears to be the virion selected for FLS cells (Apparailly et al. (2005) Human Gene Therapy 16(4):426-434; Adriaansen et al. (2005) Ann. Rheum. Dis. 64(12):1677-1684), and therefore, regardless of the original serotype of the rAAV mutant virion, the rAAV control virion preferably comprises an AAV5 capsid protein, more preferably a wild-type AAV5 (wtAAV5) capsid protein, more preferably an AAV5 capsid protein having the amino acid sequence shown in SEQ ID NO: 19, and even more preferably the rAAV control virion is a rAAV5 virion. The rAAV control virion is an rAAV virion comprising an unmodified capsid protein as defined herein rather than a modified capsid protein. In a preferred embodiment, rAAV virions (capsid protein comprising modification) use the method described in the embodiment in fibroblast-like synoviocytes (RA-FLS) and / or HEK293 from rheumatoid arthritis patients, preferably after in vitro transduction in HEK293T cells, with unmodified capsid protein as defined herein rather than the same rAAV virion of modified capsid protein compared to provide higher expression. In other words, except for capsid protein, rAAV virions and rAAV control virions are preferably identical. Preferably, transduction efficiency is detected in in vitro transduction assays: by measuring the expression level of reporter genes such as GFP, YFP and / or luciferase encoded by transgenes. In a preferred embodiment, the test for determining expression is an in vitro transduction assay as described in Example 2 / 3.Briefly, RA-FLS (as described in van de Sande MG et al. (2011) Ann Rheum Dis 70:423-427) were plated at 2500 cells / well or HEK293T cells (human embryonic kidney cells) were plated at 40,000 cells / well in 96-well plates (DMEM-GlutaMAX-I (Gibco, Ref. 31966-021), 10% FBS (heat-inactivated (HI) bovine serum gold, Gibco Ref. A15-151), 100 μg / ml penicillin / 100 μg / ml streptomycin (Sigma-Aldrich, Ref. P0781; 37°C / 5% CO2). After 24 hours, the supernatant was removed and replaced with medium containing rAAV mutant virions or rAAV control virions (DMEM-GlutaMAX-I (Gibco, Ref. 31966-021), 0.001% pluronic acid F68 (Sigma, reference number p5559), the rAAV mutant virions or rAAV control virions all express yellow fluorescent protein (yFP) and / or luciferase under the control of the cytomegalovirus (CMV) promoter, and the multiplicity of infection (MOI) is 10,000, 20,000 and 100,000. Crude lysate (i.e., unpurified supernatant of cells transfected with all plasmids required for rAAV production and containing virions expressing reporter genes) or purified AAV (preferably based on iodixanol purification or cesium chloride (CsCl) density gradient purification) can be used. Four hours after transduction, culture medium (DMEM-GlutaMAX-I, 10% FBS) containing doxorubicin (Sigma, reference number D1515; final concentration 0.4 μM) and FBS (final concentration 1%) is added. 100 U / ml penicillin, 100 μg / ml streptomycin). After 48 hours (HEK293T) or 4-6 days (RA-FLS), the percentage of cells expressing YFP or luciferase is determined by fluorescence microscopy or flow cytometry. Preferably, the in vitro transduction assay is performed multiple times with FLS isolated from different patients, such as, for example, FLS isolated from 2, 3, 4, 5, 6, 7, 8, 9, 10 or more patients.

[0059] "Serotype" is traditionally defined based on the lack of cross-reactivity between antibodies to one virus and antibodies to another virus. Such cross-reactivity differences are generally due to differences in capsid protein sequences / antigenic determinants (e.g., due to differences in the VP1, VP2, and / or VP3 sequences of AAV serotypes). According to the traditional definition, a serotype means that the neutralizing activity of the virus of interest has been tested against sera specific for all existing and characterized serotypes, and no antibodies that neutralize the virus of interest have been found. As more naturally occurring viral isolates are discovered and capsid mutants are generated, there may or may not be serological differences from any currently existing serotype. Therefore, in the case where a new AAV has no serological differences, this new AAV will be a subset or variant of the corresponding serotype. In many cases, mutant viruses with modified capsid sequences must also be serologically tested for neutralizing activity to determine whether they have another serotype according to the traditional definition of serotype. Thus, for convenience and to avoid repetition, the term "serotype" refers broadly to serologically distinct viruses (eg, AAV) as well as non-serologically distinct viruses (eg, AAV) that may be within subgroups or variants of a given serotype.

[0060] "Transduction" refers to the transfer of a transgene into a recipient host cell by a viral vector. Transduction of a target cell with the rAAV virion of the present invention results in the transfer of the transgene contained in the rAAV virion into the transduced cell. "Host cell" or "target cell" refers to a cell in which DNA delivery occurs, such as an individual's synovial cells, or such as FLS cells or HEK293T cells isolated from a patient in the case of an in vitro transduction assay. AAV vectors are capable of transducing both dividing and non-dividing cells. In cells containing a gene product of interest, such as GFP, the gene product of interest has been introduced / transferred / transduced by rAAV "transduction" of the cell. Cells into which the transgene has been introduced are referred to as "transduced" cells.

[0061] The recipient host cell of the transduced gene is preferably a cell affected by the disease to be treated, such as a synovial cell, more specifically FLS, macrophages, monocytes, neutrophils, osteoblasts, osteoclasts, chondrocytes, T lymphocytes, dendritic cells, plasma cells, mast cells, B lymphocytes in the case of arthritis. As used herein, "synovium" or "synovial tissue" or "synovial cells" refers to the cell lining covering the non-cartilage surface of the synovial joint, as further described in Tak (2000, Examination of the synovium and synovial fluid. In: Firestein GS, Panyani GS, Wollheim FA ed. Rheumatoid Arthritis. New York: Oxford Univ. Press, Inc. 55-68) and is incorporated herein by reference. The synovium is composed of an intimal lining (or synovial lining) and a subsynovial lining (subsynovial layer), which fuses with the joint capsule. The intimal lining comprises intimal macrophages (or macrophage-like synoviocytes or type A synoviocytes) and FLS (or type B synoviocytes). Thus, "synovium" may be replaced by or synonymous with "synovial tissue." Synovial cells may include any cell present in the synovium, including FLS and macrophage-like synoviocytes. Synovial cells may also be neutrophils, T cells, B cells, and / or connective tissue cells, all of which are present in the synovium.

[0062] "Fibroblast-like synoviocytes" (FLS) are cells of mesenchymal origin that exhibit many characteristics common to fibroblasts, such as expression of specific proteins, such as several types of collagen. However, FLS also secrete proteins that are not typically found in other fibroblast lineages, such as lubricin. In addition, FLS express molecules important for mediating cell adhesion, such as cadherin-11, VCAM-1, several integrins and their receptors. The specificity of FLS is the expression of CD55, and therefore this protein is commonly used to identify FLS in the synovium by immunohistochemistry. FLS represents a specialized cell type located inside the joint in the synovium, and its cells play a key role in the pathogenesis of chronic inflammatory diseases such as rheumatoid arthritis (RA). The term "rheumatoid synovium" or "rheumatoid synoviocytes" or "rheumatoid synovial tissue" refers to the inflamed synovium of the joints of individuals suffering from RA. Rheumatoid synovium is characterized by the accumulation of FLS, T cells, plasma cells, macrophages, B cells, natural killer cells and dendritic cells in the lining of the lining and the subsynovial layer. These accumulated cells are included in the definition of rheumatoid synovial cells. During the progression of RA, synovial tissue becomes a site of continuous inflammatory processes, which can ultimately lead to cartilage damage and joint destruction and deformation. It is reported that the FLS present in the synovium during RA show an altered phenotype compared to the FLS present in normal tissue. For example, the FLS in the rheumatoid synovium lose "contact inhibition", that is, when more cells come into contact with each other, they lose the property of preventing their growth. In addition, they lose their dependence on growing on adhesive surfaces. Therefore, the number of FLS in the diseased synovium increases. Inflammation is further enhanced by the production of several proinflammatory signaling molecules, particularly interleukins IL-6 and IL-8, prostaglandins and matrix metalloproteinases (MMPs).

[0063] Alternatively, or in combination with another embodiment, in another preferred embodiment of the present invention, rAAV virions comprising the modified capsid protein according to the present invention provide at least a two-fold increase in expression of the gene product of interest in human FLS when tested under the same conditions compared to rAAV virions comprising an unmodified capsid protein as defined herein, preferably compared to an unmodified capsid protein having an amino acid sequence selected from the group consisting of SEQ ID NOs: 13-19, wherein preferably the unmodified capsid protein is of the same serotype as the modified capsid protein or has the amino acid sequence shown in SEQ ID NO: 19.

[0064] More preferably, the rAAV virions of the invention result in at least a 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 50-fold increase in the expression level of the gene product of interest in human FLS cells following in vitro transduction as described above, compared to rAAV control virions.

[0065] Also preferably, and / or in addition to the above, the rAAV virions provide increased expression after in vivo administration to the air sac synovium (APS) mouse model compared to rAAV control virions, preferably compared to rAAV virions comprising wtAAV5 capsid protein, provided that the rAAV is otherwise identical (except for its capsid protein) (adapted from Edwards et al. (1981) J Pathol 134: 147-156, as described in Example 4). Preferably, expression of the gene product of interest is increased by at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35 fold using rAAV comprising a mutant capsid protein of the method of the present invention. Exemplary methods are provided in the Examples.

[0066] Also preferably, or in addition to the above, rAAV virions comprising the modified capsid protein provide similar or lower neutralizing antibody (nAb) titers compared to the same rAAV virions comprising unmodified (preferably wild-type) AAV capsid protein of the same serotype. It is known that the wtAAV5 capsid has an attractive nAb profile, and therefore, similar or lower nAb titers of rAAV comprising the modified capsid protein according to the present invention compared to wtAAV5 are preferred.

[0067] Alternatively, in vitro transduction assays can be performed similarly to those described above, but in cell types / cell lines other than FLS, depending on the cell type to be targeted, such as, for example, in cells selected from the group consisting of primary hepatocytes, hepatocyte cell lines such as HuH, HepG2, HepA1-6, cardiac cells, skeletal muscle cells, lung cells such as the cell line A549, CNS cells, ocular cells, gastrointestinal cells, bone marrow cells, and blood cells such as the cell line THP-1. This may also require a different AAV serotype as a preferred control, depending on the tropism of the wild-type capsid protein. Generally, the control vector preferably comprises a wild-type capsid protein that naturally targets the selected tissue. As will be appreciated by those skilled in the art, this may also depend on the mode of administration: local or systemic. For example, AAV2 is the most widely studied AAV, with tropism for skeletal muscle cells, neurons, vascular smooth muscle cells, and hepatocytes; AAV6 has tropism for airway epithelial cells; AAV7 has tropism for skeletal muscle cells; AAV8 has tropism for hepatocytes; and AAV1 and AAV5 have tropism for vascular endothelial cells. Following systemic administration, AAV 1-3 and 5-9 have tropism for the liver, with high protein levels observed with AAV9, 8, 7, 6, 1, and lower levels with 5 and 2; the heart is transduced by AAV4, 6, 7, 8, and 9; and thoracic expression is observed with AAV4 and 6 (Zincarelli et al. (2008) Molecular Therapy 16(6):1073-1080).

[0068] Without wishing to be bound by any theory, we believe that the increased expression achieved by rAAV virions comprising the modified capsid proteins of the present invention compared to rAAV control virions is caused by improved transduction of rAAV into cells, possibly due to altered tropism, resulting in (i) an increase in the number of cells within the transduced cell population, and / or (ii) an increase in the expression level per cell, for example due to better virion uptake and / or intracellular processing.

[0069] Another advantage of rAAV virions having modified capsid proteins according to the present invention is preferably other improvements, such as the possible avoidance of pre-existing neutralizing antibodies.

[0070] In a preferred embodiment of the present invention, the modified capsid protein comprises an amino acid sequence Z, preferably, the amino acid sequence Z is contained in the C-terminal portion of the protein. Preferably, the length of sequence Z is 12-18 amino acid residues (also referred to herein as "loop region" and "insert"). In a preferred embodiment, sequence Z is located in the C-terminal portion of the capsid protein, preferably at a position corresponding to amino acids 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160, and most preferably about 150 from the C-terminus of the wild-type capsid protein, such as, for example, as shown in SEQ ID NOs: 13-19. The residues of amino acid sequence Z are preferably exposed on the surface of the capsid protein, such as, for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 residues are exposed on the surface of the capsid protein (so-called "loop"). In a preferred embodiment, the length of sequence Z is 14-18 amino acid residues, more preferably 15, 16, 17 or 18 residues in length, and most preferably 15, 17 or 18 amino acid residues in length. Compared with unmodified, such as wild-type capsid protein sequence, sequence Z can replace some amino acid residues. Preferably, the insert replaces 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues of the same sequence, more preferably 6 or 7 amino acid residues, but does not insert preferably unmodified, more preferably wild-type sequence. In addition to sequence Z / insert, therefore in the framework, capsid protein can include other modifications, such as amino acid substitutions (e.g., conservative amino acid substitutions), or the framework capsid protein can be a wild-type amino acid sequence. The framework AAV wherein comprising insert can have any serotype, such as AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAVrh10 or AAVDJ. Preferably, the framework AAV comprising sequence Z is selected from the group consisting of AAV1, AAV2, AAV7, AAV9, AAVrh10, AAVDJ, and more preferably selected from an unmodified capsid protein having an amino acid sequence as shown in any one of SEQ ID NOs: 13 to 19. The insert according to the present invention is preferably contained in the C-terminal part of the capsid protein, preferably at a position corresponding to 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160, and most preferably about 150 amino acid residues from the C-terminus of the wild-type capsid protein, for example as shown in SEQ ID NOs: 13 to 19, wherein the position of the insert is represented by Formula II:

[0071] EEEIxxxxPVATExxGxxxxNxQy-Z-(x) n LPGMVWQxRDVYLQGPIWAKIPHTDG

[0072] wherein x represents a single amino acid residue, wherein y represents 0, 1 or 2 amino acid residues (which may therefore be absent), and wherein n is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, preferably 8, 9 or 10, or wherein the position of the insert is represented by a sequence having at least 90%, 93%, 95%, 96%, 97%, 98% or 99% sequence identity to Formula II. Preferably, the last three amino acid residues before the N-terminus of the sequence Z of the invention are NLQ, NHQ or NFQ. Preferably, y represents 0 or 2 amino acid residues. In some cases, y represents 2 amino acid residues, and thus two additional amino acid residues, preferably two serine residues, may be present between the NxQ motif and the insert of the invention. Preferred is the case where the NxQ motif is NFQ, for example if the AAV capsid is the AAV1 capsid sequence shown in SEQ ID NO: 1. One skilled in the art will be able to determine the region where these motifs and insertions are located, and if they have some variations, such as amino acid substitutions or deletions, they are also included within the scope of the present invention.

[0073] In a preferred embodiment, based on Figure 4 and 5 The alignment shown in , the insert (sequence Z) comprises or consists of a sequence of the formula: x1-GQ-x2-G-x3-x4-x5-R-x6-x7-x8-x9-x 10 -x 11 -x 12 -x 13 -x 14 -x 15 , where x1 is Q or None, x2 is S or R, x3 is N or C, x4 is D, Y, or E, x5 is C, V, S, or A, x6 is G, S, or V, x7 is None, A, V, or R, x8 is D, N, or E, x9 is C or A, x 10 is F or Q, x 11 is None, C or A, x 12 None or A, x 13 None or Q, x 14 is None or A, and X 15 is none or A. Alternatively, the insert (sequence Z) comprises or consists of a sequence of the formula: y1-GQ-y2-G-y3-y4-y5-R-y6-y7-y8-y9-y 10 -Ay 11 -y 12 -y 13, where y1 is Q or none, y2 is S or R, y3 is N or C, y4 is D, Y or E, y5 is C, V, S or A, y6 is G, S or V, y7 is none or D, y8 is none or C, y9 is A, V, R or F, y 10 N, D, E or C, y 11 None or Q, y 12 None or A, y 13 Is none or A. In yet another alternative, in the most preferred embodiment, based on Figure 6 and 7 , the insert (sequence Z) comprises or consists of a sequence of general formula I:

[0074] y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A

[0075] wherein x represents a single amino acid residue, and wherein y represents 0, 1 or 2 amino acid residues (which may therefore be absent). Preferably, (i) if y represents 0 amino acid residues at the N-terminus, the other y in formula I represents 0 amino acid residues, or (ii) if y represents 1 amino acid residue at the N-terminus, the other y in formula I represents 2 amino acid residues. More preferably, the insert (sequence Z) comprises or consists of a sequence of the more specific formula:

[0076] z0–G–Q-z1–G-z2–z3-z4–R-z5-z6-z7–z8-z9–A–Q–AA

[0077] wherein z0 is none or Q, z1 is R or S, z2 is C or N, Z3 is D, E or Y, z4 is C, A, S or V, z5 is G, V or S, z6 is d or none, z7 is C or none, z8 is F, R, V or A, and z9 is C, D, N or E. More preferably, if z0 is none, then z6 and z7 are both none.

[0078] More preferably, sequence Z / insert comprises or consists of an amino acid sequence having at least 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, most preferably 100% sequence identity to any of the amino acid sequences selected from the group consisting of SEQ ID NOs: 8 to 12. Preferably, sequence Z / insert comprises or consists of an amino acid sequence represented by any of the above formulae and having at least 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, most preferably 100% sequence identity to any of the amino acid sequences selected from the group consisting of SEQ ID NOs: 8 to 12.

[0079] In mammalian cells, the expression of the three AAV capsid proteins (VP1, VP2 and VP3) in the correct stoichiometry depends on a combination of alternating use of two splice acceptor sites and suboptimal use of the ACG start codon of VP2, which is not accurately replicated by insect cells. The correct stoichiometry is important for the infectivity of AAV particles. In order to produce the three AAV capsid proteins in insect cells with the correct stoichiometry, constructs that are transcribed into a single polycistronic messenger that can express all three VP proteins without the need for splicing are commonly used in the art. To achieve this, the VP1 protein can be under the control of a suboptimal translation start codon instead of ATG. Examples of such suboptimal translation start codons are ACG, TTG, CTG and GTG (Urabe et al. (2002) Human Gene Therapy 13:1935-1943; US20030148506; US 20040197895; WO2007 / 046703). Alternatively, in the production of rAAV in insect cells, a nucleic acid cassette can be used to express the VP1, VP2, and VP3 proteins, wherein these proteins are encoded by nucleic acid sequences comprising overlapping open reading frames (ORFs), as described in European Patent No. 2,061,891 B1, which discloses an intron-containing VP expression cassette comprising a promoter preceding the VP2 ACG start codon. The modified capsid proteins of the present invention are defined relative to the protein sequence of the VP1 capsid protein. However, since the sequence Z / insert is located in the C-terminal portion of the VP1 protein, the present invention includes VP2 and VP3 proteins that also contain the sequence Z / insert and are therefore modified (regardless of the method of production of rAAV, such as in insect cells or mammalian cells, for example).

[0080] Alternatively, or in combination with another embodiment, in another preferred embodiment of the present invention, the modified capsid protein according to the present invention comprises or consists of an amino acid sequence selected from the group consisting of: i) an amino acid sequence having at least 70%, 75%, 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, most preferably 100% sequence identity to the amino acid sequence having SEQ ID NO: 1, and wherein the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, most preferably 100% sequence identity to SEQ ID NO: 11, ii) an amino acid sequence having SEQ ID NO: 2 NO:2 has at least 70%, 75%, 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and most preferably 100% sequence identity to the amino acid sequence of SEQ ID NO:2, and wherein the amino acids at positions 585-602 of SEQ ID NO:2 have at least 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and most preferably 100% sequence identity to SEQ ID NO:10, iii) has at least 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and most preferably 100% sequence identity to the amino acid sequence of SEQ ID NO:10 NO:3 has an amino acid sequence having at least 70%, 75%, 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and most preferably 100% sequence identity, and wherein the amino acids at positions 587-601 of SEQ ID NO:3 have at least 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and most preferably 100% sequence identity to SEQ ID NO:9, iv) an amino acid sequence having SEQ ID NO:3 having at least 70%, 75%, 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and most preferably 100% sequence identity to SEQ ID NO:9, an amino acid sequence having at least 70%, 75%, 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and most preferably 100% sequence identity to SEQ ID NO:4, and wherein the amino acids at positions 586-600 of SEQ ID NO:4 have at least 80%, 85, 87, 90, 91%, 92, 93, 94, 95, 96, 97, 98, 99%, and most preferably 100% sequence identity to SEQ ID NO:8,v) an amino acid sequence that has at least 70, 75, 80, 85, 87, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99%, and most preferably 100% sequence identity to the amino acid sequence of SEQ ID NO:5, and wherein the amino acids at positions 588-602 of SEQ ID NO:5 have at least 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and most preferably 100% sequence identity to SEQ ID NO:9, vi) an amino acid sequence that has at least 70, 75, 80, 85, 87, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99%, and most preferably 100% sequence identity to the amino acid sequence of SEQ ID NO:5, NO:6 has an amino acid sequence having at least 70%, 75%, 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and most preferably 100% sequence identity, and wherein the amino acids at positions 588-602 of SEQ ID NO:6 have at least 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and most preferably 100% sequence identity to SEQ ID NO:8, and vii) an amino acid sequence having SEQ ID NO:6 having at least 70%, 75%, ... 97%, 98%, 99%, and most preferably 100% sequence identity to the amino acid sequence of SEQ ID NO: 7, and wherein the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and most preferably 100% sequence identity to SEQ ID NO: 12. Preferably, the framework AAV capsid protein comprising the insert has the amino acid sequence of a wild-type AAV capsid, such as, for example, AAV5, AAV1, AAV2, AAV7, AAV9, AAVrh10, or AAVDJ, or an amino acid sequence comprising conservative amino acid substitutions. More preferably, the framework AAV capsid protein comprising the insert has the amino acid sequence of the wtAAV5 capsid or an amino acid sequence comprising conservative amino acid substitutions.

[0081] "Sequence identity" is defined herein as the relationship between two or more amino acid (polypeptide or protein) sequences or two or more nucleic acid (polynucleotide) sequences, as determined by comparing the sequences. In a preferred embodiment, sequence identity is calculated based on the full length of two given SEQ ID NOs or a portion thereof. A portion thereof preferably means at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of the two SEQ ID NOs. In the art, "identity" also means the degree of sequence relatedness between amino acid or nucleic acid sequences, as the case may be, as determined by the match between such sequence strings. Unless otherwise indicated herein, identity or similarity to a given SEQ ID NO means identity or similarity based on the full length of the sequence (i.e., over its full length or as a whole).

[0082] "Similarity" between two amino acid sequences is determined by comparing the amino acid sequence of one polypeptide and its conserved amino acid substitutes to the sequence of a second polypeptide. "Identity" and "similarity" can be readily calculated by known methods, including but not limited to those described in Computational Molecular Biology, Lesk, AM, ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, DW, ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, AM and Griffin, HG, eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heine, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carillo, H. and Lipman, D., SIAM J. Applied Math., 48:1073 (1988).

[0083] Preferred methods for determining identity are designed to obtain the maximum match between the tested sequences. Methods for determining identity and similarity are codified in publicly available computer programs. Preferred computer program methods for determining identity and similarity between two sequences include, for example, the GCG program package (Devereux, J. et al., Nucleic Acids Research, 12(1):387(1984)), BestFit, BLASTP, BLASTN, and FASTA (Altschul, SF et al., J. Mol. Biol. 215:403-410(1990)). The BLAST X program is publicly available from NCBI and other sources (BLAST Manual, Altschul, S. et al., NCBI NLM NIH Bethesda, MD 20894; Altschul, S. et al., J. Mol. Biol. 215:403-410(1990)). The well-known Smith Waterman algorithm can also be used to determine identity.

[0084] Preferred parameters for polypeptide sequence comparison include the following algorithm: Needleman and Wunsch, J. Mol. Biol. 48:443-453 (1970); comparison matrix: BLOSSUM 62 from Hentikoff and Hentikoff, Proc. Natl. Acad. Sci. USA. 89:10915-10919 (1992); gap penalty: 12; and gap length penalty: 4. This program is publicly available as the "Ogap" program from Genetics Computer Group in Madison, Wis. The aforementioned parameters are the default parameters for amino acid comparisons (and no penalty for terminal gaps).

[0085] Preferred parameters for nucleic acid comparisons include the following algorithm: Needleman and Wunsch, J. Mol. Biol. 48:443-453 (1970); comparison matrix: match = +10, mismatch = 0; gap penalty: 50; gap length penalty: 3. Available as the Gap program from the Genetics Computer Group in Madison, Wis. (www.biology.wustl.edu / gcg / gap). Default parameters for nucleic acid comparisons are given above.

[0086] Optionally, when determining the degree of amino acid similarity, the skilled person may also consider so-called "conservative" amino acid substitutions, which will be clear to the skilled person. Conservative amino acid substitutions refer to the interchangeability of residues with similar side chains. For example, a group of amino acids with aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids with aliphatic-hydroxy side chains is serine and threonine; a group of amino acids with amide-containing side chains is asparagine and glutamine; a group of amino acids with aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids with basic side chains is lysine, arginine, and histidine; and a group of amino acids with sulfur-containing side chains is cysteine ​​and methionine. Preferred conservative amino acid substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, and asparagine-glutamine. Substitution variants of the amino acid sequences disclosed herein are those in which at least one residue in the disclosed sequence has been removed and a different residue has been inserted in its place. Preferably, the amino acid changes are conservative. Preferred conservative substitutions for each naturally occurring amino acid are as follows: Ala for Ser; Arg for Lys; Asn for Gln or His; Asp for Glu; Cys for Ser or Ala; Gln for Asn; Glu for Asp; Gly for Pro; His for Asn or Gln; Ile for Leu or Val; Leu for Ile or Val; Lys for Arg; Gln or Glu; Met for Leu or Ile; Phe for Met, Leu or Tyr; Ser for Thr; Thr for Ser; Trp for Tyr; Tyr for Trp or Phe; and Val for Ile or Leu.

[0087] Alternatively, or in combination with another embodiment, in another preferred embodiment of the present invention, the capsid protein comprises or consists of the amino acid sequence selected from the group consisting of SEQ ID NO: 1-7, more preferably selected from the group consisting of SEQ ID NO: 1, 2, 3, 4, 6 and 7, even more preferably selected from the group consisting of SEQ ID NO: 3, 4 and 6, still more preferably selected from the group consisting of SEQ ID NO: 4 and 6, most preferably SEQ ID NO: 4.

[0088] The rAAV virion of the present invention may comprise a single type of modified capsid protein, preferably a single type of modified capsid protein as defined herein. Therefore, in one embodiment, the rAAV virion of the present invention comprises a modified capsid protein, wherein each modified capsid protein has the same or substantially the same amino acid sequence. Alternatively, the rAAV virion of the present invention may comprise different types of modified capsid proteins. As a non-limiting example, the AAV virion of the present invention may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more types of modified capsid proteins. The rAAV virion of the present invention may also comprise one or wild-type capsid protein, in combination with a single type or different types of modified capsid proteins.

[0089] In a preferred embodiment, the capsid protein is a modified capsid protein as defined herein.

[0090] In a preferred embodiment, the capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein.

[0091] a. comprising or consisting of an amino acid residue sequence of formula I:

[0092] y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A

[0093] wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and

[0094] b. present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion of the invention comprises a modified capsid protein as defined herein for use in treating or preventing an arthritic disease or for treating or preventing symptoms associated with an arthritic disease.

[0095] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 1 (AAV1 P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity with SEQ ID NO: 11. Preferably, the rAAV virion of the present invention comprises an AAV1 P4 modified capsid protein for use in treating or preventing an arthritic disease or for treating or preventing symptoms associated with an arthritic disease.

[0096] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity with SEQ ID NO: 10. Preferably, the rAAV virion of the present invention comprises an AAV2 P2 modified capsid protein for use in treating or preventing arthritis or for treating or preventing symptoms associated with arthritis.

[0097] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity with SEQ ID NO: 9. Preferably, the rAAV virion of the present invention comprises an AAV7 A6 modified capsid protein for treating or preventing arthritis disease or for treating or preventing symptoms associated with arthritis disease.

[0098] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion of the present invention comprises an AAV9 A2 modified capsid protein for use in treating or preventing arthritis disease or for treating or preventing symptoms associated with arthritis disease.

[0099] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion of the present invention comprises an AAVrh10 A6 modified capsid protein for use in treating or preventing an arthritic disease or for treating or preventing symptoms associated with an arthritic disease.

[0100] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion of the present invention comprises an AAVrh10 A2 modified capsid protein for use in treating or preventing an arthritic disease or for treating or preventing symptoms associated with an arthritic disease.

[0101] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion of the present invention comprises an AAV-DJ-QR-P2 modified capsid protein for use in treating or preventing arthritis or for treating or preventing symptoms associated with arthritis.

[0102] Functional ITR sequences are essential for the replication, rescue and packaging of rAAV virions. The ITR sequence can be a wild-type sequence, or it can have at least 80%, 85%, 90%, 95% or 100% sequence identity with the wild-type sequence, or it can be changed by, for example, insertion, mutation, deletion or substitution of nucleotides, as long as they remain functional. In this article, functionality refers to the ability to package the genome directly into the capsid shell and then allow it to be expressed in the host cell or target cell to be transduced. Typically, the ITR of the wild-type AAV genome is retained in the rAAV vector. ITR can be cloned from the AAV viral genome or excised from a vector comprising AAV ITR. Standard molecular biology techniques can be used to connect the ITR nucleotide sequence to a transgene as defined herein at either end, or the wild-type AAV sequence between the ITRs can be replaced with a desired nucleotide sequence. The rAAV vector preferably comprises the nucleotide sequence of the ITR region of at least one of the AAV serotypes, or a nucleotide sequence substantially identical thereto, and at least one nucleotide sequence (under the control of suitable regulatory elements) encoding a therapeutic protein inserted between the two ITRs. Most of the rAAV vectors currently in use use ITR sequences from AAV serotype 2. The most preferred ITR present in rAAV vectors is the AAV2 serotype. Other preferred ITRs have AAV1, AAV3, AAV5 or AAV6 serotypes (Grimm et al. (2006) J Virol 80(1):426-439). The rAAV genome can comprise single-stranded or double-stranded (self-complementary) DNA. Single-stranded nucleic acid molecules are sense strands or antisense strands because both polarities can be packaged into AAV capsids. Single-stranded rAAV vectors can utilize wild-type AAV serotype 2 (AAV2) ITR sequences, and double-stranded (self-complementary) rAAV vectors can utilize modified forms of ITRs. Alternatively, in one embodiment, the double-stranded vector comprises one ITR that is derived from AAV4. The rAAV vector may also contain a marker or reporter gene, such as a gene encoding an antibiotic resistance gene, a fluorescent protein (e.g., gfp), or a gene encoding a chemically, enzymatically, or otherwise detectable and / or selectable product known in the art (e.g., lacZ, alkaline phosphatase (AP), SEAP, Luc, Neo, Bla, etc.).

[0103] rAAV vectors comprising any possible combination of AAV serotype capsids and AAV genome ITRs are produced using methods known in the art, such as using a mammalian rAAV production system or an insect cell rAAV production system. Methods known in the art are described, for example, in Pan et al. (J. of Virology (1999) 73:3410-3417), Clark et al. (Human Gene Therapy (1999) 10:1031-1039), Wang et al. (Methods Mol. Biol. (2011) 807:361-404), Grimm (Methods (2002) 28 (2):146-157), and insect cell systems are based on Urabe et al. (Human Gene Therapy (2002) 13:1935-1943), Kohlbrenner et al. (Molecular Therapy (2005) 12 (6):1217-1225), International Patent Publication WO 2007 / 046703, International Patent Publication WO 2007 / 148971, International Patent Publication WO 2009 / 014445, International Patent Publication WO 2009 / 104964, International Patent Publication WO 2009 / 154452, International Patent Publication WO2011 / 112089, International Patent Publication WO 2013 / 036118, U.S. Patent No. 6,723,551B, which are incorporated herein by reference. In brief, the method generally can involve (a) introducing rAAV genome constructs into host cells, (b) introducing AAV helper constructs into host cells, wherein the helper constructs include the viral functions of wild-type rAAV genome deletions, and (c) introducing helper virus constructs into host cells. It is necessary to have all the functions of rAAV vector replication and packaging to achieve replication and packaging of rAAV genomes into rAAV vectors. Introducing host cells can be carried out using standard molecular biology techniques, and can be carried out simultaneously or sequentially. Finally, the host cells are cultured to produce the rAAV vector, which is then purified using standard techniques, such as CsCl gradients (Xiao et al. 1996, J. Virol. 70:8098-8108) or iodixanol. The purified rAAV vector is then typically ready for use in the method. More than 10 [mu]l of rAAV vector can be obtained. 12 The total size of the transgene inserted between the ITR regions in the rAAV vector is typically less than 5 kilobases (kb).

[0104] In the context of the present invention, the capsid protein shell may have a serotype different from the rAAV genome, the rAAV genome comprising (i) a nucleotide sequence encoding a gene product of interest and (ii) at least one AAV ITR sequence. Thus, the rAAV genome of the present invention may be encapsidated by the capsid protein shell of the present invention, i.e., an icosahedral capsid, comprising a capsid protein (VP1, VP2, and / or VP3) according to the present invention, such as a mutant of an AAV capsid protein according to the present invention, and the ITR sequence contained in the rAAV vector may be any of the above-mentioned AAV serotypes, including, for example, AAV2 or AAV5. In one embodiment, the rAAV genome or ITR present in the rAAV virion is derived from AAV serotype 2, AAV serotype 5, or AAV serotype 8. The complete genomes of AAV5 and other AAV serotypes have been sequenced (Chiorini et al. 1999, J. of Virology Vol. 73, No. 2, pp. 1309-1319), and the nucleotide sequence of AAV5 is available in GenBank (accession number AF085716). Therefore, the ITR nucleotide sequences of AAV2 and AAV5 are readily available to those skilled in the art. The complete genome of AAV2 is available at NCBI (NCBI reference sequence NC_001401.2). They can be cloned or prepared by chemical synthesis known in the art, using, for example, an oligonucleotide synthesizer such as that provided by Applied Biosystems Inc. (Fosters, CA, USA) or by standard molecular biology techniques.

[0105] Alternatively, or in combination with another embodiment, in another preferred embodiment of the present invention, the rAAV vector comprises a nucleotide sequence encoding a gene product of interest.

[0106] The term "transgenic" is used to refer to a polynucleotide that can be introduced into a cell or organism. Transgenic includes any polynucleotide, such as a gene encoding a polypeptide or protein, a polynucleotide that is transcribed into an inhibitory polynucleotide, or a polynucleotide that is not transcribed (e.g., lacking an expression control element, such as a promoter that drives transcription). The transgenic of the present invention can comprise at least two nucleotide sequences, each of which is different or encodes different therapeutic molecules. At least two different nucleotide sequences can be connected by an IRES (internal ribosome entry site) element to provide a bicistronic transcript under the control of a single promoter. Suitable IRES elements are described in, for example, Hsieh et al. (1995, Biochem.Biophys.Res.Commun.214:910-917). In addition, at least two different nucleotide sequences encoding different (therapeutic) polypeptides or proteins can be connected by a viral 2A sequence to allow two transgenics to be effectively expressed from a single promoter. Examples of 2A sequences include those from foot-and-mouth disease virus, equine rhinitis A virus, Thosea asigna virus, and porcine Teschovirus-1 (Kim et al., PLoS One (2011) 6(4):e18556). The transgene is preferably inserted into the rAAV genome or between ITR sequences. The transgene may also be an expression construct comprising expression regulatory elements such as a promoter or a transcriptional regulatory sequence operably linked to a coding sequence and a 3' termination sequence. The transgene may be a functional mutant allele that replaces or supplements a defective allele. Gene therapy also includes inserting a transgene that is inhibitory in nature, i.e., a transgene that inhibits, reduces, or decreases the expression, activity, or function of an endogenous or exogenous gene or protein, such as an undesirable or abnormal (e.g., pathogenic) gene or protein. Such transgenes may be exogenous. Exogenous molecules or sequences are understood to be molecules or sequences that are not normally present in the cells, tissues, and / or individuals to be treated. Both acquired and congenital diseases are suitable for gene therapy.

[0107] "Gene" or "coding sequence" refers to a region of DNA or RNA that "encodes" a specific protein. A coding sequence is transcribed (DNA) and translated (RNA) into a polypeptide when placed under the control of appropriate regulatory regions, such as a promoter. A gene may comprise several operably linked segments, such as a promoter, a 5' leader sequence, introns, a coding sequence, and a 3' untranslated sequence, which may include a polyadenylation site or a signal sequence. A chimeric or recombinant gene is a gene that is not normally found in nature, such as a gene in which, for example, a promoter is not associated with part or all of the transcribed DNA region in nature. "Expression of a gene" refers to the process by which a gene is transcribed into RNA and / or translated into an active protein.

[0108] As used herein, the term "promoter" or "transcriptional regulatory sequence" refers to a nucleic acid fragment that is used to control the transcription of one or more coding sequences and is located upstream relative to the direction of transcription of the transcription start site of the coding sequence and is structurally identified by the presence of a binding site for a DNA-dependent RNA polymerase, a transcription start site, and any other DNA sequence, including but not limited to transcription factor binding sites, repressor and activator protein binding sites, and any other nucleotide sequences known to those skilled in the art that are directly or indirectly used to regulate the amount of transcription by the promoter. A "constitutive" promoter is a promoter that is active in most tissues under most physiological and developmental conditions. An "inducible" promoter is a promoter that is physiologically or developmentally regulated, for example, by the application of a chemical inducer. A "tissue-specific" promoter is preferentially active in a specific type of tissue or cell. The selection of an appropriate promoter sequence generally depends on the host cell selected for expressing the DNA segment. A transgene can be operably linked to a promoter that allows effective systemic expression or allows tissue-specific expression.

[0109] promoter

[0110] In a preferred embodiment, the expression of a transgenic encoding a gene product of interest, preferably a gene product of interest as defined herein, is operably linked to a promoter. Thus, preferably, the rAAV virion of the present invention comprises a promoter sequence. Preferably, the promoter is selected from the group consisting of a constitutive promoter, an inducible promoter, a tissue-specific promoter, a promoter that confers expression in joint cells, a CMV promoter, a CAG (cytomegalovirus early enhancer / chicken beta-actin) promoter, a EF1α promoter, a SV40 promoter, a CBA (chicken beta-actin) promoter, a liver-specific promoter, a NFκB responsive (inducible) promoter, a promoter of an inflammatory regulatory gene, an IL1β promoter, an IL-6 (HGF) promoter, a IL8 (CXCL) promoter, a 8) promoter, CXCL10 promoter, MMP3 promoter, MMP2 promoter, ICAM1 promoter, MMP13 promoter, ADAMTS4 promoter, ADAMDEC1 promoter, COL1A1 promoter, MMP12 promoter, RUNX2 promoter, ADAMTS5 promoter, COX2 (PTGS2) promoter, TNFα (TNF) promoter, VEGF (VEGFA) promoter, (basic) FGF (FGF2) promoter, and TGF-β (TGB1) promoter.

[0111] Preferably, the promoter is selected from the group consisting of: an NFκB-responsive (inducible) minimal CMV promoter, a promoter of a proinflammatory cytokine gene, a minimal promoter of a proinflammatory cytokine gene, a promoter that confers expression in arthritic joint cells, a promoter that confers expression in connective tissue cells, a promoter that confers expression in synovial cells, a promoter that confers expression in subsynovial cells, a promoter that confers expression in intimal macrophages, a promoter that confers expression in FLS, a promoter that confers expression in chondrocytes, a promoter that confers expression in chondrocytes, a promoter that confers expression in chondroblasts, a promoter that confers expression in adipocytes, a promoter that confers expression in osteoclasts, a promoter that confers expression in T cells, human alpha-1 antitrypsin (hAAT) promoter and TBG (thyroxine-binding globulin) promoter.

[0112] Preferably, the promoter is selected from the group consisting of: NFκB-responsive (inducible) minimal CMV promoter, CMV promoter, EF1α promoter, CAG promoter, MMP13 promoter, IL-6 promoter and IL8 promoter, preferably NFκB-responsive (inducible) minimal CMV promoter. Preferably, the NFκB-responsive (inducible) CMV promoter is the promoter described in Khoury et al. 2007, J Gene Med, 9: 596-604.

[0113] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by a constitutive promoter.

[0114] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by an inducible promoter.

[0115] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by a tissue-specific promoter.

[0116] In a preferred embodiment, expression of a transgene, preferably a transgene as defined herein, is controlled by a promoter that confers expression in joint cells, preferably arthritic joint cells. Preferred promoters confers expression in at least one of connective tissue cells, synovial cells, subsynovial cells, intimal macrophages, FLS, chondrocytes, chondrocytes, chondroblasts, adipocytes, osteoclasts and T cells, preferably said promoter confers expression in FLS cells.

[0117] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by a CMV promoter.

[0118] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the CAG (cytomegalovirus early enhancer / chicken beta-actin) promoter.

[0119] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the EF1α promoter.

[0120] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the SV40 promoter.

[0121] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the CBA (chicken beta-actin) promoter.

[0122] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by a liver-specific promoter.Preferred liver-specific promoters are at least one of the human alpha 1 antitrypsin (hAAT) promoter and the TBG (thyroxine binding globulin) promoter.

[0123] In a preferred embodiment, expression of a transgene, preferably a transgene as defined herein, is controlled by an NFκB-responsive (inducible) promoter. A preferred NFκB-responsive (inducible) promoter is an NFκB-responsive (inducible) CMV promoter, preferably an NFκB-responsive (inducible) minimal CMV promoter. Preferably, the NFκB-responsive (inducible) CMV promoter is a promoter described in Khoury et al. 2007, J Gene Med, 9:596-604.

[0124] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by a promoter of an inflammatory regulator, preferably a promoter of a proinflammatory cytokine gene. Preferably, the promoter of a proinflammatory cytokine gene is a minimal promoter of a proinflammatory cytokine gene.

[0125] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the IL1β promoter.

[0126] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the IL-6 (HGF) promoter.

[0127] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the IL8 (CXCL8) promoter.

[0128] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the CXCL10 promoter.

[0129] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the MMP3 promoter.

[0130] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the MMP2 promoter.

[0131] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the ICAM1 promoter.

[0132] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the MMP13 promoter.

[0133] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the ADAMTS4 promoter.

[0134] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the ADAMDEC1 promoter.

[0135] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the COL1A1 promoter.

[0136] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the MMP12 promoter.

[0137] In a preferred embodiment, expression of a transgene, preferably a transgene as defined herein, is controlled by the RUNX2 promoter.

[0138] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the ADAMTS5 promoter.

[0139] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the COX2 (PTGS2) promoter.

[0140] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the TNFα (TNF) promoter.

[0141] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the VEGF (VEGFA) promoter.

[0142] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the (essential) FGF (FGF2) promoter.

[0143] In a preferred embodiment, expression of the transgene, preferably a transgene as defined herein, is controlled by the TGF-β (TGB1) promoter.

[0144] In a preferred embodiment, the promoter within the rAAV virus is not a steroid-inducible promoter. Preferably, the promoter within the rAAV virus is not a dexamethasone-inducible promoter.

[0145] In a preferred embodiment, the modified capsid protein is a modified capsid protein as defined herein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter for controlling transgene expression. Preferably, the promoter is a promoter as defined above.

[0146] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein.

[0147] a. comprising or consisting of an amino acid residue sequence of formula I:

[0148] y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A

[0149] wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and

[0150] b. present at a position corresponding to an amino acid residue 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter that controls transgene expression. Preferably, the promoter is a promoter as defined above.

[0151] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1 P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity with SEQ ID NO: 11. Preferably, the rAAV virion comprising the AAV1 P4 modified capsid protein further comprises a promoter for controlling transgene expression. Preferably, the promoter is a promoter as defined above.

[0152] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising the AAV2 P2 modified capsid protein further comprises a promoter for controlling transgene expression. Preferably, the promoter is a promoter as defined above.

[0153] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity with SEQ ID NO: 9. Preferably, the rAAV virion comprising the AAV7 A6 modified capsid protein further comprises a promoter for controlling transgene expression. Preferably, the promoter is a promoter as defined above.

[0154] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising the AAV9 A2 modified capsid protein further comprises a promoter for controlling transgene expression. Preferably, the promoter is a promoter as defined above.

[0155] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity with SEQ ID NO: 9. Preferably, the rAAV virion comprising the AAVrh10A6 modified capsid protein further comprises a promoter for controlling transgene expression. Preferably, the promoter is a promoter as defined above.

[0156] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising the AAVrh10A2 modified capsid protein further comprises a promoter for controlling transgene expression. Preferably, the promoter is a promoter as defined above.

[0157] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising the AAV-DJ-QR-P2 modified capsid protein further comprises a promoter for controlling transgene expression. Preferably, the promoter is a promoter as defined above.

[0158] The terms "control expression" and "operably linked" are used interchangeably herein. As used herein, the term "operably linked" refers to the connection of polynucleotide (or polypeptide) elements in a functional relationship. A nucleic acid is "operably linked" when it is placed in a functional relationship with another nucleic acid sequence. For example, if a transcriptional regulatory sequence affects the transcription of a coding sequence, it is operably linked to a coding sequence. "Operably linked" means that the DNA sequences being linked are generally contiguous, and when necessary to connect two protein coding regions, are contiguous and in reading frame.

[0159] Target gene product

[0160] A transgene as defined herein preferably encodes a gene product of interest as defined herein. A "gene product of interest" may be a "therapeutic polypeptide" or "therapeutic protein," which is understood herein to mean a polypeptide or protein that has a beneficial effect on an individual, preferably a human, more preferably a human suffering from a disease. Such therapeutic polypeptides may be selected from, but are not limited to, the group consisting of enzymes, cofactors, cytokines, antibodies, growth factors, hormones, and anti-inflammatory proteins.

[0161] Alternatively, or in combination with another embodiment, in another preferred embodiment of the present invention, the nucleotide sequence encoding the gene product of interest is located between two AAV ITR sequences. Alternatively, the nucleotide sequence encoding the gene product of interest is flanked by two AAV ITR sequences, i.e., one ITR is at either end of the nucleotide sequence encoding the gene product of interest.

[0162] Alternatively, or in combination with another embodiment, in another preferred embodiment of the present invention, the gene product of interest treats, prevents or inhibits symptoms associated with an arthritic disease.

[0163] It is understood herein that a gene product of interest may include a biosimilar of the gene product of interest.

[0164] In a preferred embodiment, the gene product of interest is an immunosuppressant.

[0165] In a preferred embodiment, the gene product of interest is selected from the group consisting of: ANP32A, Nrf2, IL-6 inhibitors, soluble IL-6 receptor, IL-6 receptor antagonists, humanized anti-IL-6 monoclonal antibodies, chimeric anti-IL-6 monoclonal antibodies, humanized rabbit anti-IL-6 monoclonal antibodies, interleukin 1 (IL-1) inhibitors, tumor necrosis factor alpha (TNFα) inhibitors, IL-1 receptor antagonists, soluble IL-1 receptor, IL-17 inhibitors, IL-12 / IL-23 inhibitors, T cell co-stimulation inhibitors, B cell depletion and inhibitors, IL-15 inhibitors, IL-22 inhibitors, GM-CSF inhibitors, insulin-like growth factor (IGF-1), fibroblast growth factor (FGF), receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors, complement 5a inhibitors, bone morphogenetic protein family members (BMPs), transforming growth factor-β (TGF-β), mitochondrial ischemia-reperfusion injury (MIT) inhibitors, ... β), growth differentiation factor family members (GDFs), interleukin-18 inhibitors, IL-2 inhibitors, soluble TNFα (sTNFα) receptor p55, sTNFα receptor p75, sTNFα receptor fused to IgG, TNFα receptor p55 inhibitor, sTNFα receptor p75 inhibitor, dominant-negative IκB kinase (dn-IKK-β), interleukin 4 (IL-4), interleukin 10 (IL-10), interleukin 13 (IL-13), IL-33 inhibitors, CCL17 inhibitors, interferon β (IFN-β), tissue inhibitors of the MMP family members (TIMPs), plasminogen activator inhibitors (PAIs), serine protease inhibitors (serpins), signaling molecules / transcription factors, extracellular matrix components, vasoactive intestinal peptide (VIP), cluster of differentiation 39 (CD39), cluster of differentiation 73 (CD73), and superoxide dismutase (SOD).

[0166] In a preferred embodiment, the gene product of interest is selected from the group consisting of tocilizumab, sanofi, olomituzumab, sirukumab, siltuximab, clazakizumab, anakinra, canakinumab, rilonacept, givuzumab and rugetuzumab, etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, secukinumab, brodalumab, ixekizumab, ustekinumab, risankizumab, guselkumab, and selegiline. lkumab, tildrakizumab, abatacept, rituximab, belimumab, ianalumab, tabalumab, AMG-714, fezakunimab, lenzilumab, namilumab, rhFGF-18 / sprifermin, denosumab, C5aR-151, Tadekinig alfa / IL-18 binding protein, basiliximab, daclizumab, F8IL10 / Dekavil, SMADs, Sox9, IkB, collagen, cartilage oligomeric matrix protein (COMP), proteoglycans, and elastin.

[0167] In a preferred embodiment, the gene product of interest is etanercept. Preferably, etanercept is encoded by the sequence of SEQ ID NO: 28. The etanercept protein may comprise a signal peptide, for example, the protein may have the amino acid sequence of SEQ ID NO: 29, and after cleavage of the signal peptide, the protein may have the amino acid sequence of SEQ ID NO: 30.

[0168] In a preferred embodiment, the gene product of interest is ANP32A.

[0169] In a preferred embodiment, the gene product of interest is Nrf2.

[0170] In a preferred embodiment, the gene product of interest is an IL-6 inhibitor.

[0171] In a preferred embodiment, the gene product of interest is soluble IL-6 receptor.

[0172] In a preferred embodiment, the target gene product is an IL-6 receptor antagonist. Preferably, the IL-6 receptor antagonist is at least one of tocilizumab and sanofi.

[0173] In a preferred embodiment, the target gene product is a humanized anti-IL-6 monoclonal antibody. Preferably, the humanized anti-IL-6 monoclonal antibody is at least one of olozumab and sirukumab.

[0174] In a preferred embodiment, the gene product of interest is a chimeric anti-IL-6 monoclonal antibody. Preferably, the chimeric anti-IL-6 monoclonal antibody is siltuximab.

[0175] In a preferred embodiment, the gene product of interest is a humanized rabbit anti-IL-6 monoclonal antibody. Preferably, the humanized rabbit anti-IL-6 monoclonal antibody is clazakizumab.

[0176] In a preferred embodiment, the gene product of interest is an interleukin-1 (IL-1) inhibitor. Preferably, the interleukin-1 (IL-1) inhibitor is selected from the group consisting of anakinra, canakinumab, rilonacept, givolumab and rugiperzumab. Preferably, the IL-1 inhibitor is selected from the group consisting of: i) an IL-1 receptor antagonist, preferably a human IL-1 receptor antagonist, preferably the human IL-1 receptor antagonist anakinra; ii) an anti-IL-1 monoclonal antibody, preferably a human anti-IL-1 monoclonal antibody, preferably the human IL-1 monoclonal antibody canakinumab or givolumab, iii) a human dimeric anti-IL-1 fusion protein, preferably a human dimeric anti-IL-1 fusion protein rilonacept; and iv) a human dual variable domain anti-IL-1 immunoglobulin, preferably the human dual variable domain anti-IL-1 immunoglobulin rugiperzumab.

[0177] In a preferred embodiment, the target gene product is a tumor necrosis factor alpha (TNFα) inhibitor. Preferably, the tumor necrosis factor alpha (TNFα) inhibitor is selected from the group consisting of etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab. Preferably, the TNFα inhibitor is etanercept. Preferably, the target gene product is etanercept.

[0178] In a preferred embodiment, the gene product of interest is an IL-1 receptor antagonist.

[0179] In a preferred embodiment, the gene product of interest is a soluble IL-1 receptor.

[0180] In a preferred embodiment, the gene product of interest is an IL-17 inhibitor. Preferably, the IL-17 inhibitor is selected from the group consisting of secukinumab, brodalumab, and ixekizumab.

[0181] In a preferred embodiment, the gene product of interest is an IL-12 / IL-23 inhibitor. Preferably, the IL-12 / IL-23 inhibitor is selected from the group consisting of ustekinumab, risankizumab, guselkumab, and tilazumab.

[0182] In a preferred embodiment, the gene product of interest is a T cell co-stimulation inhibitor. Preferably, the T cell co-stimulation inhibitor is abatacept.

[0183] In a preferred embodiment, the gene product of interest is a B cell depletion or inhibitor. Preferably, the B cell depletion or inhibitor is selected from the group consisting of rituximab, belimumab, ipilimumab, and tabecirumab.

[0184] In a preferred embodiment, the gene product of interest is an IL-15 inhibitor. Preferably, the IL-15 inhibitor is AMG-714.

[0185] In a preferred embodiment, the gene product of interest is an IL-22 inhibitor. Preferably, the IL-22 inhibitor is fezakunimab.

[0186] In a preferred embodiment, the target gene product is a GM-CSF inhibitor. Preferably, the GM-CSF inhibitor is at least one of renzilumab and namezumab.

[0187] In a preferred embodiment, the gene product of interest is insulin-like growth factor (IGF-1).

[0188] In a preferred embodiment, the gene product of interest is fibroblast growth factor (FGF). Preferably, the fibroblast growth factor (FGF) is rhFGF-18 / serifilamine.

[0189] In a preferred embodiment, the gene product of interest is a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor. Preferably, the RANKL inhibitor is denosumab.

[0190] In a preferred embodiment, the gene product of interest is a complement 5a inhibitor. Preferably, the complement 5a inhibitor is C5aR-151.

[0191] In a preferred embodiment, the gene product of interest is a member of the bone morphogenetic protein family (BMP).

[0192] In a preferred embodiment, the gene product of interest is transforming growth factor beta (TGF-β).

[0193] In a preferred embodiment, the gene product of interest is a member of the growth differentiation factor family (GDF).

[0194] In a preferred embodiment, the gene product of interest is an inhibitor of interleukin 18. Preferably, the interleukin 18 inhibitor is Tadekinig alfa / IL-18 binding protein.

[0195] In a preferred embodiment, the target gene product is an IL-2 inhibitor. Preferably, the IL-2 inhibitor is at least one of basiliximab and daclizumab.

[0196] In a preferred embodiment, the gene product of interest is the soluble TNFα (sTNFα) receptor p55.

[0197] In a preferred embodiment, the gene product of interest is the sTNFα receptor p75.

[0198] In a preferred embodiment, the gene product of interest is the sTNFα receptor fused to IgG.

[0199] In a preferred embodiment, the gene product of interest is an inhibitor of the TNFα receptor p55.

[0200] In a preferred embodiment, the gene product of interest is an inhibitor of the sTNFα receptor p75.

[0201] In a preferred embodiment, the gene product of interest is a dominant negative IκB kinase (dn-IKK-β).

[0202] In a preferred embodiment, the gene product of interest is interleukin 4 (IL-4).

[0203] In a preferred embodiment, the gene product of interest is interleukin 10 (IL-10). Preferably, the IL-10 is F8IL10 / Dekavil.

[0204] In a preferred embodiment, the gene product of interest is interleukin 13 (IL-13).

[0205] In a preferred embodiment, the gene product of interest is an IL-33 inhibitor.

[0206] In a preferred embodiment, the gene product of interest is a CCL17 inhibitor.

[0207] In a preferred embodiment, the gene product of interest is interferon beta (IFN-β).

[0208] In a preferred embodiment, the gene product of interest is a tissue inhibitor of MMP family member (TIMP),

[0209] In a preferred embodiment, the gene product of interest is plasminogen activator inhibitor (PAI).

[0210] In a preferred embodiment, the gene product of interest is a serine protease inhibitor (serpin).

[0211] In a preferred embodiment, the target gene product is a signaling molecule / transcription factor. Preferably, the signaling molecule / transcription factor is selected from the group consisting of SMAD, Sox9 and IkB.

[0212] In a preferred embodiment, the gene product of interest is an extracellular matrix component. Preferably, the extracellular matrix component is selected from the group consisting of collagen, cartilage oligomeric matrix protein (COMP), proteoglycans and elastin.

[0213] In a preferred embodiment, the gene product of interest is vasoactive intestinal peptide (VIP).

[0214] In a preferred embodiment, the gene product of interest is cluster of differentiation 39 (CD39).

[0215] In a preferred embodiment, the gene product of interest is cluster of differentiation 73 (CD73).

[0216] In a preferred embodiment, the gene product of interest is superoxide dismutase (SOD).

[0217] In a preferred embodiment, the gene product of interest is a sequence-specific nuclease (complex) for functional genome editing. Functional genome editing systems for all embodiments of the present invention are known to those skilled in the art and include: transcription activator-like effector nucleases (TALENs, Gaj et al. (2013) Trends Biotechnol. 31(7): 397-405), zinc finger nucleases (ZFNs, Gaj et al. (2013) supra), meganucleases such as I-SceI (Arnould et al. (2007) J Mol Biol 371(1): 49-65; Takeuchi et al. (2011) PNAS USA 108(32): 13077-13082), RNA-guided endonuclease systems such as CRISPR / Cas (Mali et al. (2013) Nat Methods 10(10): 957-963; Mali et al. (2013) Nat Biotechnol 31(9):833-838; Cong et al. (2013) Science 339(6121):819-823) and CRISPR / Cpf1 (Zetsche et al. (2015) Cell 163(3):759-771), triplex-forming molecules, synthetic polyamides and designed zinc finger proteins (Uil et al. (2003) Nucleic Acids Res 31(21):6064-6078). Functional genome editing systems use nucleases that produce site-specific double-strand breaks at the desired location in the genome. The induced double-strand breaks are repaired by non-homologous end joining or homologous recombination. Thus, targeted mutations are obtained. It is advantageous to replace a defective gene (causing a disease or condition) with a normal allele in its natural location by any of these methods because when only a small part of the gene needs to be changed, it is not necessary to include the complete coding sequence and regulatory sequences in the rAAV virion. The expression of the partially replaced gene is also considered to be more consistent with normal cell biology than the complete gene carried by the virion. The preferred gene editing system is CRISPR (including CRISPR / Cpf1 and CRISPR-Cas) because it is faster and cheaper than other methods. A major advantage is that CRISPR can be easily retargeted to different DNA sequences using a single CRISPR guide RNA.Thus, alternatively, or in combination with another embodiment, in another preferred embodiment of the present invention, the rAAV genome comprises at least one of: (i) a polynucleotide comprising a sequence encoding at least one guide RNA (gRNA); wherein the guide RNA is substantially complementary, preferably complementary, to a target polynucleotide sequence in the genome; and (ii) a polynucleotide comprising a sequence encoding a nuclease; wherein the nuclease forms a ribonuclease complex with the guide RNA, and wherein the ribonuclease complex causes site-specific double-stranded DNA breaks in the genome.

[0218] In a preferred embodiment, the modified capsid protein is a modified capsid protein as defined herein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a transgene encoding a gene product of interest. Preferably, the gene product of interest is a gene product of interest as defined above.

[0219] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein.

[0220] a. comprising or consisting of an amino acid residue sequence of formula I:

[0221] y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A

[0222] wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and

[0223] b. present at a position corresponding to an amino acid residue 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a transgene encoding a gene product of interest. Preferably, the gene product of interest is a gene product of interest as defined above.

[0224] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1 P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising the AAV1 P4 modified capsid protein further comprises a transgene encoding a gene product of interest. Preferably, the gene product of interest is a gene product of interest as defined above.

[0225] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising the AAV2 P2 modified capsid protein further comprises a transgene encoding a gene product of interest. Preferably, the gene product of interest is a gene product of interest as defined above.

[0226] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity with SEQ ID NO: 9. Preferably, the rAAV virion comprising the modified capsid protein of AAV7 A6 further comprises a transgene encoding a gene product of interest. Preferably, the gene product of interest is a gene product of interest as defined above.

[0227] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising the AAV9 A2 modified capsid protein further comprises a transgene encoding a gene product of interest. Preferably, the gene product of interest is a gene product of interest as defined above.

[0228] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising the AAVrh10A6 modified capsid protein further comprises a transgene encoding a gene product of interest. Preferably, the gene product of interest is a gene product of interest as defined above.

[0229] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising the AAVrh10A2 modified capsid protein further comprises a transgene encoding a gene product of interest. Preferably, the gene product of interest is a gene product of interest as defined above.

[0230] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising the AAV-DJ-QR-P2 modified capsid protein further comprises a transgene encoding a gene product of interest. Preferably, the gene product of interest is a gene product of interest as defined above.

[0231] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises a constitutive promoter that controls the expression of a transgene (preferably a transgene as defined herein).

[0232] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of an amino acid residue sequence of Formula I: y–G–Q–x–G–(x) 3–R–(x) 3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises a tissue-specific promoter that controls the expression of a transgene (preferably a transgene as defined herein).

[0233] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises a CMV promoter that controls the expression of a transgene (preferably a transgene as defined herein).

[0234] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises a CBA (chicken beta actin) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0235] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an EF1α promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0236] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TGF-β (TGB1) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0237] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an IL1β promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0238] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL8 (CXCL8) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0239] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A, wherein x represents a single amino acid residue and y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue 100-200, preferably 120-180, more preferably 130-170, and more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an MMP3 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0240] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A, wherein x represents a single amino acid residue and wherein y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue 100-200, preferably 120-180, more preferably 130-170, and more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an ICAM1 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0241] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of an amino acid residue sequence of formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS4 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0242] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A, wherein x represents a single amino acid residue and wherein y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, and more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises a COL1A1 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0243] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of an amino acid residue sequence of formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a RUNX2 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0244] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, and more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises a COX2 (PTGS2) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0245] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises a VEGF (VEGFA) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0246] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a constitutive promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0247] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a tissue-specific promoter that controls the expression of a transgene (preferably a transgene as defined herein).

[0248] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CMV promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0249] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CBA (chicken beta actin) promoter controlling expression of a transgene, preferably a transgene as defined herein.

[0250] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an EF1α promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0251] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TGF-β (TGB1) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0252] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL1β promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0253] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL8 (CXCL8) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0254] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP3 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0255] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ICAM1 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0256] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS4 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0257] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COL1A1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0258] In a preferred embodiment, the modified capsid protein is included in the C-terminal portion of the protein. In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV1 P4) having SEQ ID NO: 1. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a RUNX2 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0259] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COX2 (PTGS2) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0260] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a VEGF (VEGFA) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0261] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a constitutive promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0262] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a tissue-specific promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0263] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CMV promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0264] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity with SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CBA (chicken beta actin) promoter controlling expression of a transgene, preferably a transgene as defined herein.

[0265] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an EF1α promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0266] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TGF-β (TGB1) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0267] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity with SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL1β promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0268] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL8 (CXCL8) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0269] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity with SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP3 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0270] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity with SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ICAM1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0271] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS4 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0272] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COL1A1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0273] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a RUNX2 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0274] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2 P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a controlled COX2 (PTGS2) promoter. In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2 P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a VEGF (VEGFA) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0275] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a constitutive promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0276] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a tissue-specific promoter that controls the expression of a transgene (preferably a transgene as defined herein).

[0277] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CMV promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0278] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CBA (chicken beta actin) promoter controlling expression of a transgene (preferably a transgene as defined herein).

[0279] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an EF1α promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0280] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TGF-β (TGB1) promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0281] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL1β promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0282] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL8 (CXCL8) promoter controlling expression of a transgene (preferably a transgene as defined herein).

[0283] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 3 (AAV7A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity with SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP3 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0284] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity with SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ICAM1 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0285] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS4 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0286] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity with SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COL1A1 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0287] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a RUNX2 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0288] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COX2 (PTGS2) promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0289] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a VEGF (VEGFA) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0290] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a constitutive promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0291] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a tissue-specific promoter that controls the expression of a transgene (preferably a transgene as defined herein).

[0292] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CMV promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0293] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CBA (chicken beta actin) promoter controlling expression of a transgene, preferably a transgene as defined herein.

[0294] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an EF1α promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0295] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TGF-β (TGB1) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0296] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL1β promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0297] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL8 (CXCL8) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0298] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP3 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0299] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ICAM1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0300] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS4 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0301] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COL1A1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0302] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a RUNX2 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0303] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COX2 (PTGS2) promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0304] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a VEGF (VEGFA) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0305] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a constitutive promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0306] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a tissue-specific promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0307] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CMV promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0308] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CBA (chicken beta actin) promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0309] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an EF1α promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0310] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TGF-β (TGB1) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0311] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity with SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL1β promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0312] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL8 (CXCL8) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0313] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP3 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0314] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ICAM1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0315] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS4 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0316] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COL1A1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0317] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a RUNX2 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0318] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COX2 (PTGS2) promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0319] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a VEGF (VEGFA) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0320] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a constitutive promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0321] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a tissue-specific promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0322] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CMV promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0323] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CBA (chicken beta actin) promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0324] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an EF1α promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0325] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TGF-β (TGB1) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0326] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL1β promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0327] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL8 (CXCL8) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0328] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP3 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0329] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ICAM1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0330] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS4 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0331] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COL1A1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0332] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a RUNX2 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0333] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COX2 (PTGS2) promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0334] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a VEGF (VEGFA) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0335] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a constitutive promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0336] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a tissue-specific promoter that controls the expression of a transgene (preferably a transgene as defined herein).

[0337] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CMV promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0338] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CBA (chicken beta actin) promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0339] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an EF1α promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0340] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TGF-β (TGB1) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0341] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL1β promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0342] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL8 (CXCL8) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0343] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP3 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0344] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ICAM1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0345] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS4 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0346] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COL1A1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0347] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a RUNX2 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0348] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a COX2 (PTGS2) promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0349] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a VEGF (VEGFA) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0350] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an inducible promoter that controls the expression of a transgene (preferably a transgene as defined herein).

[0351] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of an amino acid residue sequence of formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter that confers expression in joint cells, said promoter controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter that confers expression in joint cells is a promoter that confers expression in cells in arthritic joints. Preferred promoters confer expression in at least one of connective tissue cells, synovial cells, subsynovial cells, intimal macrophages, FLS, chondrocytes, chondrocytes, chondroblasts, adipocytes, osteoclasts, and T cells, preferably the promoter conferring expression in FLS cells.

[0352] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an SV40 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0353] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, and more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises a CAG (cytomegalovirus early enhancer / chicken β-actin) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0354] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter that controls expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is the human alpha-1 antitrypsin (hAAT) promoter.

[0355] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of an amino acid residue sequence of formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter that controls the expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a TBG (thyroxine-binding globulin) promoter.

[0356] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A, wherein x represents a single amino acid residue and wherein y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, and more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an NFκB-responsive (inducible) promoter that controls expression of a transgene (preferably a transgene as defined herein). Preferably, the NFκB-responsive (inducible) promoter is the NFκB-responsive (inducible) minimal CMV promoter. Preferably, the NFκB-responsive (inducible) CMV promoter is the promoter described in Khoury et al. 2007, J Gene Med, 9:596-604.

[0357] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter for an inflammatory regulator that controls expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter is a promoter of a proinflammatory cytokine gene. Preferably, the promoter of a proinflammatory cytokine gene is a minimal promoter of a proinflammatory cytokine gene.

[0358] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an IL-6 (HGF) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0359] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A, wherein x represents a single amino acid residue and wherein y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, and more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises a CXCL10 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0360] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A, wherein x represents a single amino acid residue and y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, and more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an MMP2 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0361] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A, wherein x represents a single amino acid residue and wherein y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, and more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an MMP13 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0362] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A, wherein x represents a single amino acid residue and y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, and more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an ADAMDEC1 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0363] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A, wherein x represents a single amino acid residue and y represents 0, 1, or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, and more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an MMP12 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0364] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of an amino acid residue sequence of formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS5 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0365] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of Formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises a TNFα (TNF) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0366] In a preferred embodiment, the modified capsid protein comprises an amino acid sequence Z at the C-terminal portion of the protein, the residues of which are exposed on the surface of the capsid protein. Preferably, the amino acid sequence Z; a) comprises or consists of the amino acid residue sequence of formula I: y–G–Q–x–G–(x)3–R–(x)3–y–A–Q–A–A wherein x represents a single amino acid residue and wherein y represents 0, 1 or 2 amino acid residues; and b) is present at a position corresponding to an amino acid residue at position 100-200, preferably 120-180, more preferably 130-170, more preferably 140-160 from the C-terminus of the wild-type AAV capsid protein. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises a basic FGF (FGF2) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0367] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an inducible promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0368] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV1P4) having SEQ ID NO: 1. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter that confers expression in joint cells, the promoter controlling transgene expression (preferably a transgene as defined herein). Preferably, the promoter that confers expression in joint cells is a promoter that confers expression to cells in arthritic joints. Preferred promoters confer expression in at least one of connective tissue cells, synovial cells, subsynovial cells, intimal macrophages, FLS, chondrocytes, chondrocytes, chondroblasts, adipocytes, osteoclasts, and T cells, preferably the promoter conferring expression in FLS cells.

[0369] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an SV40 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0370] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CAG (cytomegalovirus early enhancer / chicken beta-actin) promoter controlling expression of a transgene (preferably a transgene as defined herein).

[0371] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV1P4) having SEQ ID NO: 1. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity with SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a human alpha-1 antitrypsin (hAAT) promoter.

[0372] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV1P4) having SEQ ID NO: 1. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity with SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a TBG (thyroxine-binding globulin) promoter.

[0373] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV1P4) having SEQ ID NO: 1. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity with SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an NFκB-responsive (inducible) promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the NFκB-responsive (inducible) promoter is an NFκB-responsive (inducible) minimal CMV promoter. Preferably, the NFκB-responsive (inducible) CMV promoter is the promoter described in Khoury et al. 2007, J Gene Med, 9:596-604.

[0374] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV1P4) having SEQ ID NO: 1. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity with SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter for an inflammatory regulator that controls the expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter is a promoter of a proinflammatory cytokine gene. Preferably, the promoter of a proinflammatory cytokine gene is a minimal promoter of a proinflammatory cytokine gene.

[0375] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL-6 (HGF) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0376] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CXCL10 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0377] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP2 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0378] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP13 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0379] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMDEC1 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0380] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP12 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0381] In a preferred embodiment, the modified capsid protein is included in the C-terminal portion of the protein. In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV1 P4) having SEQ ID NO: 1. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising the modified capsid protein as defined herein further comprises an ADAMTS5 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0382] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TNFα (TNF) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0383] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 1 (AAV1P4). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 1 have at least 80% sequence identity to SEQ ID NO: 11. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a basic FGF (FGF2) promoter controlling expression of a transgene, preferably a transgene as defined herein.

[0384] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an inducible promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0385] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV2P2) having SEQ ID NO: 2. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter that confers expression in joint cells, the promoter controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter that confers expression in joint cells is a promoter that confers expression to cells in arthritic joints. Preferred promoters confer expression in at least one of connective tissue cells, synovial cells, subsynovial cells, intimal macrophages, FLS, chondrocytes, chondrocytes, chondroblasts, adipocytes, osteoclasts, and T cells, preferably the promoter conferring expression in FLS cells.

[0386] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an SV40 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0387] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CAG (cytomegalovirus early enhancer / chicken beta-actin) promoter controlling expression of a transgene (preferably a transgene as defined herein).

[0388] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a human alpha-1 antitrypsin (hAAT) promoter.

[0389] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity with SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a TBG (thyroxine-binding globulin) promoter.

[0390] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV2P2) having SEQ ID NO: 2. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an NFκB responsive (inducible) promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the NFκB responsive (inducible) promoter is an NFκB responsive (inducible) minimal CMV promoter. Preferably, the NFκB-responsive (inducible) CMV promoter is the promoter described in Khoury et al. 2007, J Gene Med, 9:596-604.

[0391] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV2P2) having SEQ ID NO: 2. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter for an inflammatory regulator that controls the expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter is a promoter of a proinflammatory cytokine gene. Preferably, the promoter of a proinflammatory cytokine gene is a minimal promoter of a proinflammatory cytokine gene.

[0392] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL-6 (HGF) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0393] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CXCL10 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0394] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP2 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0395] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP13 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0396] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMDEC1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0397] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP12 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0398] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS5 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0399] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2 P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a controlled TNFα (TNF) promoter. In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 2 (AAV2 P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 2. Preferably, the amino acids at positions 585-602 of SEQ ID NO: 2 have at least 80% sequence identity to SEQ ID NO: 10. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a minimal FGF (FGF2) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0400] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an inducible promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0401] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) with SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter conferring expression in joint cells, the promoter controlling transgene expression (preferably transgene as defined herein). Preferably, the promoter conferring expression in joint cells is a promoter conferring expression of cells in arthritic joints. Preferred promoters confer expression in at least one of connective tissue cells, synovial cells, subsynovial cells, intimal macrophages, FLS, chondrocytes, chondrocytes, chondroblasts, adipocytes, osteoclasts, and T cells, preferably the promoter conferring expression in FLS cells.

[0402] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an SV40 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0403] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CAG (cytomegalovirus early enhancer / chicken beta-actin) promoter controlling expression of a transgene (preferably a transgene as defined herein).

[0404] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a human alpha-1 antitrypsin (hAAT) promoter.

[0405] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a TBG (thyroxine-binding globulin) promoter.

[0406] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an NFκB responsive (inducible) promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the NFκB responsive (inducible) promoter is an NFκB responsive (inducible) minimal CMV promoter. Preferably, the NFκB-responsive (inducible) CMV promoter is the promoter described in Khoury et al. 2007, J Gene Med, 9:596-604.

[0407] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity with SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter for an inflammatory regulator that controls the expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter is a promoter of a proinflammatory cytokine gene. Preferably, the promoter of a proinflammatory cytokine gene is a minimal promoter of a proinflammatory cytokine gene.

[0408] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL-6 (HGF) promoter controlling expression of a transgene (preferably a transgene as defined herein).

[0409] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 3 (AAV7A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CXCL10 promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0410] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity with SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP2 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0411] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP13 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0412] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMDEC1 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0413] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP12 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0414] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS5 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0415] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TNFα (TNF) promoter that controls expression of a transgene (preferably a transgene as defined herein).

[0416] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV7A6) having SEQ ID NO: 3. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3. Preferably, the amino acids at positions 587-601 of SEQ ID NO: 3 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a basic FGF (FGF2) promoter controlling expression of a transgene (preferably a transgene as defined herein).

[0417] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an inducible promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0418] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter that confers expression in joint cells, the promoter controlling transgene expression (preferably a transgene as defined herein). Preferably, the promoter that confers expression in joint cells is a promoter that confers expression in cells in arthritic joints. Preferred promoters confer expression in at least one of connective tissue cells, synovial cells, subsynovial cells, intimal macrophages, FLS, chondrocytes, chondrocytes, chondroblasts, adipocytes, osteoclasts, and T cells, preferably the promoter conferring expression in FLS cells.

[0419] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an SV40 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0420] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CAG (cytomegalovirus early enhancer / chicken beta-actin) promoter controlling expression of a transgene (preferably a transgene as defined herein).

[0421] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a human alpha-1 antitrypsin (hAAT) promoter.

[0422] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a TBG (thyroxine-binding globulin) promoter.

[0423] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an NFκB-responsive (inducible) promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the NFκB-responsive (inducible) promoter is an NFκB-responsive (inducible) minimal CMV promoter. Preferably, the NFκB-responsive (inducible) CMV promoter is the promoter described in Khoury et al. 2007, J Gene Med, 9:596-604.

[0424] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter for an inflammatory regulator that controls the expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter is a promoter of a proinflammatory cytokine gene. Preferably, the promoter of a proinflammatory cytokine gene is a minimal promoter of a proinflammatory cytokine gene.

[0425] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL-6 (HGF) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0426] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CXCL10 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0427] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP2 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0428] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP13 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0429] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMDEC1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0430] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP12 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0431] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS5 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0432] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 4 (AAV9A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TNFα (TNF) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0433] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV9A2) having SEQ ID NO: 4. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 4. Preferably, the amino acids at positions 586-600 of SEQ ID NO: 4 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a basic FGF (FGF2) promoter controlling expression of a transgene (preferably a transgene as defined herein).

[0434] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an inducible promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0435] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO:5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO:5. Preferably, the amino acids at positions 588-602 of SEQ ID NO:5 have at least 80% sequence identity to SEQ ID NO:9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter that confers expression in joint cells, said promoter controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter that confers expression in joint cells is a promoter that confers expression in cells in arthritic joints. Preferred promoters confer expression in at least one of connective tissue cells, synovial cells, subsynovial cells, intimal macrophages, FLS, chondrocytes, chondrocytes, chondroblasts, adipocytes, osteoclasts, and T cells, preferably the promoter conferring expression in FLS cells.

[0436] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an SV40 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0437] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CAG (cytomegalovirus early enhancer / chicken beta-actin) promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0438] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a human alpha-1 antitrypsin (hAAT) promoter.

[0439] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity with SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a TBG (thyroxine-binding globulin) promoter.

[0440] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an NFκB-responsive (inducible) promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the NFκB-responsive (inducible) promoter is an NFκB-responsive (inducible) minimal CMV promoter. Preferably, the NFκB-responsive (inducible) CMV promoter is the promoter described in Khoury et al. 2007, J Gene Med, 9:596-604.

[0441] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter for an inflammatory regulator that controls expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter is a promoter of a proinflammatory cytokine gene. Preferably, the promoter of a proinflammatory cytokine gene is a minimal promoter of a proinflammatory cytokine gene.

[0442] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL-6 (HGF) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0443] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CXCL10 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0444] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP2 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0445] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP13 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0446] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMDEC1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0447] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP12 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0448] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS5 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0449] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TNFα (TNF) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0450] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 5 (AAVrh10 A6). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 5 have at least 80% sequence identity to SEQ ID NO: 9. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a basic FGF (FGF2) promoter controlling expression of a transgene, preferably a transgene as defined herein.

[0451] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an inducible promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0452] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO:6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO:6. Preferably, the amino acids at positions 588-602 of SEQ ID NO:6 have at least 80% sequence identity to SEQ ID NO:8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter that confers expression in joint cells, said promoter controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter that confers expression in joint cells is a promoter that confers expression in cells in arthritic joints. Preferred promoters confer expression in at least one of connective tissue cells, synovial cells, subsynovial cells, intimal macrophages, FLS, chondrocytes, chondrocytes, chondroblasts, adipocytes, osteoclasts, and T cells, preferably the promoter conferring expression in FLS cells.

[0453] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an SV40 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0454] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CAG (cytomegalovirus early enhancer / chicken beta-actin) promoter controlling expression of a transgene, preferably a transgene as defined herein.

[0455] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a human alpha-1 antitrypsin (hAAT) promoter.

[0456] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter that controls expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a TBG (thyroxine-binding globulin) promoter.

[0457] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an NFκB-responsive (inducible) promoter controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the NFκB-responsive (inducible) promoter is an NFκB-responsive (inducible) minimal CMV promoter. Preferably, the NFκB-responsive (inducible) CMV promoter is the promoter described in Khoury et al. 2007, J Gene Med, 9:596-604.

[0458] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter of an inflammatory regulator that controls expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter is a promoter of a proinflammatory cytokine gene. Preferably, the promoter of a proinflammatory cytokine gene is a minimal promoter of a proinflammatory cytokine gene.

[0459] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL-6 (HGF) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0460] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CXCL10 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0461] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP2 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0462] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP13 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0463] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMDEC1 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0464] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity with SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP12 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0465] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS5 promoter for controlling expression of a transgene, preferably a transgene as defined herein.

[0466] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TNFα (TNF) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0467] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 6 (AAVrh10 A2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6. Preferably, the amino acids at positions 588-602 of SEQ ID NO: 6 have at least 80% sequence identity to SEQ ID NO: 8. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a basic FGF (FGF2) promoter controlling expression of a transgene, preferably a transgene as defined herein.

[0468] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an inducible promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0469] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter that confers expression in joint cells, the promoter controlling transgene expression (preferably a transgene as defined herein). Preferably, the promoter that confers expression in joint cells is a promoter that confers expression in cells in arthritic joints. Preferred promoters confer expression in at least one of connective tissue cells, synovial cells, subsynovial cells, intimal macrophages, FLS, chondrocytes, chondrocytes, chondroblasts, adipocytes, osteoclasts, and T cells, preferably the promoter conferring expression in FLS cells.

[0470] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an SV40 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0471] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CAG (cytomegalovirus early enhancer / chicken beta-actin) promoter controlling expression of a transgene (preferably a transgene as defined herein).

[0472] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a human alpha-1 antitrypsin (hAAT) promoter.

[0473] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a liver-specific promoter for controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the liver-specific promoter is a TBG (thyroxine-binding globulin) promoter.

[0474] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence having SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an NFκB responsive (inducible) promoter controlling expression of a transgene (preferably a transgene as defined herein). Preferably, the NFκB responsive (inducible) promoter is an NFκB responsive (inducible) minimal CMV promoter. Preferably, the NFκB-responsive (inducible) CMV promoter is the promoter described in Khoury et al. 2007, J Gene Med, 9:596-604.

[0475] In a preferred embodiment, the modified capsid protein comprises or consists of an amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a promoter for an inflammatory regulator that controls the expression of a transgene (preferably a transgene as defined herein). Preferably, the promoter is a promoter of a proinflammatory cytokine gene. Preferably, the promoter of a proinflammatory cytokine gene is a minimal promoter of a proinflammatory cytokine gene.

[0476] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an IL-6 (HGF) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0477] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a CXCL10 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0478] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP2 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0479] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence of SEQ ID NO: 7 (AAV-DJ-QR-P2). Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP13 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0480] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMDEC1 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0481] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an MMP12 promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0482] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises an ADAMTS5 promoter for controlling expression of a transgene (preferably a transgene as defined herein).

[0483] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity with SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a TNFα (TNF) promoter that controls expression of a transgene, preferably a transgene as defined herein.

[0484] In a preferred embodiment, the modified capsid protein comprises or consists of the amino acid sequence (AAV-DJ-QR-P2) having SEQ ID NO: 7. Preferably, the modified capsid protein has at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7. Preferably, the amino acids at positions 587-604 of SEQ ID NO: 7 have at least 80% sequence identity to SEQ ID NO: 12. Preferably, the rAAV virion comprising a modified capsid protein as defined herein further comprises a basic FGF (FGF2) promoter controlling expression of a transgene, preferably a transgene as defined herein.

[0485] In a second aspect, the present invention relates to rAAV compositions for treating, preventing or suppressing symptoms associated with arthritis diseases, wherein the rAAV compositions comprise rAAV virions of the present invention and pharmaceutically acceptable carriers, diluents, solubilizers, fillers, preservatives and / or excipients, preferably pharmaceutically acceptable carriers. Such pharmaceutically acceptable carriers, diluents, solubilizers, fillers, preservatives and / or excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, 20th edition. Baltimore, MD: Lippincott Williams & Wilkins, 2000. Any suitable pharmaceutically acceptable carrier, diluent, solubilizer, filler, preservative and / or excipient can be used in the compositions of the present invention (see, for example, Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro (Editor) Mack Publishing Company, April 1997). Preferred pharmaceutical forms will be combined with sterile saline, glucose solution or buffer solution or other pharmaceutically acceptable sterile fluids. Alternatively, solid supports may be used, such as, for example, microcarrier beads.

[0486] Pharmaceutical compositions are usually sterile and stable under manufacturing and storage conditions. Pharmaceutical compositions can be formulated as solutions, microemulsions, liposomes or other ordered structures suitable for adapting to high drug concentrations. Carriers can be solvents or dispersion media, and the solvents or dispersion media contain, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Suitable fluidity can be maintained, for example, by using a coating agent such as lecithin, by maintaining the required particle size in the case of a dispersion, and by using a surfactant. In many cases, isotonic agents, for example sugars, polyols such as mannitol, sorbitol, or sodium chloride will preferably be included in the composition. Extended absorption of injectable compositions can be achieved by including, for example, monostearate and gelatin in the composition for extended absorption. Parvovirus virions can be used as pills or in controlled release formulations, for example, in compositions comprising slow-release polymers or other carriers that protect compounds from rapid release, including implants and microencapsulated delivery systems. Can for example use biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic acid, polyglycolic acid copolymer (PLG).As used herein, "pharmaceutically acceptable carrier" or "excipient" preferably include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents that are physiologically compatible.Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the temporary preparation of sterile injectable solutions or dispersions.The purposes of such media and agents for pharmaceutically active substances are well known in the art.Unless any conventional media or agent are incompatible with the active compound, it is expected that its purposes in the pharmaceutical composition of the present invention will be used.

[0487] It can be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, "dosage unit form" refers to physically discrete units suitable as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect, and the required pharmaceutical carrier. The specifications for the dosage unit forms of the present invention may be dictated by the unique characteristics of the active compound and the specific therapeutic effect to be achieved, as well as by the limitations inherent in the art of compounding such active compounds for the treatment of individual conditions.

[0488] Supplementary active compounds may also be incorporated into the pharmaceutical compositions of the invention.Guidance regarding the co-administration of additional therapeutic agents can be found, for example, in the Canadian Pharmacists Association's Pharmaceutical and Professional Synopsis (CPS).

[0489] In one embodiment, the rAAV composition further comprises empty particles (i.e., only capsid particles, therefore not comprising the rAAV genome). Therefore, alternatively, or in combination with another embodiment, in another embodiment of the present invention, the rAAV composition of the present invention further comprises empty capsids, and the ratio of empty capsids to rAAV virions is at least 1: 1, more preferably at least 5: 1, even more preferably at least 10: 1. The rAAV composition may comprise rAAV virions and empty capsids as defined above, for example as defined in WO 2016 / 055437, which is incorporated herein by reference, and as described in Aalbers et al. (2017) Hum. Gene Ther. 28 (2): 168-178. Compared to the rAAV transgenic vector of the composition of the present invention, the empty capsid may have the same serotype or a different serotype. Preferably, the empty capsid has the same serotype as the rAAV virion. In such rAAV compositions, the capsids of the empty capsids and rAAV virions may comprise modified capsid proteins of the present invention, preferably modified capsid proteins of the same type. However, also included are rAAV compositions in which the empty capsids have a different serotype or a different modified capsid protein than the modified capsid protein of the rAAV virion. Also included are rAAV compositions in which the empty capsids have a mixture of serotypes, such as, but not limited to, a mixture of AAV2 and AAV5 capsids. The inventors have reported an increased effect on transgene expression in the joints following intra-articular administration of rAAV virions mixed with a significant amount of empty capsids. Preferably, the rAAV virions and empty capsids are present in the composition at a ratio of empty capsids to rAAV virions of at least 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 15:1, 20:1, 50:1, 100:1 or 1000:1, preferably at least 5:1 (i.e., the amount of empty capsids is at least 5 times the amount of rAAV transgenic vector). Preferably, the composition comprises rAAV virions and empty capsids, and the ratio of empty capsids to rAAV-transgene vectors is at most 10000:1, 5000:1, 4000:1, 3000:1, 2000:1, 1000:1, 500:1, 400:1, 300:1, 200:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 10:1 or 5:1, preferably at most 1000:1. Preferably, the composition comprises rAAV virions and empty capsids, and the ratio of empty capsids to rAAV virions is 1:1 to 100:1, 2:1 to 100:1, 5:1 to 100:1, 1:1 to 20:1, 2:1 to 20:1 or preferably between 5:1 and 20:1.

[0490] An embodiment is provided above, wherein rAAV virions and empty capsids are present in a single composition. The present invention also includes an alternative embodiment, wherein rAAV virions and empty capsids are present in (at least two or more) separate, different compositions. In this alternative embodiment, rAAV virions and empty capsids can be administered separately in terms of time (e.g., sequentially) and / or position, wherein the position is understood to be an administration site. In addition, rAAV virions and empty capsids can be administered simultaneously, for example, at substantially the same time, optionally in separate positions.

[0491] In a third aspect, the present invention relates to a rAAV composition and an immunosuppressant for treating or preventing an arthritis disease or for treating or preventing symptoms associated with an arthritis disease, wherein the rAAV composition is as defined above, and wherein the treatment or prevention comprises administering the rAAV composition and administering the immunosuppressant to the individual. WO 2016 / 055437, incorporated herein by reference, discloses the increasing effect of immunosuppressants on AAV transgene expression when a subject is treated with both an immunosuppressant and a rAAV virion. In addition, WO 2016 / 055437 discloses the surprising synergistic effect of immunosuppressants on rAAV transgene expression together with an empty vector. In one embodiment, the immunosuppressant is applied separately from the rAAV composition, and separate means separate in position and / or time. In such an embodiment, the immunosuppressant and the rAAV composition can be present in separate and different compositions. The immunosuppressant, rAAV virion, and optional empty vector can even each be present in separate, different compositions. In another embodiment, the immunosuppressant and the rAAV composition can be present in a single composition. In another embodiment, the rAAV virions and the immunosuppressant are present in a single composition, and preferably, this composition is used for treatment together with a separate composition comprising empty capsids. In a further embodiment, the immunosuppressant and the empty capsid are present in a single composition, and preferably, this composition is used for treatment together with a separate composition comprising rAAV virions. Therefore, the present invention also provides a composition comprising an empty capsid and an immunosuppressant as defined herein, a composition comprising rAAV virions and an immunosuppressant as defined herein, and a composition comprising an rAAV composition as defined herein and an immunosuppressant.

[0492] Preferably, the immunosuppressant for the present invention is an innate immune cell inhibitor, preferably a macrophage inhibitor. Innate immune cells are defined in this article as neutrophils, macrophages, monocytes, eosinophils, basophils or dendritic cells, which have the potential to participate in the inflammatory response to foreign substances. Innate immune cell inhibitors are defined in this article as agents that cause innate immune cell activity and / or innate immune cell number to reduce. Macrophage inhibitors are defined in this article as agents that cause macrophage activity and / or macrophage number to reduce." macrophage" is understood in this article as innate immune cells that engulf and digest cell debris, foreign substances, microorganisms and cancer cells in the process referred to as phagocytosis. Preferably, the innate immune cell or macrophage inhibitor of the invention results in a decrease in the number or activity of innate immune cells or macrophages by at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 45%, 55%, 65%, 75%, 85%, 95% or preferably 100% compared to the initial number or activity of innate immune cells or macrophages before treatment. Innate immune cell or macrophage activity and / or number can be detected by any suitable assay known to those skilled in the art, such as, but not limited to, the MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide) colorimetric assay for in vitro testing of macrophage cytotoxic activity as described by Ferrari et al. (Journal of Immunological Methods, 131 (1990) 165-172), by measuring cytokine levels (e.g., CCL2, TNF), by histological and histochemical detection methods, such as by CD68 labeling, or by in vivo magnetic resonance imaging (MRI) to detect the uptake of superparamagnetic iron oxide (SPIO) by macrophages (preferably after intravenous administration of SPIO), as reviewed by Yi-Xiang J. Wang (Quant. Imaging Med Surg (2011) 1: 35-40). Detection can be performed in vitro or in vivo. Preferably, in vivo detection is performed in an animal model, preferably a rat or mouse model.

[0493] Preferably, the immunosuppressant is a glucocorticoid and / or a bisphosphonate, preferably a liposomal bisphosphonate. Specific non-limiting examples of glucocorticoids are cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, and aldosterone. Preferably, the immunosuppressant is triamcinolone. Specific non-limiting examples of bisphosphonates are etidronate, clodronate, tiludronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, and zoledronate. Preferably, the bisphosphonate is a liposomally encapsulated bisphosphonate or a liposomal bisphosphonate, preferably a liposomal clodronate. Preferably, the glucocorticoid is not dexamethasone. It should be understood that the inflammatory or macrophage inhibitor of the present invention is not limited to glucocorticoids and / or bisphosphonates. For example, the inflammatory or macrophage inhibitor of the present invention can also be an inflammatory or macrophage depleting antibody, such as an anti-F4 / 80 antibody. Preferably, such an antibody is a human or humanized antibody. Other related immunosuppressants used in the present invention are cytostatic drugs (e.g., alkylating agents and / or antimetabolites such as methotrexate), drugs that change the purinergic signaling pathway (e.g., methotrexate, adenosine analogs, adenosine receptor antagonists or agonists), non-steroidal anti-inflammatory drugs (NSAIDS, such as ibuprofen, diclofenac, meloxicam, naproxen, acetylsalicylic acid), biological agents such as TNF blockers (e.g., infliximab, etanercept, adalimumab, certolizumab pegol, golimumab), IL-6 blockers (e.g., tocilizumab), IL-2 blockers (e.g., basiliximab), TNF blockers (e.g., TNF blockers), IL-6 blockers (e.g., cytokine blockers ...2 blockers (e.g., basiliximab), TNF blockers (e.g., TNF blockers), IL-6 blockers (e.g., cytokine blockers), IL-2 blockers (e.

[00135] In some embodiments, the present invention includes but is not limited to: anti-IL-1β inhibitors (e.g., anakinra, rilonacept, canakinumab), anti-IL-17 (secukinumab, brodalumab, ixekinumab), anti-IL-12 / IL-23 (ustekinumab), PDE4 inhibitors (apremilast), muromonab, abatacept, and / or rituximab, and / or other compounds such as hydroxychloroquine, chloroquine, leflunomide, sulfasalazine, azathioprine, cyclophosphamide, cyclosporine, gold salts, mTOR inhibitors (e.g., rapamycin / sirolimus, everolimus), and penicillamine.

[0494] Preferably, the rAAV composition and / or the composition comprising empty capsids and / or the composition comprising an immunosuppressive agent further comprises a pharmaceutically acceptable carrier, diluent, solubilizer, filler, preservative and / or excipient as defined elsewhere herein.

[0495] Preferably, the gene therapy according to the present invention also includes the administration of an immunosuppressant as defined herein, which is present in the rAAV composition, or contained in a separate, different composition, i.e., a composition separate and different from the rAAV composition. When administered, the rAAV composition and / or empty capsid and / or immunosuppressant of the present invention are delivered to an individual, a cell, a tissue or an organ of the individual, preferably an individual suffering from a condition or disease as defined herein. Preferably, the rAAV composition and the immunosuppressant are administered simultaneously. Simultaneous administration should be understood herein as more or less simultaneous administration, preferably with a time interval of no more than 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 12 hours or 24 hours, preferably with a time interval of no more than 15 minutes. In another embodiment, the rAAV composition and the immunosuppressant are administered sequentially, wherein the immunosuppressant is preferably administered before the rAAV composition. Preferably, the immunosuppressant is administered at least 1 hour, 3 hours, 12 hours, 24 hours, 2 days, 4 days or 1 week before the administration of the rAAV composition. Where the rAAV virions and empty capsids are present in separate compositions, the immunosuppressant can be administered simultaneously with the empty capsids or within at...

Claims

1. Use of a recombinant adeno-associated virus (rAAV) virion comprising a modified capsid protein and a promoter operably linked to a nucleotide sequence encoding a gene product of interest in the preparation of a medicament for treating or preventing an arthritic disease or for treating or preventing a symptom associated with an arthritic disease, wherein the arthritic disease is gout, pseudogout, ankylosing spondylitis, rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis, juvenile idiopathic arthritis and Still's disease, wherein the symptom is joint pain or inflammation of one or more arthritic joints, (a) the target gene product is an IL-6 inhibitor; and (b) The modified capsid protein is represented by any one of SEQ ID NOs: 1-7.

2. The use according to claim 1, wherein the IL-6 inhibitor is selected from the group consisting of IL-6 receptor antagonists, humanized anti-IL-6 monoclonal antibodies, chimeric anti-IL-6 monoclonal antibodies, humanized rabbit anti-IL-6 monoclonal antibodies and soluble IL-6 receptors.

3. The use according to claim 2, wherein at least one i) the IL-6 receptor antagonist is at least one of tocilizumab and sanofizumab; ii) the humanized anti-IL-6 monoclonal antibody is at least one of olozumab and sirukumab; iii) the chimeric anti-IL-6 monoclonal antibody is siltuximab; and iv) The humanized rabbit anti-IL-6 monoclonal antibody is clazakizumab.

4. The use according to any one of claims 1 to 3, wherein the promoter is a constitutive promoter or an inducible promoter. The use according to claim 4 , wherein the promoter is a NFκB-responsive promoter. The use according to claim 5, wherein the NFκB-responsive promoter is a NFκB-responsive CMV promoter. The use according to claim 6, wherein the NFκB-responsive CMV promoter is a NFκB-responsive minimal CMV promoter.

8. The use according to claims 1-3, wherein the sequence of the capsid protein is represented by SEQ ID NO: 4 or SEQ ID NO:

6.

9. Use of a rAAV composition in the preparation of a medicament for treating or preventing an arthritic disease or for treating or preventing a symptom associated with an arthritic disease, wherein the symptom is joint pain or inflammation of one or more arthritic joints, wherein the arthritic disease is gout, pseudogout, ankylosing spondylitis, rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis, juvenile idiopathic arthritis and Still's disease, wherein the rAAV composition comprises a rAAV virion as defined in any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. Use of a rAAV composition and an immunosuppressant in the preparation of a medicament for treating or preventing an arthritic disease or for treating or preventing a symptom associated with an arthritic disease, wherein the arthritic disease is gout, pseudogout, ankylosing spondylitis, rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis, juvenile idiopathic arthritis and Still's disease, wherein the symptom is joint pain or inflammation of one or more arthritic joints, wherein the rAAV composition is as defined in claim 9, and wherein the treatment or prevention comprises administering the rAAV composition and administering the immunosuppressant to the individual. The use according to claim 10, wherein the rheumatoid arthritis is juvenile rheumatoid arthritis.

12. The use according to claim 10, wherein the gout is pseudogout.

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