Compositions and methods of generating fusion products

Abstract

Disclosed herein are compositions for and methods of generating chimeric RNA molecules via trans-splicing and methods of treating, preventing, and / or minimizing progression of a disease or disorder using those chimeric RNA molecules to generate fusion products.

Description

COMPOSITIONS AND METHODS OF GENERATING FUSION PRODUCTS I. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 779,507 filed 28 March 2025, which is incorporated by reference herein in its entirety.II. REFERENCE TO THE SEQUENCE LISTING

[0002] The Sequence Listing submitted 27 March 2026 as an XML file named “25-4046-WO SL”, created on 27 March 2026 and having a size of 176,128 bytes is hereby incorporated by reference pursuant to 37 C. F. R. § 1.52(e)(5).III. BACKGROUND

[0003] RNA trans-splicing is a method to precisely rewrite large stretches of RNA that leverages splicing mechanisms to join two transcripts in trans, forming a single chimeric RNA product. One such strategy hijacks the canonical RNA splicing machinery to achieve mRNA trans-splicing, which involves targeted incorporation of recombinant exon(s) into a pre-mRNA transcript. This approach termed spliceosome-mediated RNA trans-splicing or SMaRT features an RNA molecule comprised of an antisense sequence linked to a hemi-intron and one or more exons. Following delivery to the nucleus, the hybridization of the antisense binding domain to the target pre-mRNA enables the intronic sequence to incorporate the recombinant exons in trans by co-opting the splicing machinery, resulting in a chimeric mRNA product.

[0004] However, there remains an urgent need for a minimally invasive, definitive, and durable therapy to address the sequelae of symptoms associated with various diseases and disorders. Consequently, the present disclosure provides compositions for and methods of generating chimeric RNA molecules via trans-splicing and ensuring production of a fusion product (without CRISPR), thereby treating, preventing, and / or minimizing progression of a disease and / or disorder, which can be used alone or in combination with other treatments.IV. BRIEF DESCRIPTION OF THE FIGURES

[0005] FIG. 1A shows a schematic of the albumin trans-splicing approach while FIG. 1B shows albumin fused to a protein, an enzyme, or a scFv

[0006] FIG. 2 shows a schematic of single binding domain guide tiling design for 50 bp guides (top) and 150 bp guides (bottom).

[0007] FIG. 3 shows a heat map of single binding domain guide trans-splicing efficiency.

[0008] FIG. 4 Shows a schematic of double binding domain guide optimization.

[0009] FIG. 5 shows a heat map of barcode counts for the human albumin trans-splicing RNA library. X-axis was the guide position for the upstream guide in the trans-splicing RNA. Y-axis was the guide position for the downstream guide in the trans-splicing RNA. The % reads were proportional to guide efficiency.1110026078 1

[0010] FIG.6 shows a DNA gel of human albumin-HA fusion PCR reactions. Expected product size for precise trans-splicing was 1 kilobase. Lane 1 was NEB 1 kb plus DNA ladder. Lanes 2 and 3 were PCR reactions from HUH-7 cells transfected with trans-splicing RNA constructs lacking a targeting domain. Lanes 4 and 5 were PCR reactions from HUH-7 cells transfected with trans-splicing RNA constructs containing the optimal targeting domain (465-514 + 165-214). Lane 6 was NEB 1 kb plus DNA ladder.

[0011] FIG. 7 shows a Sanger trace of trans-spliced RNA comprised of endogenous human albumin exon 1-13 and cargo exon.

[0012] FIG. 8 shows the quantification of trans-splicing efficiency in HUH-7 cells measured by targeted amplicon sequencing.

[0013] FIG. 9 shows a heat map of barcode counts for the mouse albumin trans-splicing RNA library. X-axis was the guide position for the upstream guide in the trans-splicing RNA. Y-axis was the guide position for the downstream guide in the trans-splicing RNA. The % reads were proportional to guide efficiency.

[0014] FIG. 10 shows a DNA gel of mouse albumin-HA fusion PCR reactions. Expected product size for precise trans-splicing was 1 kilobase. Lane 1 was a PCR reaction from AML-12 cells transfected with pUC19. Lanes 2 was a PCR reaction from AML- 12 cells transfected with trans-splicing RNA constructs lacking a targeting domain. Lanes 3, 4, and 5 were PCR reactions from AML- 12 cells transfected with trans-splicing RNA constructs containing the targeting domains (470-519 + 20-69), (420-469 + 220-269), and (420-469 + 170-219) respectively. Lane 6 was NEB 1 kb plus DNA ladder.

[0015] FIG. 11 shows a Sanger trace of trans-spliced RNA comprised of endogenous mouse albumin exon 1-13 and cargo exon (bottom) aligned to the endogenous mouse albumin sequence (top). Single nucleotide polymorphisms in the third position of codons encoding Gly1, Leu4, Val5, Thr6confirmed the product was a from trans-spliced transcripts.

[0016] FIG. 12A-FIG. 12B show fluorescence microscopy images of mouse AML- 12 cells transfected with albumin-egfp trans-splicing RNA. that either lacked a targeting domain (FIG.12A) or contained the optimal targeting domain (FIG. 12B).

[0017] FIG. 13A-FIG. 13B show a Western blot of mouse serum following HA-immunoprecipitation with anti-HA antibody (FIG. 13A) or anti-albumin (FIG. 13B). Serum was harvested from mice injected intravenously with AAV expressing on-target albumin-HA trans-splicing RNA (G20 HA), albumin-HA trans-splicing RNA lacking a targeting domain (NT HA), or on-target albumin-EGFP trans-splicing RNA (G20 EGFP).2110026078 1

[0018] FIG. 14 shows the quantification of trans-splicing efficiency in mouse hepatocytes 8 weeks after intravenous injection of AAV8 vectors expressing on-target albumin-apelin trans-splicing RNA.

[0019] FIG. 15 shows the differential gene expression analysis of mouse hepatocytes treated with PBS (Group A) and AAV8 vectors expressing on-target albumin-apelin trans-splicing RNA (Group B).

[0020] FIG. 16 shows a qPCR comparison of Tgfbl mRNA expression in mouse kidneys following unilateral ischemia reperfusion injury (IRI) treated with PBS or escalating doses of AAV8 vectors expressing on-target albumin-apelin trans-splicing RNA. Expression was normalized to Tgfbl mRNA expression in sham surgery mouse injected with PBS.

[0021] FIG. 17 shows a Western blot of non-human primate serum following HA-immunoprecipitation with anti-HA antibody. Serum was harvested from non-human primates injected intravenously with AAV expressing on-target albumin-HA trans-splicing containing the optimal targeting domain (465-514 + 165-214). Serum was harvested pre-injection (lane 1), one-(lane 2), two (lane 3), three- (lane 4), and five-months post injection (lane 5).

[0022] FIG. 18 shows a heat map of barcode counts for the mouse transferrin trans-splicing RNA library. X-axis was the guide position for the upstream guide in the trans-splicing RNA. Y-axis was the guide position for the downstream guide in the trans-splicing RNA. The % reads were proportional to guide efficiency.

[0023] FIG. 19 shows a Western blot of mouse serum following HA-immunoprecipitation with anti -transferrin antibody. Serum was harvested from mice injected intravenously with AAV expressing on-target transferrin-HA trans-splicing RNA for three efficient guide architectures identified by the barcode screen in FIG. 18. Duplicates of serum samples from mice injected with each guide pair were as follows: upstream guide targeting intron position 1317-1366 linked to a downstream guide targeting intron position 1167-1216 (lanes 1&2), upstream guide targeting intron position 1167-1216 linked to a downstream guide targeting intron position 817-866 (lanes 3&4), upstream guide targeting intron position 417-466 linked to a downstream guide targeting intron position 167-216 (lanes 5&6).

[0024] FIG. 20 shows a Sanger trace of trans-spliced RNA comprised of endogenous mouse transferrin exon 1-16 and cargo exon (bottom) aligned to the endogenous mouse transferrin sequence (top). Single nucleotide polymorphisms in the third position of codons encoding Leu, Leu, Thr confirmed the product was a from trans-spliced transcripts.

[0025] FIG. 21 shows a Western blot of mouse tissue lysates following HA-immunoprecipitation with anti-HA antibody (left) or anti-transferrin (right). Organs and serum were harvested from3110026078 1mice injected intravenously with AAV expressing on-target transferrin-HA trans-splicing RNA at escalating doses of AAV and compared to a PBS injected control.

[0026] FIG.22 shows a heat map of barcode counts for the human transferrin trans-splicing RNA library. X-axis is the guide position for the upstream guide in the trans-splicing RNA. Y-axis is the guide position for the downstream guide in the trans-splicing RNA. %reads are proportional to guide efficiency.

[0027] FIG. 23 shows a DNA gel of human transferrin-HA fusion PCR reactions. Expected product size for precise trans-splicing was 1 kilobase. Lane 1 was PCR reaction from HUH-7 cells transfected with trans-splicing RNA constructs lacking a targeting domain. Lanes 3. 4 and 5 were PCR reactions from HUH-7 cells transfected with transferrin trans-splicing RNA constructs containing the targeting domains [1098-1147 + 748-797], [598-647+248-297], and [448-497+148-197] respectively. Lane 5 was NEB Ikb plus DNA ladder.

[0028] FIG. 24 shows a Western blot of mouse serum following HA-immunoprecipitation with anti-transferrin antibody. Serum was harvested from cDNA-uPA / SCID mice transplanted and engrafted with primary human hepatocytes, 4 weeks following intravenous administration of AAV containing genomes that express transferrin trans-splicing RNA containing the targeting domain [448-497+148-197], Lane 1 was serum from a PBS injected mouse. Lanes 2-4 were serum from mice injected with the AAV.V. BRIEF SUMMARY

[0029] Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence; wherein the exogenous RNA to be transspliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0030] Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3' hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and a second targeting guide sequence; wherein each of the targeting guide sequences bind to a complementary sequence in any intron of the targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is 4110026078 1a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence; wherein each of the targeting guide sequences bind to a complementary sequence in any intron of the targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0031] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and one or more targeting guide sequences; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0032] Disclosed herein is a nucleic acid molecule for trans-splicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5 ’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0033] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0034] Disclosed herein is a nucleic acid molecule for trans-splicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.5110026078 1

[0035] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0036] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0037] Disclosed herein is a nucleic acid molecule for trans-splicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0038] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0039] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0040] Disclosed herein is a nucleic acid molecule for trans-splicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5 ’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0041] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0042] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-6110026078 1mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0043] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0044] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0045] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences; a 3' hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.VI. DETAILED DESCRIPTION

[0046] The present disclosure describes formulations, compounded compositions, kits, capsules, containers, and / or methods thereof. It is to be understood that the inventive aspects of which are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may. of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.7110026078 1

[0047] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be constmed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.A. Definitions

[0048] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0049] This disclosure describes inventive concepts with reference to specific examples. However, the intent is to cover all modifications, equivalents, and alternatives of the inventive concepts that are consistent with this disclosure.

[0050] As used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

[0051] In an aspect, “consisting essentially of’ limits the scope of a claim to the recited components in a composition or the recited steps in a method as well as those that do not materially affect the basic and novel characteristic or characteristics of the claimed composition or claimed method. The phrase “consisting of’ excludes any component, step, or element that is not recited in the claim. The phrase “comprising” is synonymous with “including”, “containing”, or “characterized by”, and is inclusive or open-ended. “Comprising” does not exclude additional, unrecited components or steps.

[0052] In an aspect, when referring to any numerical value, the term “about” means a value falling within a range that is ± 10% of the stated value.

[0053] In an aspect, ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value 8110026078 1■‘10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0054] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0055] In an aspect, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. In an aspect, a disclosed method can optionally comprise one or more additional steps, such as, for example, repeating an administering step or altering an administering step.

[0056] In an aspect, “isolated” refers to a nucleic acid molecule or a nucleic acid sequence that has been substantially separated, produced apart from, or purified away from other biological components in the cell or tissue of an organism in which the component occurs, such as other cells, chromosomal and extrachromosomal DNA and RNA, and proteins. Nucleic acids and proteins that have been “isolated” include nucleic acids and proteins purified by standard purification methods. The term also embraces nucleic acids and proteins prepared by recombinant expression in a host cell as well as chemically synthesized nucleic acids and proteins.

[0057] In an aspect, the term “diagnosed” means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by one or more of the disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof, or by one or more of the disclosed methods. For example, “diagnosed with a disease or disorder” means having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can be treated by one or more of the disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof, or by one or more of the disclosed methods. For example, “suspected of having a disease or disorder” can mean having been subjected to an examination by a person of skill, for example, a physician, and found to have a condition that can likely be treated by one or more of by one or more of the disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof, or by one or more of the disclosed methods. In an aspect, an examination can be physical, can9110026078 1involve various tests (e.g., blood tests, genotyping, biopsies, etc.) and assays (e.g., enzymatic assay), or a combination thereof.

[0058] In an aspect, the term “prevent” or “preventing” or “prevention” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit, or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. In an aspect, preventing a disease or disorder having chromatin deregulation and / or chromatin dysregulation is intended. The words “prevent”, “preventing”, and “prevention” also refer to prophylactic or preventative measures for protecting or precluding a subject (e.g., an individual) not having a given a disease or disorder or related complication from progressing to that complication.

[0059] In an aspect, the skilled person can determine an efficacious dose, an efficacious schedule, and an efficacious route of administration for one or more of the disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof to treat or prevent a disease or disorder. In an aspect, the skilled person can also alter, change, or modify an aspect of an administering step to improve efficacy of one or more of the disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof.

[0060] By “determining the amount” is meant both an absolute quantification of a particular analyte (e g., an mRNA sequence containing a particular tag) or a determination of the relative abundance of a particular analyte (e.g., an amount as compared to a mRNA sequence including a different tag). The phrase includes both direct or indirect measurements of abundance (e.g., individual mRNA transcripts may be quantified or the amount of amplification of an mRNA sequence under certain conditions for a certain period may be used a surrogate for individual transcript quantification) or both.

[0061] In an aspect, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. In an aspect, a pharmaceutical carrier employed can be a solid, liquid, or gas. In an aspect, examples of solid carriers can include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. In an aspect, examples of liquid carriers can include sugar syrup, peanut oil, olive oil, and water. In an aspect, examples of gaseous carriers can include carbon dioxide and nitrogen. In preparing a disclosed composition for oral dosage 10110026078 1form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly (orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0062] In an aspect, the term “excipient7’ refers to an inert substance which is commonly used as a diluent, vehicle, preservative, binder, or stabilizing agent, and includes, but is not limited to, proteins (e.g., serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid, lysine, arginine, glycine, histidine, etc.), fatty acids and phospholipids (e.g., alkyl sulfonates, caprylate, etc.), surfactants (e.g.. SDS, polysorbate, nonionic surfactant, etc.), saccharides (e.g., sucrose, maltose, trehalose, etc.) and polyols (e.g., mannitol, sorbitol, etc.). See, also, for reference. Remington’s Pharmaceutical Sciences, (1990) Mack Publishing Co., Easton, Pa., which is hereby incorporated by reference in its entirety7.11110026078 1

[0063] In an aspect, “concurrently” means (1) simultaneously in time, or (2) at different times during the course of a common treatment schedule.

[0064] In an aspect, “expression cassette” or “transgene cassette” can refer to a distinct component of a DNA sequence comprising a transgene and one or more regulatory sequences to be expressed by a transfected cell. In an aspect, “expression cassette” or “transgene cassette” can refer to a distinct component of a DNA sequence comprising an internal construct, an amino or 5’ construct, or a carboxy or 3’ construct and one or more regulator}' sequences to be expressed by a transfected cell. Generally, an expression cassette or transgene cassette can comprise a promoter sequence, an open reading frame (i.e.. the transgene), and a 3’ untranslated region (e.g., in eukaryotes a polyadenylation site).

[0065] In an aspect, a disclosed cargo can comprise any sequence (encoding any biologically active or biologically relevant molecule) that can be packaged into an AAV capsid. In an aspect, a disclosed cargo can comprise a sequence for a peptide or a protein. In an aspect, a sequence encoding a cargo can comprise a portion of the full-length cargo peptide or full-length cargo protein. In an aspect, for example, a portion of the full-length cargo peptide or full-length cargo protein can comprise one or more exons. In an aspect, a disclosed cargo can be referred to by the resulting translation product (e.g., a protein, a peptide, an enzyme, a hormone, a biosimilar, a monoclonal antibody, a scFv, etc.) or can be referred to by the nucleic acid sequence encoding the disclosed translation product. In an aspect, a sequence encoding a cargo can comprise the open reading frame for an enzyme (or fragment thereof) for enzyme replacement therapy. In an aspect, a disclosed cargo can encode a hormone. In an aspect, a disclosed cargo can encode an enzyme (or fragment thereof) or a biosimilar (or fragment thereof) for enzyme replacement therapy. In an aspect, a disclosed cargo can encode a monoclonal antibody. In an aspect, a disclosed cargo can encode an antibody fragment such as F(ab’)2, Fab, Fab’, or Fv. In an aspect, a disclosed cargo can encode a scFv. In an aspect, a disclosed cargo can encode a gene or a part of a gene associated with and / or responsible for a genetic disease or genetic disorder.

[0066] In an aspect, small nuclear ribonucleoproteins (snRNPs) are complexes composed of small nuclear RNA (snRNA) and proteins in specific structures. Some of these snRNAs were uridine rich compared to ribosomal or messenger RNAs and thus were described as U snRNAs. These U snRNAs were further numbered (e.g., U1 snRNA) by their order of discover}', and not by size, location or abundance. The spliceosomes. comprising large complexes that catalyze splicing, are divided into major and minor spliceosomes: Ul, U2, U4, U5, U6 and Uli, U12, U4atac, U5atac and U6atac snRNP, respectively. Exceptionally, one of the U snRNPs, U7 snRNP, is not involved in splicing but is a key factor in the unique 3' end processing of replication-dependent histone (RDH) pre-mRNAs. Moreover, U7 snRNA is an important tool in therapeutic studies, with 12110026078 1reports based on modified U7 snRNP (U7 Sm OPT) targeting splicing to induce efficient skipping or inclusion of selected exons. U7 Sm OPT is designed by changing the histone binding sequence at the 5' region of U7 snRNA to the complementary sequence of the gene to be modified. Further modifications include changing of U7 snRNP specific proteins, LsmlO and Lsmll, to the consensus protein ring of spliceosomal snRNPs. In U7 Sm OPT-based therapy, an antisense oligonucleotide is incorporated into the U7 snRNA. For this purpose, as a tool of manipulation of pre-mRNA splicing, antisense oligonucleotides are used in the U7 Sm OPT therapeutic strategy.

[0067] In an aspect, the term “contacting” can refer to bringing one or more of the disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof together with a target area or intended target area in such a manner that the one or more of the disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof exert an effect on the intended target or targeted area either directly or indirectly. A target area can comprise one or more cells, and in an aspect, one or more cells can be in a subject. A target area or intended target area can be one or more of a subject’s organs (e.g., lungs, heart, liver, kidney, brain, etc.). In an aspect, a target area or intended target area can be any cell or any organ infected by a disease or disorder. In an aspect, a target area or intended target area can be any organ, tissue, or cells that are affected by a disease or disorder.

[0068] In an aspect, “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired result such as, for example, the treatment and / or prevention of a disease or disorder or a suspected disease or disorder. In an aspect, the terms “effective amount” and “amount effective” can refer to an amount that is sufficient to achieve the desired an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. In an aspect, “therapeutically effective amount” means an amount of a disclosed nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation; that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations employed; the disclosed methods employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the disclosed nucleic acid molecules, disclosed vectors, or disclosed 13110026078 1pharmaceutical formulations employed; the duration of the treatment; drugs used in combination or coincidental with the disclosed nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations employed, and other like factors well know n in the medical arts. For example, it is well within the skill of the art to start doses of the disclosed nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, then the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, a single dose of the disclosed nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition, such as, for example, a disease or disorder due to a missing, deficient, and / or mutant protein or enzyme (e.g., a product encoded by targeted endogenous pre-mRNA).

[0069] In an aspect, “RNA therapeutics” can refer to the use of oligonucleotides to target RNA. RNA therapeutics can offer the promise of uniquely targeting the precise nucleic acids involved in a particular disease with greater specificity', improved potency, and decreased toxicity7. This could be particularly powerful for genetic diseases where it is most advantageous to aim for the RNA as opposed to the protein. In an aspect, a therapeutic RNA can comprise one or more expression sequences. As known to the art, expression sequences can comprise an RNAi, shRNA, mRNA, non-coding RNA (ncRNA), an antisense such as an antisense RNA, miRNA, morpholino oligonucleotide, peptide-nucleic acid (PNA) or ssDNA (with natural, and modified nucleotides, including but not limited to, LNA, BNA, 2’-0-Me-RNA, 2’-MEO-RNA, 2 -F-RNA), or analog or conjugate thereof. In an aspect, a disclosed therapeutic RNA can comprise one or more long non-coding RNA (IncRNA), such as, for example, a long intergenic non-coding RNA (lincRNA), pre-transcript, pre-miRNA, pre-mRNA, competing endogenous RNA (ceRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), pseudo-gene, rRNA, or tRNA. In an aspect, ncRNA can be piwi-interacting RNA (piRNA). primary miRNA (pri-miRNA). or premature miRNA (pre-miRNA). In an aspect, a disclosed therapeutic RNA or an RNA therapeutic can comprise antisense oligonucleotides (ASOs) that inhibit mRNA translation, oligonucleotides that function via RNA interference (RNAi) pathway, RNA molecules that behave like enzymes (ribozymes), RNA oligonucleotides that bind to proteins and other cellular molecules, and ASOs 14110026078 1that bind to mRNA and form a structure that is recognized by RNase H resulting in cleavage of the mRNA target. In an aspect, RNA therapeutics can comprise RNAi and ASOs that inhibit mRNA translation. Generally speaking, as know n to the art, RNAi operates sequence specifically and post-transcriptionally by activating ribonucleases which, along with other enzymes and complexes, coordinately degrade the RNA after the original RNA target has been cut into smaller pieces while antisense oligonucleotides bind to their target nucleic acid via Watson-Crick base pairing, and inhibit or alter gene expression via steric hindrance, splicing alterations, initiation of target degradation, or other events.

[0070] In an aspect, "‘operably linked” means that expression of a gene or a transgene is under the control of a promoter with which it is spatially connected. A promoter can be positioned 5’ (upstream) or 3’ (downstream) of a gene under its control. The distance between the promoter and a gene can be approximately the same as the distance between that promoter and the gene it controls in the gene from which the promoter is derived. As is known in the art, variation in this distance can be accommodated without loss of promoter function.

[0071] In an aspect, “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein must contain at least two amino acids and there is no limitation on the maximum number of amino acids that can comprise a protein’s sequence. The term “peptide” can refer to a short chain of amino acids including, for example, natural peptides, recombinant peptides, synthetic peptides, or any combination thereof. Proteins and peptides can include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, and fusion proteins, among others.

[0072] In an aspect, “nucleic acid” or “oligonucleotide” or “polynucleotide” means at least two nucleotides covalently linked together. The depiction of a single strand can also define the sequence of the complementary strand. Thus, a nucleic acid can encompass the complementary’ strand of a depicted single strand. Many variants of a nucleic acid can be used for the same purpose as a given nucleic acid. Thus, a nucleic acid can encompass substantially identical nucleic acids and complements thereof. A single strand can provide a probe that can hybridize to a target sequence under stringent hybridization conditions. Thus, a nucleic acid can encompass a probe that hybridizes under stringent hybridization conditions. A nucleic acid can be single-stranded, or double-stranded, or can contain portions of both double-stranded and single-stranded sequence. The nucleic acid can be DNA, both genomic and cDNA, RNA, or a hybrid, where the nucleic acid can contain combinations of deoxy ribo- and ribo-nucleotides, and combinations of bases including uracil, adenine, thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine and 15110026078 1isoguanine. Nucleic acids can be obtained by chemical synthesis methods or by recombinant methods. In an aspect, the terms "‘nucleic acid,” “nucleic acid molecule,” “nucleic acid construct,” “nucleotide sequence”, and “polynucleotide” can refer to RNA or DNA that is linear or branched, single or double stranded, or a hybrid thereof. The term can encompass RNA / DNA hybrids. When dsRNA is produced synthetically, less common bases, such as inosine, 5 -methylcytosine, 6-methyladenine, hypoxanthine and others can also be used for antisense, dsRNA, and ribozyme pairing. For example, polynucleotides that contain C-5 propyne analogues of uridine and cytidine have been shown to bind RNA with high affinity' and to be potent antisense inhibitors of gene expression. Other modifications, such as modification to the phosphodiester backbone, or the 2’-hydroxy in the ribose sugar group of the RNA can also be made. In an aspect, a “synthetic” nucleic acid or polynucleotide refers to a nucleic acid or polynucleotide that is not found in nature but is constructed by the hand of man and therefore is not a product of nature.

[0073] In an aspect, “polynucleotide” is a sequence of nucleotide bases, and may be RNA, DNA, or DNA- RNA hybrid sequences (including both naturally occurring and non-naturally occurring nucleotides).

[0074] In an aspect, “fragment” or “portion” of a nucleotide sequence can be understood to mean a nucleotide sequence of reduced length relative (e.g., reduced by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. 13. 14. 15. 16. 17. 18. 19. 20 or more nucleotides) to a reference nucleic acid or nucleotide sequence and comprising, consisting essentially of, or consisting of a nucleotide sequence of contiguous nucleotides identical or almost identical (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%. 95%. 96%. 97%. 98%. 99% identical) to the reference nucleic acid or nucleotide sequence. Such a nucleic acid fragment or portion according to the disclosure can be, where appropriate, included in a larger polynucleotide of which it is a constituent. In an aspect, a fragment or portion of a nucleotide sequence or nucleic acid sequence can comprise the sequence encoding an exon having one or more mutations or aberrations.

[0075] In an aspect, “fragment” or “portion” of an amino acid sequence can be understood to mean an amino acid sequence of reduced length relative (e.g., reduced by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, or more amino acids) to a reference amino acid sequence and comprising, consisting essentially of, or consisting of an amino acid sequence of contiguous amino acids identical or almost identical (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical) to the reference amino acid sequence. Such an amino acid fragment or portion according to the16110026078 1disclosure can be, where appropriate, included in a larger amino acid sequence of which it is a constituent.

[0076] In an aspect, “heterologous” or a “recombinant” nucleotide or amino acid sequence as used interchangeably herein can refer to a nucleotide or an amino acid sequence not naturally associated with a host cell into which it is introduced, including non-naturally occurring multiple copies of a naturally occurring nucleotide or amino acid sequence.

[0077] In an aspect, the term “endogenous” can refer to a gene, protein, compound, or activity that is normally present in a host cell (e.g., a targeted pre-mRNA). In an aspect, an “exogenous” nucleic acid molecule, construct, or sequence (e.g., an RNA sequence to be trans-spliced) can refer to a nucleic acid molecule or portion of a nucleic acid molecule that is not native to a host cell, but may be homologous to a nucleic acid molecule or portion of a nucleic acid molecule from the host cell.

[0078] In an aspect, “promoter” or “promoters” are known to the art. Depending on the level and tissue-specific expression desired, a variety of promoter elements can be used. A promoter can be tissue-specific or ubiquitous and can be constitutive or inducible, depending on the pattern of the gene expression desired. A promoter can be native (endogenous) or foreign (exogenous) and can be a natural or a synthetic sequence. By foreign or exogenous, it is intended that the transcriptional initiation region is not found in the wild-type host into which the transcriptional initiation region is introduced.

[0079] In an aspect, “sequence identity” and “sequence similarity” can be determined by alignment of two peptide or two nucleotide sequences using global or local alignment algorithms. Sequences may then be referred to as “substantially identical” or “essentially similar” when they are optimally aligned. For example, sequence similarity or identity can be determined by searching against databases such as FASTA, BLAST, etc., but hits should be retrieved and aligned pairwise to compare sequence identity. Two proteins or two protein domains, or two nucleic acid sequences can have “substantial sequence identity” if the percentage sequence identity is at least 70%. 75%. 80%. 85%. 90%. 95%. 98%. 99% or more, preferably 90%. 95%. 98%. 99% or more. Such sequences are also referred to as “variants” herein, e.g., other variants of a missing, deficient, and / or mutant protein or enzyme. It should be understood that sequence with substantial sequence identity do not necessarily have the same length and may differ in length. For example, sequences that have the same nucleotide sequence but of which one has additional nucleotides on the 3’-and / or 5’-side are 100% identical.

[0080] In an aspect, “RNA editing” can be a post-transcriptional modification where a precursor mRNA (pre-mRNA) nucleotide sequence is changed by base insertion, deletion, or modification. The extent of RNA editing varies from a few hundred bases, in mitochondrial DNA of 17110026078 1trypanosomes, to a just single base, in nuclear genes of mammals. Even a single base change in the pre-mRNA can convert a codon for one amino acid into the codon for another amino acid or a stop codon. This type of re-coding can significantly affect the structure and function of a protein and may lead to the production of multiple variants of a protein from a single gene.

[0081] In an aspect, insertional and deletional RNA editing can involve the addition and deletion of specific nucleotides or sequences of nucleotides from pre-mRNA. In an aspect, substitutional RNA editing by base modifications is observed in higher eukaryotes, where the base is modified without changing the length of the pre-mRNA.

[0082] In an aspect, “immune tolerance,’" “immunological tolerance,” and “immunotolerance” refers to a state of unresponsiveness or blunted response of the immune system to substances (e.g., a disclosed nucleic acid molecule, a disclosed vector, a disclosed transgene product, a disclosed pharmaceutical formulation, a disclosed therapeutic agent, etc.) that have the capacity7to elicit an immune response in a subject. Immune tolerance is induced by prior exposure to a specific antigen. Immune tolerance can be determined in a subject by measuring antibodies against a particular antigen or by liver-restricted transgene expression with a viral vector (such as, for example, AAV). Low or absent antibody titers over time is an indicator of immune tolerance. For example, in some embodiments, immune tolerance can be established by having IgG antibody titers of less than or equal to about 12,000, 11,500, 11,000. 10.500, 10,000, 9.500, 9,000, 8.500, 8,000, 7,500, 7,000, 6,500, or 6,000 within following gene therapy (such as the administration of the transgene encoding, for example, a missing, deficient, and / or mutant protein or enzyme).

[0083] In an aspect, the term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0084] In an aspect, the term “in combination” in the context of the administration of other therapies (e.g.. other agents) includes the use of more than one therapy (e.g., drug therapy). Administration "in combination with” one or more further therapeutic agents includes simultaneous (e g., concurrent) and consecutive administration in any order. The use of the term “in combination” does not restrict the order in which therapies are administered to a subject. By way of non-limiting example, a first therapy (e.g., a disclosed nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or a combination thereof) may be administered prior to (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks), concurrently, or after (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 218110026078 1hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks or longer) the administration of a second therapy (e.g., agent) to a subject having or diagnosed with a disease or disorder.

[0085] Disclosed are the components to be used to prepare the disclosed nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations as well as the disclosed nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and even- combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E. B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.B. Compositions1. Nucleic Acid MoleculesInternal Constructs

[0086] Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence; wherein the exogenous RNA to be transspliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an 19110026078 1internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0087] Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence; wherein each of the targeting guide sequences bind to a complementary sequence in any intron of the targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence; wherein each of the targeting guide sequences bind to a complementary sequence in any intron of the targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0088] Disclosed herein is an internal fusion construct comprising a nucleic acid molecule comprising a first targeting guide sequence; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is an internal fusion construct comprising a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0089] Disclosed herein is an internal fusion construct comprising a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence; wherein each of the targeting guide sequences bind to a complementary sequence in any intron of the targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is an internal fusion construct comprising a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and 20110026078 1a second targeting guide sequence; wherein each of the targeting guide sequences bind to a complementary sequence in any intron of the targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0090] Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence, wherein each of the targeting guide sequences comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is an nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron: and a second targeting guide sequence, wherein each of the targeting guide sequences comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0091] Disclosed herein is an nucleic acid molecule comprising a first targeting guide sequence: a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0092] Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence, wherein each of the targeting guide sequences comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73, wherein the 21110026078 1exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; a second targeting guide sequence, wherein each of the targeting guide sequences comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0093] Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0094] Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; and a 5' hemi intron; a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.22110026078 1

[0095] Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; and a 5’ hemi intron; a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0096] Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; and a 5’ hemi intron; a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0097] Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary- sequence in SEQ ID NO: 99 or SEQ ID NO:100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising a first targeting guide sequence; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a second targeting guide sequence, wherein each of the targeting guide sequences bind to a complementary- sequence in SEQ ID NO:99 or SEQ ID NO: 100, wherein the exogenous RNA to be trans-spliced 23110026078 1comprises a sequence encoding an internal portion of the targeted endogenous pre-mRNA, a pair of linkers, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0098] In an aspect, a disclosed internal construct can be used to rewrite or replace an internal exon of the targeted endogenous pre-mRNA in a trans-splicing event. In such a trans-splicing event, the rewritten and / or the replaced internal exon of the targeted endogenous pre-mRNA can be linked to a disclosed cargo.

[0099] In an aspect of a disclosed internal construct, a disclosed pair of linkers can flank the construct. Disclosed herein is an expression cassette comprising a disclosed an internal construct.

[0100] In an aspect of a disclosed internal construct, a disclosed cargo can comprise any sequence (encoding any biologically active or biologically relevant molecule) that can be packaged into an AAV capsid. In an aspect of a disclosed internal construct, a disclosed cargo can comprise a sequence for a peptide or a protein. In an aspect of a disclosed internal construct, a sequence encoding a cargo can comprise a portion of the full-length cargo peptide or full-length cargo protein. In an aspect of a disclosed internal construct, for example, a portion of the full-length cargo peptide or full-length cargo protein can comprise one or more exons. In an aspect of a disclosed internal construct, a disclosed cargo can be referred to by the resulting translation product (e.g., a protein, a peptide, an enzyme, a hormone, a biosimilar, a monoclonal antibody, a scFv, etc.) or can be referred to by the nucleic acid sequence encoding the disclosed translation product. In an aspect of a disclosed internal construct, a sequence encoding a cargo can comprise the open reading frame for an enzyme (or fragment thereof) for enzyme replacement therapy. In an aspect of a disclosed internal construct, a disclosed cargo can encode a hormone. In an aspect of a disclosed internal construct, a disclosed cargo can encode an enzyme (or fragment thereof) or a biosimilar (or fragment thereof) for enzyme replacement therapy. In an aspect of a disclosed internal construct, a disclosed cargo can encode a monoclonal antibody. In an aspect of a disclosed internal construct, a disclosed cargo can encode an antibody fragment such as F(ab’)2, Fab, Fab', or Fv. In an aspect of a disclosed internal construct, a disclosed cargo can encode a scFv. In an aspect of a disclosed internal construct, a disclosed cargo can encode a gene or a part of a gene associated with and / or responsible for a genetic disease or genetic disorder. In an aspect, a disclosed internal construct can be used to generate a fusion product. In an aspect, a disclosed internal construct can be used to generate a fusion product in situ.

[0101] In an aspect, a target cell can be any cell that expresses a targeted endogenous pre-mRNA having a transcript per million (nTPM) value that is at least 1,000, at least 5,000, at least 10,000, at least 20,000, at least 30,000, at least 40,000, at least 50,000, at least 60,000, at least 70,000, at least 80,000, at least 90,000, at least 100,000, or at least 100,000.24110026078 1Amino or 5’ Constructs

[0102] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0103] Disclosed herein is a nucleic acid molecule for trans-splicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0104] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0105] Disclosed herein is a nucleic acid molecule for trans-splicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5 ’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0106] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5 ' hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences,25110026078 1wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0107] Disclosed herein is a nucleic acid molecule for trans-splicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5 ' hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0108] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0109] Disclosed herein is a nucleic acid molecule for trans-splicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0110] Disclosed herein is a 5‘ fusion construct comprising a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a 5’ fusion construct comprising a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0111] Disclosed herein is a 5’ fusion construct comprising a nucleic acid molecule for trans-splicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5 ’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5 ’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a 5' fusion construct comprising a 26110026078 1nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0112] Disclosed herein is a 5’ fusion construct comprising a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0113] Disclosed herein is a 5’ fusion construct comprising a nucleic acid molecule for transsplicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0114] Disclosed herein is a 5' fusion construct comprising a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a 5’ fusion construct comprising a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0115] Disclosed herein is a 5’ fusion construct comprising a nucleic acid molecule for transsplicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo. Disclosed herein is a 5' fusion construct comprising a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5 ’ portion of the targeted27110026078 1endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0116] Disclosed herein is a 5’ fusion construct comprising a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a 5’ fusion construct comprising a nucleic acid molecule for transsplicing comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0117] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37. wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0118] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0119] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; wherein the exogenous RNA to be trans-spliced comprises a sequence28110026078 1encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0120] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0121] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0122] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0123] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, a 5’ hemi intron; and two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.29110026078 1

[0124] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and a two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO: 37; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5 ’ hemi intron; and two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0125] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0126] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0127] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0128] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a30110026078 1sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0129] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0130] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO: 01 -SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0131] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0132] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced 31110026078 1comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0133] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0134] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0135] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and one or more targeting guide sequences, wherein the 32110026078 1targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0136] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0137] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0138] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA. a 5’ hemi intron; and two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA,33110026078 1a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0139] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0140] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0141] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0142] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0143] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0144] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide 34110026078 1sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0145] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0146] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0147] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA. a 5' hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0148] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0149] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5' portion of the targeted endogenous pre-mRNA, a linker, and 35110026078 1a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0150] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0151] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0152] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0153] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0154] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0155] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide 36110026078 1sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0156] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0157] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0158] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0159] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0160] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker,37110026078 1and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0161] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0162] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0163] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0164] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0165] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5 ' hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0166] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide 38110026078 1sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0167] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5 ' hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0168] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0169] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0170] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0171] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, a 5' hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.39110026078 1

[0172] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0173] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5' hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0174] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0175] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0176] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary’ sequence in SEQ ID NO: 103, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0177] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.40110026078 1

[0178] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0179] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0180] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0181] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0182] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103. wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0183] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.41110026078 1

[0184] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103. wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0185] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0186] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO:100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5 ’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO: 100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo.

[0187] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary’ sequence in SEQ ID NO:99 OR SEQ ID NO: 100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5 ' hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO: 100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.42110026078 1

[0188] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO: 100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO: 100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0189] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO: 100; wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5‘ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5 ’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO: 100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo.

[0190] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO: 100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, a 5 ' hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO: 100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.43110026078 1

[0191] Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO: 100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding an amino terminus of a targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; and two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO: 100, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 5’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0192] In an aspect, a disclosed amino or 5’ construct can be used to rewrite or replace the first exon of the targeted endogenous pre-mRNA in a trans-sphcing event. In such a trans-splicing event, the rewritten and / or the replaced first exon of the targeted endogenous pre-mRNA can be linked to a disclosed cargo.

[0193] Disclosed herein is an expression cassette comprising a disclosed an amino or 5' construct.

[0194] In an aspect of a disclosed amino or 5' construct, a disclosed cargo can comprise any sequence (encoding any biologically active or biologically relevant molecule) that can be packaged into an AAV capsid. In an aspect of a disclosed amino or 5’ construct, a disclosed cargo can comprise a sequence for a peptide or a protein. In an aspect of a disclosed amino or 5’ construct, a sequence encoding a cargo can comprise a portion of the full-length cargo peptide or full-length cargo protein. In an aspect of a disclosed amino or 5’ construct, for example, a portion of the full-length cargo peptide or full-length cargo protein can comprise one or more exons. In an aspect of a disclosed amino or 5’ construct, a disclosed cargo can be referred to by the resulting translation product (e.g., a protein, a peptide, an enzyme, a hormone, a biosimilar, a monoclonal antibody, a scFv, etc.) or can be referred to by the nucleic acid sequence encoding the disclosed translation product. In an aspect of a disclosed amino or 5’ construct, a sequence encoding a cargo can comprise the open reading frame for an enzyme (or fragment thereof) for enzyme replacement therapy. In an aspect of a disclosed amino or 5’ construct, a disclosed cargo can encode a hormone. In an aspect of a disclosed amino or 5’ construct, a disclosed cargo can encode an enzyme (or fragment thereof) or a biosimilar (or fragment thereof) for enzyme replacement therapy. In an aspect of a disclosed amino or 5’ construct, a disclosed cargo can encode a monoclonal antibody. In an aspect of a disclosed amino or 5' construct, a disclosed cargo can encode an antibody fragment such as F(ab’)2, Fab, Fab', or Fv. In an aspect of a disclosed amino 44110026078 1or 5’ construct, a disclosed cargo can encode a scFv. In an aspect of a disclosed amino or 5’ construct, a disclosed cargo can encode a gene or a part of a gene associated with and / or responsible for a genetic disease or genetic disorder.

[0195] In an aspect, a disclosed amino or 5’ construct can be used to generate a fusion product. In an aspect, a disclosed amino or 5’ construct can be used to generate a fusion product in situ

[0196] In an aspect, a target cell can be any cell that expresses a targeted endogenous pre-mRNA having a transcript per million (nTPM) value that is at least 1,000, at least 5,000, at least 10,000, at least 20,000, at least 30,000, at least 40,000, at least 50,000, at least 60,000, at least 70,000, at least 80,000, at least 90,000. at least 100,000, or at least 100,000.Carboxy or 3’ Constructs

[0197] Disclosed herein is a 3’ fusion construct comprising a nucleic acid molecule comprising one or more targeting guide sequences; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0198] Disclosed herein is a 3’ fusion construct comprising a nucleic acid molecule comprising one or more targeting guide sequences; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a 3’ fusion construct comprising a nucleic acid molecule comprising one or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0199] Disclosed herein is a 3’ fusion construct comprising a nucleic acid molecule comprising one or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a 3’ fusion construct comprising a nucleic acid molecule comprising one or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA 45110026078 1to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be transspliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0200] Disclosed herein is a 3’ fusion construct comprising a nucleic acid molecule comprising two or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3‘ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a 3’ fusion construct comprising a nucleic acid molecule comprising two or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0201] Disclosed herein is a 3’ fusion construct comprising a nucleic acid molecule comprising two or more targeting guide sequences; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a 3’ fusion construct comprising a nucleic acid molecule comprising two or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0202] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0203] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’46110026078 1portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0204] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences; a 3‘ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0205] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences; a 3' hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, w herein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0206] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0207] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a 47110026078 1targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3‘ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0208] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0209] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0210] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo.48110026078 1Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0211] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37: a 3' hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0212] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13; a 3‘ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0213] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3‘ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting 49110026078 1guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13; a 3’ hemi intron; and an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0214] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3‘ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0215] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO:13; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13; a 3‘ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0216] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more 50110026078 1targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be transspliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0217] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:01-SEQ ID NO: 13; a 3’ hemi intron; and an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:26-SEQ ID NO:37; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0218] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3‘ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0219] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting 51110026078 1guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3‘ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0220] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0221] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0222] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA. wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA,52110026078 1wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0223] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA. wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0224] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0225] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA. wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced 53110026078 1comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0226] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0227] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3’ hemi intron; an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary’ sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0228] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0229] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3' hemi intron; and an exogenous RNA to be trans- 54110026078 1spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0230] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3’ hemi intron; and an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA. a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0231] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:80-SEQ ID NO:95; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0232] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; a 3‘ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0233] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3‘ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting 55110026078 1guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; a 3’ hemi intron; and an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3' portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0234] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3‘ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0235] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; a 3‘ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0236] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more 56110026078 1targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be transspliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0237] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98; a 3’ hemi intron; and an exogenous RNA to be transspliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in any one of SEQ ID NO:96–SEQ ID NO:98; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0238] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0239] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting 57110026078 1guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; a 3’ hemi intron; and an exogenous RNAto be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3‘ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0240] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; a 3‘ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0241] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0242] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.58110026078 1

[0243] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; a 3’ hemi intron; and an exogenous RNAto be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0244] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102; a 3' hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0245] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in SEQ ID NO: 101 or SEQ ID NO: 102; a 3‘ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0246] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0247] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences,59110026078 1wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0248] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103; a 3' hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103; a 3‘ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0249] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3‘ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0250] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103; a 3' hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in 60110026078 1SEQ ID NO: 103; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0251] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 103; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0252] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in SEQ ID NO: 103; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 or SEQ ID NO: 100; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0253] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 or SEQ ID NO: 100; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0254] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 or SEQ ID NO: 100; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 or SEQ ID NO: 100; a 3’ hemi intron; and an exogenous RNA to be trans-spliced 61110026078 1to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0255] Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 or SEQ ID NO: 100; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising one or more targeting guide sequences, wherein the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 or SEQ ID NO: 100; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0256] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 or SEQ ID NO: 100; a 3' hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0257] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 or SEQ ID NO: 100; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 or SEQ ID NO: 100; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

[0258] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 or SEQ ID NO: 100; a 3’ hemi intron; and an exogenous RNA to be trans-spliced 62110026078 1to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0259] Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 OR SEQ ID NO:100; a 3’ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell. Disclosed herein is a nucleic acid molecule comprising two or more targeting guide sequences, wherein each comprises a sequence set forth in SEQ ID NO: 99 OR SEQ ID NO: 100; a 3‘ hemi intron; and an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a 3’ portion of the targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo, wherein the molecule is used to create a chimeric RNA in a target cell.

[0260] In an aspect, a disclosed carboxy or 3’ construct can be used to rewrite or replace the last exon of the targeted endogenous pre-mRNA in a trans-splicing event. In such a trans-splicing event, the rewritten and / or the replaced last exon of the targeted endogenous pre-mRNA can be linked to a disclosed cargo.

[0261] Disclosed herein is an expression cassette comprising a disclosed an carboxy or 3’ construct.

[0262] In an aspect of a disclosed carboxy or 3’ construct, a disclosed cargo can comprise any sequence (encoding any biologically active or biologically relevant molecule) that can be packaged into an AAV capsid. In an aspect of a disclosed carboxy or 3’ construct, a disclosed cargo can comprise a sequence for a peptide or a protein. In an aspect of a disclosed carboxy or 3’ construct, a sequence encoding a cargo can comprise a portion of the full-length cargo peptide or full-length cargo protein. In an aspect of a disclosed carboxy or 3’ construct, for example, a portion of the full-length cargo peptide or full-length cargo protein can comprise one or more exons. In an aspect of a disclosed carboxy or 3’ construct, a disclosed cargo can be referred to by the resulting translation product (e.g., a protein, a peptide, an enzyme, a hormone, a biosimilar, a monoclonal antibody, a scFv, etc.) or can be referred to by the nucleic acid sequence encoding the disclosed translation product. In an aspect of a disclosed carboxy or 3’ construct, a sequence encoding a cargo can comprise the open reading frame for an enzyme (or fragment thereof) for enzyme replacement therapy. In an aspect of a disclosed carboxy or 3’ construct, a disclosed cargo can encode a hormone. In an aspect of a disclosed carboxy or 3' construct, a disclosed cargo 63110026078 1can encode an enzyme (or fragment thereof) or a biosimilar (or fragment thereof) for enzyme replacement therapy. In an aspect of a disclosed carboxy or 3’ construct, a disclosed cargo can encode a monoclonal antibody. In an aspect of a disclosed carboxy or 3’ construct, a disclosed cargo can encode an antibody fragment such as F(ab')2, Fab, Fab', or Fv. In an aspect of a disclosed carboxy or 3’ construct, a disclosed cargo can encode a scFv. In an aspect of a disclosed internal construct, a disclosed cargo can encode a gene or a part of a gene associated with and / or responsible for a genetic disease or genetic disorder.

[0263] In an aspect, a disclosed amino or 5’ construct can be used to generate a fusion product. In an aspect, a disclosed amino or 5’ construct can be used to generate a fusion product in situ.

[0264] In an aspect, a target cell can be any cell that expresses a targeted endogenous pre-mRNA having a transcript per million (nTPM) value that is at least 1,000, at least 5,000, at least 10,000, at least 20,000, at least 30,000, at least 40,000, at least 50,000, at least 60,000, at least 70,000, at least 80,000, at least 90,000, at least 100,000, or at least 100,000.Targeted Pre-mRNAs

[0265] In an aspect, a disclosed targeted endogenous pre-mRNA can encode a molecule that is part of the secretome. As known to the skilled person, secretome can refer to a variety of molecules that are secreted from living cells. In an aspect, secretome can refer to a rather heterogenous group of proteins in terms of both abundance and tissue specificity.

[0266] In an aspect, a disclosed targeted endogenous pre-mRNA for a secretable molecule can be highly expressed in a targeted cell. In an aspect, expression of a disclosed targeted endogenous pre-mRNA for a secretable molecule in a targeted cell can comprise a transcript per million (nTPM) value that is at least 1,000, at least 5,000. at least 10,000. at least 20.000, at least 30.000, at least 40,000, at least 50,000, at least 60,000, at least 70,000, at least 80,000, at least 90,000, at least 100,000, or at least 100,000.

[0267] In an aspect, expression of a disclosed targeted endogenous pre-mRNA for a secretable molecule in a targeted cell can comprise a transcript per million (nTPM) value that is greater than 1,000, greater than 5,000, greater than 10,000, greater than 20,000, greater than 30.000, greater than 40,000, greater than 50,000, greater than 60,000, greater than 70,000, greater than 80,000, greater than 90,000, at least 100,000, or greater than 100,000.

[0268] In an aspect, expression of a disclosed targeted endogenous pre-mRNA for a secretable molecule in a targeted cell can comprise a transcript per million (nTPM) value that is between about 1,000 to about 5,000, about 5,000 to about 10,000, about 10,000 to about 20,000, about 20,000 to about 30,000, about 30,000 to about 40,000, about 40,000 to about 50,000, about 50,000 to about 60,000, about 60,000 to about 70,000, about 70,000 to about 80,000, about 80,000 to about 90.000, about 90,000 to about 100,000, or more than about 100,000.64110026078 1

[0269] In an aspect, a disclosed targeted endogenous pre-mRNA for a secreted molecule be highly expressed in a targeted cell. In an aspect, expression of a disclosed targeted endogenous pre-mRNA for a secreted molecule in a targeted cell can comprise a transcript per million (nTPM) value that is at least 1,000. at least 5,000, at least 10,000, at least 20,000. at least 30.000, at least 40.000. at least 50,000, at least 60,000. at least 70.000, at least 80,000. at least 90.000, at least 100,000, or at least 100,000. In an aspect, expression of a disclosed targeted endogenous pre-mRNA for a secreted molecule in a targeted cell can comprise a transcript per million (nTPM) value that is greater than 1.000, greater than 5,000, greater than 10,000, greater than 20,000, greater than 30,000, greater than 40,000, greater than 50,000, greater than 60,000, greater than 70,000, greater than 80,000, greater than 90,000, at least 100,000, or greater than 100,000. In an aspect, expression of a disclosed targeted endogenous pre-mRNA for a secreted molecule in a targeted cell can comprise a transcript per million (nTPM) value that is between about 1,000 to about 5,000, about 5,000 to about 10.000, about 10,000 to about 20,000, about 20,000 to about 30,000, about 30,000 to about 40,000, about 40,000 to about 50,000, about 50,000 to about 60,000, about 60,000 to about 70,000, about 70,000 to about 80,000, about 80,000 to about 90,000, about 90,000 to about 100,000, or more than about 100,000.

[0270] Table 1 provides a non-exhaustive listing of exemplary endogenous RNAs that could be targeted by the GRAFT trans-splicing approach to generate in situ fusion biologies. In Table 1, nTPM = normalized RNA transcripts per million.Table 1 - Exemplary and Non-Exhaustive List of Targeted Endogenous RNAsTarget RNA nTPM nTPM Tissue Cell Type(Gene Symbol) (Tissue) (Cell) Albumin (ALB) Liver Hepatocyte 205952 59612Choroid plexusBrain epithelial cells 692067 40087 Transthyretin (TTR) Motor neuronsLiver Hepatocyte 6144 26585 Thymus T-Cell 4101 13576 Lymph Node B-Cell 9081 9006 Beta-2-microglobulin (B2M)Spleen NK-Cell 7686 200023 Bone Marrow 7738Transferrin (TF) Liver Hepatocyte 7278 5785 Apolipoprotein B (APOB) Liver Hepatocyte 1114 3326 Apolipoprotein E (APOE) Liver Hepatocyte 6533 996265110026078 1

[0271] In an aspect, disclosed targeted endogenous pre-mRNA can encode a secreted molecule (e.g., serum protein, a growth factor, an angiogenic factor, a hormone, a cytokine, an extracellular matrix protein, a lipid mediator, or genetic material (e.g., an miRNA)).

[0272] In an aspect, disclosed targeted endogenous pre-mRNA can encode a serum protein, a growth factor, an angiogenic factor, a hormone, a cytokine, an extracellular matrix protein, a lipid mediator, or genetic material (e g., an miRNA).

[0273] In an aspect, disclosed secreted molecules can comprise serum proteins, growth factors, angiogenic factors, hormones, cytokines, extracellular matrix proteins, lipid mediators, genetic material (e.g., miRNAs). or any combination thereof.

[0274] In an aspect, disclosed targeted endogenous pre-mRNA can encode a secreted molecule having a key role in cell signaling, communication, and migration.

[0275] In an aspect, a disclosed targeted pre-mRNA can encode an organ-specific peptide or an organ-specific protein. In an aspect, a disclosed targeted pre-mRNA can encode a peptide or a protein secreted from adipose tissue, the brain, one or more female reproductive organs, the heart, a kidney, the liver, one or more male reproductive organs, the pancreas, skeletal muscle, or any combination thereof.

[0276] In an aspect, a disclosed targeted pre-mRNA can encode a secretable blood peptide or a secretable blood protein. In an aspect, a secretable blood peptide or a secretable blood protein can comprise Alpha- 1-B glycoprotein (A1BG); Alpha- 2-macroglobulin (A2M); Abhydrolase domain containing 15 (ABHD15); ABO, alpha 1-3-N-acetylgalactosaminyltransferase and alpha 1-3-galactosyltransferase (ABO); Angiotensin I converting enzyme (ACE); Angiotensin converting enzyme 2 (ACE2); Acid phosphatase 3 (ACP3); Adenosine deaminase 2 (ADA2); ADAM metallopeptidase domain 28 (ADAM28); ADAM metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13); Adhesion G protein-coupled receptor E3 (ADGRE3); Adhesion G protein-coupled receptor E5 (ADGRE5); Adhesion G protein-coupled receptor G1 (ADGRG1); Adiponectin, C1Q and collagen domain containing (ADIPOQ); Adrenomedullin (ADM); Adrenomedullin 2 (ADM2); Adrenomedullin 5 (putative) (ADM5); Afamin (AFM); Alpha fetoprotein (AFP); Angiogenic factor with G-patch and FHA domains 1 (AGGF1); Angiotensinogen (AGT); Alpha 2-HS glycoprotein (AHSG); Aminoacyl tRNA synthetase complex interacting multifunctional protein 1 (AIMP1); Albumin (ALB); Activated leukocyte cell adhesion molecule (ALCAM); ALK and LTK ligand 1 (ALKALI); ALK and LTK ligand 2 (ALKAL2); Alpha-1 -microglobulin / bikunin precursor (AMBP); Anti-Mullerian hormone (AMH); Angiogenin (ANG); Angiopoietin 1 (ANGPT1); Angiopoietin 2 (ANGPT2); Angiopoietin 4 (ANGPT4); Angiopoietin like 1 (ANGPTL1); Angiopoietin like 2 (ANGPTL2); Angiopoietin like 3 (ANGPTL3); Angiopoietin like 4 (ANGPTL4); Angiopoietin like 666110026078 1(ANGPTL6); Angiopoietin like 8 (ANGPTL8); Annexin Al (ANXA1); Annexin A2 (ANXA2); Acyloxyacyl hydrolase (AOAH); Amyloid P component, serum (APCS); Apolipoprotein Al (APOA1); Apolipoprotein A2 (APOA2); Apolipoprotein A4 (APOA4); Apolipoprotein A5 (APOA5); Apolipoprotein B (APOB); Apolipoprotein C1 (APOC1); Apolipoprotein C2 (APOC2); Apolipoprotein C3 (APOC3); Apolipoprotein C4 (APOC4); Apolipoprotein D (APOD); Apolipoprotein E (APOE); Apolipoprotein F (APOF); Apolipoprotein H (APOH); Apolipoprotein LI (APOL1); Apolipoprotein L4 (APOL4); Apolipoprotein M (APOM); Apolipoprotein O (APOO); Amyloid beta precursor protein (APP); ADP-ribosyltransferase 4 (inactive) (Dombrock blood group) (ART4); Asialoglycoprotein receptor 1 (ASGR1); Agouti signaling protein (ASIP); Attractin (ATRN); Arginine vasopressin (AVP); Alpha-2-gly coprotein 1, zinc-binding (AZGP1); Azurocidin 1 (AZU1); Beta-2 -microglobulin (B2M); Butyrylcholinesterase (BCHE); Brain derived neurotrophic factor (BDNF); Bone gammacarboxyglutamate protein (BGLAP); Bone morphogenetic protein 10 (BMP 10); Bone morphogenetic protein 2 (BMP2); Bone morphogenetic protein 4 (BMP4); Bone morphogenetic protein 6 (BMP6); Bone morphogenetic protein 7 (BMP7); Bone morphogenetic protein 8a (BMP8A); Bone morphogenetic protein 8b (BMP8B); Bactericidal permeability increasing protein (BPI); Betacellulin (BTC); Biotinidase (BTD); B and T lymphocyte associated (BTLA); Chromosome 14 open reading frame 93 (C14orf93); Chromosome 16 open reading frame 89 (C16orf89); Chromosome 17 open reading frame 67 (C17orf67); Chromosome 17 open reading frame 99 (C17orf99); Chromosome 1 open reading frame 54 (C1orf54); Chromosome 1 open reading frame 56 (C1orf56); Complement Clq A chain (C1QA); Complement Clq B chain (Cl QB); Complement Clq binding protein (C1QBP); Complement Clq C chain (C1QC); Clq and TNF related 1 (C1QTNF1); Clq and TNF related 12 (C1QTNF12); Clq and TNF related 2 (C1QTNF2); Clq and TNF related 3 (C1QTNF3); Clq and TNF related 5 (C1QTNF5); Clq and TNF related 6 (C1QTNF6); Clq and TNF related 7 (C1QTNF7); Clq and TNF related 9 (C1QTNF9); Complement Clr subcomponent like (C1RL); Complement C1s (C1S); Complement C2 (C2); Complement C3 (C3); Complement C4A (Rodgers blood group) (C4A); Complement C4B (Chido blood group) (C4B); Complement component 4 binding protein alpha (C4BPA); Complement component 4 binding protein beta (C4BPB); Chromosome 4 open reading frame 48 (C4orf48); Complement C5 (C5); Complement C6 (C6); Chromosome 6 open reading frame 120 (C6orf120); Complement C7 (C7); Complement C8 alpha chain (C8A); Complement C8 beta chain (C8B); Complement C8 gamma chain (C8G); Complement C9 (C9); Calcitonin related polypeptide alpha (CALCA); Calcitonin related polypeptide beta (CALCB); Cathelicidin antimicrobial peptide (CAMP); CART prepropeptide (CARTPT); Coiled-coil domain containing 126 (CCDC126); Coiled-coil domain containing 134 (CCDC134); Coiled-coil domain containing 67110026078 13 (CCDC3); Cholecystokinin (CCK); C-C motif chemokine ligand 1 (CCL1); C-C motif chemokine ligand 11 (CCL11); C-C motif chemokine ligand 13 (CCL13); C-C motif chemokine ligand 14 (CCL14); C-C motif chemokine ligand 15 (CCL15); C-C motif chemokine ligand 16 (CCL16); C-C motif chemokine ligand 17 (CCL17); C-C motif chemokine ligand 18 (CCL18); C-C motif chemokine ligand 19 (CCL19); C-C motif chemokine ligand 2 (CCL2); C-C motif chemokine ligand 20 (CCL20); C-C motif chemokine ligand 21 (CCL21); C-C motif chemokine ligand 22 (CCL22); C-C motif chemokine ligand 23 (CCL23); C-C motif chemokine ligand 24 (CCL24); C-C motif chemokine ligand 25 (CCL25); C-C motif chemokine ligand 26 (CCL26); C-C motif chemokine ligand 27 (CCL27); C-C motif chemokine ligand 28 (CCL28); C-C motif chemokine ligand 3 (CCL3); C-C motif chemokine ligand 3 like 1 (CCL3L1); C-C motif chemokine ligand 4 (CCL4); C-C motif chemokine ligand 4 like 2 (CCL4L2); C-C motif chemokine ligand 5 (CCL5); C-C motif chemokine ligand 7 (CCL7); C-C motif chemokine ligand 8 (CCL8); Cellular communication network factor 3 (CCN3); CD14 molecule (CD14); CD160 molecule (CD160); CD163 molecule (CD163); CD300H molecule (gene / pseudogene) (CD300H); CD40 molecule (CD40); CD40 ligand (CD40LG); CD44 molecule (Indian blood group) (CD44); CD48 molecule (CD48); CD55 molecule (Cromer blood group) (CD55); CD5 molecule like (CD5L); CD6 molecule (CD6); CD74 molecule (CD74); Cholesteryl ester transfer protein (CETP); Complement factor B (CFB); Complement factor D (CFD); Complement factor H (CFH); Complement factor H related 1 (CFHR1); Complement factor H related 2 (CFHR2); Complement factor H related 3 (CFHR3); Complement factor H related 4 (CFHR4); Complement factor H related 5 (CFHR5); Complement factor I (CFI); Complement factor properdin (CFP); Glycoprotein hormones, alpha polypeptide (CGA); Chorionic gonadotropin subunit beta 1 (CGB1); Chorionic gonadotropin subunit beta 3 (CGB3); Chorionic gonadotropin subunit beta 5 (CGB5); Chorionic gonadotropin subunit beta 8 (CGB8); Chitinase 3 like 1 (CHI3L1); Chitinase 3 like 2 (CHI3L2); Chitinase 1 (CHIT1); Chondroitin sulfate synthase 1 (CHSY1); Chemokine like factor (CKLF); Cardiotrophin like cytokine factor 1 (CLCF1); C-type lectin domain family 18 member A (CLEC18A); C-type lectin domain family 18 member B (CLEC18B); C-type lectin domain family 18 member C (CLEC18C); C-type lectin domain family 3 member B (CLEC3B); Clusterin (CLU); Chymase 1 (CMA1); Carnosine dipeptidase 1 (CNDP1); Collectin subfamily member 10 (COLEC10); Collectin subfamily member 11 (COLEC11); Collagen like tail subunit of asymmetric acetylcholinesterase (COLQ); COPI coat complex subunit alpha (COPA); Ceruloplasmin (CP); Carboxypeptidase A3 (CP A3); C3 and PZP like alpha-2-macroglobulin domain containing 8 (CPAMD8); Carboxypeptidase B2 (CPB2); Carboxypeptidase N subunit 1 (CPN1); Carboxypeptidase N subunit 2 (CPN2); Carboxypeptidase Q (CPQ); Cellular repressor of E1A stimulated genes 1 (CREG1); Corticotropin releasing hormone (CRH); Corticotropin 68110026078 1releasing hormone binding protein (CRHBP); Cysteine rich secretory protein LCCL domain containing 2 (CRISPLD2); C-reactive protein (CRP); Cartilage associated protein (CRTAP); Colony stimulating factor 1 (CSF1); Colony stimulating factor 2 (CSF2); Colony stimulating factor 2 receptor subunit alpha (CSF2RA); Colony stimulating factor 3 (CSF3); Chorionic somatomammotropin hormone 1 (CSH1); Chorionic somatomammotropin hormone 2 (CSH2); Chorionic somatomammotropin hormone like 1 (CSHL1); Cystatin C (CST3); Cystatin F (CST7); Cardiotrophin 1 (CTF1); Cathepsin B (CTSB); Cathepsin D (CTSD); CutA divalent cation tolerance homolog (CUTA); C-X3-C motif chemokine ligand 1 (CX3CL1); C-X-C motif chemokine ligand 1 (CXCL1); C-X-C motif chemokine ligand 10 (CXCL10); C-X-C motif chemokine ligand 11 (CXCL11); C-X-C motif chemokine ligand 12 (CXCL12); C-X-C motif chemokine ligand 13 (CXCL13); C-X-C motif chemokine ligand 14 (CXCL14); C-X-C motif chemokine ligand 16 (CXCL16); C-X-C motif chemokine ligand 17 (CXCL17); C-X-C motif chemokine ligand 2 (CXCL2); C-X-C motif chemokine ligand 3 (CXCL3); C-X-C motif chemokine ligand 5 (CXCL5); C-X-C motif chemokine ligand 6 (CXCL6); C-X-C motif chemokine ligand 8 (CXCL8); C-X-C motif chemokine ligand 9 (CXCL9); Cytochrome b5 domain containing 2 (CYB5D2); Defensin alpha 1 (DEFA1); Defensin alpha IB (DEFA1B); Defensin alpha 3 (DEFA3); Defensin alpha 4 (DEFA4); Dehydrogenase / reductase X-linked (DHRSX); Deoxyribonuclease 1 like 3 (DNASE1L3); Dipeptidyl peptidase 4 (DPP4); Epstein-Barr virus induced 3 (EBI3); ECRG4 augurin precursor (ECRG4); EGF like repeats and discoidin domains 3 (EDIL3); Endothelin 1 (EDN1); Endothelin 2 (EDN2); Endothelin 3 (EDN3); Ephrin Al (EFNA1); Ephrin A4 (EFNA4); Epidermal growth factor receptor (EGFR); Elastase, neutrophil expressed (ELANE); ER membrane protein complex subunit 10 (EMC 10); Ectonucleotide pyrophosphatase / phosphodiesterase 2 (ENPP2); Ectonucleoside triphosphate diphosphohydrolase 5 (inactive) (ENTPD5); Ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6); Erythropoietin (EPO); Endoplasmic reticulum aminopeptidase 1 (ERAP1); Endoplasmic reticulum aminopeptidase 2 (ERAP2); Epiregulin (EREG); Erythroferrone (ERFE); Endogenous retrovirus group MER34 member 1, envelope (ERVMER34-1); Endothelial cell specific molecule 1 (ESM1); Coagulation factor X (F10); Coagulation factor XI (F11); Coagulation factor XII (F12); Coagulation factor XIII A chain (F13A1); Coagulation factor XIII B chain (F13B); Coagulation factor II, thrombin (F2); Coagulation factor III, tissue factor (F3); Coagulation factor V (F5); Coagulation factor VII (F7); Coagulation factor VIII (F8); Coagulation factor IX (F9); Family with sequence similarity 177 member Al (FAM177A1); FAM3 metabolism regulating signaling molecule A (FAM3A); FAM3 metabolism regulating signaling molecule B (FAM3B); Fibroblast activation protein alpha (FAP); Fas cell surface death receptor (FAS); Fas ligand (FASLG); Fibrillin 1 (FBN1); Fibrillin 2 (FBN2); Fc epsilon receptor II 69110026078 1(FCER2); Fc gamma receptor Illa (FCGR3A); Fc gamma receptor Illb (FCGR3B); Fc mu receptor (FCMR); Ficolin 1 (FCN1); Ficolin 2 (FCN2); Ficolin 3 (FCN3); Fc receptor like 5 (FCRL5); Fetuin B (FETUB); Fibrinogen alpha chain (FGA); Fibrinogen beta chain (FGB); Fibroblast growth factor 19 (FGF19); Fibroblast growth factor 21 (FGF21); Fibroblast growth factor 23 (FGF23); Fibroblast growth factor binding protein 2 (FGFBP2); Fibrinogen gamma chain (FGG); Fibrinogen like 1 (FGL1); Fibrinogen like 2 (FGL2); Fukutin related protein (FKRP); Fms related receptor tyrosine kinase 1 (FLT1); Fms related receptor tyrosine kinase 3 ligand (FLT3LG); Fms related receptor tyrosine kinase 4 (FLT4); Fibronectin 1 (FN1); Folate receptor alpha (F0LR1); Folate receptor beta (FOLR2); Folate receptor gamma (FOLR3): Follicle stimulating hormone subunit beta (FSHB); Follistatin (FST); Follistatin like 1 (FSTL1); Follistatin like 4 (FSTL4); Alpha-L-fucosidase 2 (FUCA2); Fucosyltransferase 6 (FUT6); Galanin and GMAP prepropeptide (GAL); Growth arrest specific 6 (GAS6); Glutamine amidotransferase class 1 domain containing 1 (GATD1); GC vitamin D binding protein (GC); Glucagon (GCG); Growth differentiation factor 1 (GDF1); Growth differentiation factor 11 (GDF11); Growth differentiation factor 15 (GDF15); Growth differentiation factor 2 (GDF2); Growth differentiation factor 3 (GDF3); Growth differentiation factor 5 (GDF5); Growth differentiation factor 6 (GDF6); Growth factor, augmenter of liver regeneration (GFER); Glucose-fructose oxidoreductase domain containing 2 (GFOD2); Growth hormone 1 (GH1); Growth hormone 2 (GH2); Growth hormone receptor (GHR); Ghrelin and obestatin prepropeptide (GHRL); Gastric inhibitory polypeptide (GIP); Glycosyltransferase 1 domain containing 1 (GLT1D1); Granulysin (GNLY); Gonadotropin releasing hormone 1 (GNRH1); Gonadotropin releasing hormone 2 (GNRH2); Glycoprotein hormone subunit alpha 2 (GPHA2); Glycoprotein hormone subunit beta 5 (GPHB5); Glucose-6-phosphate isomerase (GPI); Glycosylphosphatidylinositol specific phospholipase DI (GPLD1); Glutathione peroxidase 3 (GPX3); Glutathione peroxidase 7 (GPX7); Gremlin 1, DAN family BMP antagonist (GREM1); Gremlin 2, DAN family BMP antagonist (GREM2); Granulin precursor (GRN); Gelsolin (GSN); Guanylate cyclase activator 2A (GUCA2A); Guanylate cyclase activator 2B (GUCA2B); Granzyme A (GZMA); Granzyme B (GZMB): Granzyme H (GZMH); Granzyme K (GZMK); Granzyme M (GZMM); Hyaluronan binding protein 2 (HABP2); Hepcidin antimicrobial peptide (HAMP); Heparin binding EGF like growth factor (HBEGF); Hypocretin neuropeptide precursor (HCRT); Heparin binding growth factor (HDGF); Hepatocyte growth factor (HGF); HGF activator (HGFAC); Major histocompatibility complex, class I, E (HLA-E); Major histocompatibility complex, class I, G (HLA-G); High mobility group box 1 (HMGB1); High mobility group box 2 (HMGB2); Histocompatibility minor serpin domain containing (HMSD); Haptoglobin (HP); Haptoglobin-related protein (HPR); Hemopexin (HPX); Histidine rich glycoprotein (HRG); HtrA serine peptidase 1 (HTRA1); Hyaluronidase 170110026078 1(HYAL1); Hyaluronidase 3 (HYAL3); Islet amyloid polypeptide (IAPP); Interferon induced protein 35 (IFI35); Interferon alpha 1 (IFNA1); Interferon alpha 10 (IFNA10); Interferon alpha 13 (IFNA13); Interferon alpha 14 (IFNA14); Interferon alpha 16 (IFNA16); Interferon alpha 17 (IFNA17); Interferon alpha 2 (IFNA2); Interferon alpha 21 (IFNA21); Interferon alpha 4 (IFNA4): Interferon alpha 5 (IFNA5); Interferon alpha 6 (IFNA6); Interferon alpha 7 (IFNA7); Interferon alpha 8 (IFNA8); Interferon alpha and beta receptor subunit 2 (IFNAR2); Interferon beta 1 (IFNB1); Interferon epsilon (IFNE); Interferon gamma (IFNG); Interferon kappa (IFNK); Interferon lambda 1 (IFNL1); Interferon lambda 2 (IFNL2); Interferon lambda 3 (IFNL3); Interferon omega 1 (IFNW1); Insulin like growth factor 1 (IGF1); Insulin like growth factor 2 (IGF2); Insulin like growth factor binding protein acid labile subunit (IGFALS); Insulin like growth factor binding protein 1 (IGFBP1); Insulin like growth factor binding protein 2 (IGFBP2); Insulin like growth factor binding protein 3 (IGFBP3); Insulin like growth factor binding protein 4 (IGFBP4); Insulin like growth factor binding protein 5 (IGFBP5); Insulin like growth factor binding protein 6 (IGFBP6); Insulin like growth factor binding protein 7 (IGFBP7); Insulin like growth factor binding protein like 1 (IGFBPL1); IgA inducing protein (IGIP); Immunoglobulin lambda like polypeptide 1 (IGLL1); Immunoglobulin lambda like polypeptide 5 (IGLL5); Interleukin 10 (IL10); Interleukin 11 (IL11); Interleukin 11 receptor subunit alpha (IL11RA); Interleukin 12A (IL12A); Interleukin 12B (IL12B); Interleukin 13 (IL 13); Interleukin 15 (IL 15); Interleukin 15 receptor subunit alpha (IL15RA); Interleukin 16 (IL16); Interleukin 17A (IL17A); Interleukin 17B (IL17B); Interleukin 17C (IL17C); Interleukin 17D (IL17D); Interleukin 17F (IL17F); Interleukin 17 receptor A (IL17RA); Interleukin 18 (IL18); Interleukin 18 binding protein (IL18BP); Interleukin 19 (IL19); Interleukin 1 alpha (ILIA); Interleukin 1 beta (IL1B); Interleukin 1 family member 10 (IL1F10); Interleukin 1 receptor type 1 (IL1R1); Interleukin 1 receptor type 2 (IL1R2); Interleukin 1 receptor accessory protein (IL 1 RAP); Interleukin 1 receptor like 1 (IL1RL1); Interleukin 1 receptor antagonist (IL1RN); Interleukin 2 (IL2); Interleukin 20 (IL20); Interleukin 21 (IL21); Interleukin 22 (IL22); Interleukin 22 receptor subunit alpha 2 (IL22RA2); Interleukin 23 subunit alpha (IL23A); Interleukin 24 (IL24); Interleukin 25 (IL25); Interleukin 26 (IL26); Interleukin 27 (IL27); Interleukin 3 (IL3); Interleukin 31 (IL31); Interleukin 32 (IL32); Interleukin 33 (IL33); Interleukin 34 (IL34); Interleukin 36 alpha (IL36A); Interleukin 36 beta (IL36B); Interleukin 36 gamma (IL36G); Interleukin 36 receptor antagonist (IL36RN); Interleukin 37 (IL37); Interleukin 4 (IL4); Interleukin 4 induced 1 (IL4I1); Interleukin 4 receptor (IL4R); Interleukin 5 (IL5); Interleukin 6 (IL6); Interleukin 6 receptor (IL6R); Interleukin 6 cytokine family signal transducer (IL6ST); Interleukin 7 (IL7); Interleukin 9 (IL9); Inhibin subunit alpha (INHA); Inhibin subunit beta A (INHBA); Inhibin subunit beta B (INHBB); Inhibin subunit beta C (INHBC); Inhibin subunit beta E (INHBE); Insulin (INS); Insulin like 3 (INSL3); Insulin 71110026078 1like 4 (INSL4); Insulin like 5 (INSL5); Insulin like 6 (INSL6); ISG15 ubiquitin like modifier (ISG15); Inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1); Inter-alpha-trypsin inhibitor heavy chain 2 (ITIH2); Inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3); Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4); Inter-alpha-trypsin inhibitor heavy chain 5 (ITIH5); Inter-alpha-trypsin inhibitor heavy chain family member 6 (ITIH6); Intelectin 1 (ITLN 1); Integral membrane protein 2B (ITM2B); Junctional adhesion molecule 3 (JAM3); Joining chain of multimeric IgA and IgM (JCHAIN); Killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 4 (KIR2DS4); Klotho (KL); Kallikrein related peptidase 15 (KLK15); Kallikrein Bl (KLKB1); Kininogen 1 (KNG1); Leukocyte associated immunoglobulin like receptor 2 (LAIR2); Lipopolysaccharide binding protein (LBP); Lecithin-cholesterol acyltransferase (LCAT); Liver enriched antimicrobial peptide 2 (LEAP2); Leukocyte cell derived chemotaxin 2 (LECT2); Leptin (LEP); Galectin 1 (LGALS1); Galectin 3 (LGALS3); Galectin 3 binding protein (LGALS3BP); Galectin 9 (LGALS9); Leucine rich repeat LGI family member 2 (LGI2); Luteinizing hormone subunit beta (LHB); Leukocyte immunoglobulin like receptor A2 (LILRA2); Leukocyte immunoglobulin like receptor A5 (LILRA5); Lipase C, hepatic type (LIPC); Lipase G, endothelial type (LIPG); Lipase H (LIPH); Lipoprotein(a) (LPA); Lipoprotein lipase (LPL); Leucine rich alpha-2 -glycoprotein 1 (LRG1); Lymphotoxin alpha (LTA); Latent transforming growth factor beta binding protein 3 (LTBP3); Lactotransferrin (LTF); Lymphocyte antigen 6 family member G5B (LY6G5B); Lymphocyte antigen 86 (LY86); Lymphocyte antigen 96 (LY96); Lysozyme (LYZ); Mannosidase alpha class 2B member 2 (MAN2B2); Mesencephalic astrocyte derived neurotrophic factor (MANF); Microtubule associated protein tau (MAPT); MBL associated serine protease 1 (MASP1); MBL associated serine protease 2 (MASP2); Mannose binding lectin 2 (MBL2); Midkine (MDK); Multiple EGF like domains 6 (MEGF6); MET proto-oncogene, receptor tyrosine kinase (MET); Meteorin like, glial cell differentiation regulator (METRNL); Milk fat globule EGF and factor V / VIII domain containing (MFGE8); Alpha- 1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A); Matrix Gia protein (MGP); MIA SH3 domain containing (MIA); Macrophage migration inhibitory factor (MIF); Multiple inositol-polyphosphate phosphatase 1 (MINPP1); Motilin (MLN); Matrix metallopeptidase 25 (MMP25); Matrix metallopeptidase 9 (MMP9); Macrophage expressed 1 (MPEG1); Macrophage stimulating 1 (MST1); Myeloid derived growth factor (MYDGF); Marginal zone B and Bl cell specific protein (MZB1); Nicotinamide phosphoribosyltransferase (NAMPT); NAD(P)HX epimerase (NAXE); Neural EGFL like 2 (NELL2); Neudesin neurotrophic factor (NENF); NHL repeat containing 3 (NHLRC3); Neuromedin B (NMB); N-myc and STAT interactor (NMI); Nodal growth differentiation factor (NODAL); Noggin (NOG); Notch 2 N-terminal like A (NOTCH2NLA); Notch 2 N-terminal like B (NOTCH2NLB); Notch 2 N-terminal like C 72110026078 1(NOTCH2NLC); NPC intracellular cholesterol transporter 2 (NPC2); Natriuretic peptide A (NPPA); Natriuretic peptide B (NPPB); Natriuretic peptide C (NPPC); Neuronal pentraxin 2 (NPTX2); Neuropeptide W (NPW); Neuropeptide Y (NPY); Neuregulin 1 (NRG1); Neurturin (NRTN); Nucleobindin 1 (NUCB1); Nucleobindin 2 (NUCB2); Neurexophilin and PC-esterase domain family member 3 (NXPE3); Oncoprotein induced transcript 3 (OIT3); Orosomucoid 1 (ORM1); Orosomucoid 2 (ORM2); Oncostatin M (OSM); Oxytocin / neurophysin I prepropeptide (OXT); Protocadherin 12 (PCDH12); Proprotein convertase subtilisin / kexin type 1 inhibitor (PCSK1N); Proprotein convertase subtilisin / kexin type 5 (PCSK5); Proprotein convertase subtilisin / kexin type 9 (PCSK9); Prenylcysteine oxidase 1 like (PCYOX1L); Platelet derived growth factor subunit A (PDGFA); Platelet derived growth factor subunit B (PDGFB); Platelet derived growth factor C (PDGFC); Platelet derived growth factor D (PDGFD); Platelet factor 4 (PF4); Platelet factor 4 variant 1 (PF4V1); Placental growth factor (PGF); Peptidoglycan recognition protein 1 (PGLYRP1); Peptidoglycan recognition protein 2 (PGLYRP2); Peptidase inhibitor 16 (PI16); Peptidase inhibitor 3 (PI3); Progesterone immunomodulatory binding factor 1 (PIBF1); Paired immunoglobin like type 2 receptor alpha (PILRA); Phospholipase A2 inhibitor and LY6 / PLAUR domain containing (PINLYP); Protein kinase domain containing, cytoplasmic (PKDCC); Phospholipase A2 group XIIA (PLA2G12A); Phospholipase A2 group XIIB (PLA2G12B); Phospholipase A2 group IIA (PLA2G2A); Phospholipase A2 group III (PLA2G3); Phospholipase A2 group VII (PLA2G7); Phospholipase A2 receptor 1 (PLA2R1); Plasminogen activator, tissue type (PLAT); Plasminogen activator, urokinase (PLAU); Plasminogen (PLG); Plasminogen like Bl (PLGLB1); Plasminogen like B2 (PLGLB2); Phospholipid transfer protein (PLTP); Pro-melanin concentrating hormone (PMCH); Prepronociceptin (PNOC); Proopiomelanocortin (POMC); Paraoxonase 1 (PON1); Paraoxonase 2 (PON2); Paraoxonase 3 (PON3); Pro-platelet basic protein (PPBP); Peptidylprolyl isomerase A (PPIA); Peptidylprolyl isomerase B (PPIB); Pancreatic polypeptide (PPY); Protease associated domain containing 1 (PRADC1); Prolactin (PRL); Protein C, inactivator of coagulation factors Va and Villa (PROC); Prokineticin 1 (PR0K1); Prokineticin 2 (PROK2); Protein S (PROS1); Protein Z, vitamin K dependent plasma glycoprotein (PROZ); Serine protease 23 (PRSS23); Serine protease 33 (PRSS33); Serine protease 57 (PRSS57); Proteinase 3 (PRTN3); Prostaglandin D2 synthase (PTGDS); Parathyroid hormone (PTH); Protein tyrosine kinase 7 (inactive) (PTK7); Pleiotrophin (PTN); Protein tyrosine phosphatase receptor type J (PTPRJ); Pentraxin 3 (PTX3); Peptide YY (PYY); PZP alpha-2-macroglobulin like (PZP); Glutaminyl-peptide cyclotransferase (QPCT); Retinoic acid receptor responder 2 (RARRES2); Retinol binding protein 4 (RBP4); Renin (REN); Resistin (RETN); Resistin like beta (RETNLB); Relaxin 1 (RLN1); Relaxin 2 (RLN2); Relaxin 3 (RLN3); Ribonuclease A family member 2 (RNASE2); Ribonuclease A family member 373110026078 1(RNASE3); Ribonuclease A family member 4 (RNASE4); Ribonuclease A family member k6 (RNASE6); Ribonuclease T2 (RNASET2); Renalase, FAD dependent amine oxidase (RNLS); R-spondin 3 (RSPO3); Ring finger and SPRY domain containing 1 (RSPRY1); S100 calcium binding protein A12 (S100A12); S100 calcium binding protein A4 (S100A4); S100 calcium binding protein A8 (S100A8): SI 00 calcium binding protein A9 (S100A9); Serum amyloid Al (SAA1); Serum amyloid A2 (AA2); Serum amyloid A4, constitutive (SAA4); Secretogranin II (SCG2); Secretogranin V (SCG5); Secretoglobin family 3 A member 1 (SCGB3A1); Serine carboxypeptidase 1 (SCPEP1); Secretin (SCT); Signal peptide, CUB domain and EGF like domain containing 1 (SCUBE1): Signal peptide, CUB domain and EGF like domain containing 2 (SCUBE2); Signal peptide, CUB domain and EGF like domain containing 3 (SCUBE3); Syndecan 1 (SDC1); Syndecan 4 (SDC4); Secreted and transmembrane 1 (SECTM1); Selenoprotein P (SELENOP); Semaphorin 3F (SEMA3F); Semaphorin 3G (SEMA3G); Serpin family A member 1 (SERPINA1); Serpin family A member 10 (SERPINA10); Serpin family A member 11 (SERPINA11); Serpin family A member 3 (SERPINA3); Serpin family A member 4 (SERPINA4); Serpin family A member 5 (SERPINA5); Serpin family A member 6 (SERPINA6); Serpin family A member 7 (SERPINA7); Serpin family A member 9 (SERPINA9); Serpin family B member 1 (SERPINB1); Serpin family C member 1 (SERPINC1); Serpin family D member 1 (SERPIND1); Serpin family E member 1 (SERPINE1); Serpin family F member 1 (SERPINF1); Serpin family F member 2 (SERPINF2); Serpin family G member 1 (SERPING1); Sex hormone binding globulin (SHBG); Sialic acid binding Ig like lectin 6 (SIGLEC6); Signaling lymphocytic activation molecule family member 1 (SLAMF1); Secretory leukocyte peptidase inhibitor (SLPI); Small integral membrane protein 20 (SMIM20); Sphingomyelin phosphodiesterase 1 (SMPD1); Sphingomyelin phosphodiesterase acid like 3A (SMPDL3A); Sphingomyelin phosphodiesterase acid like 3B (SMPDL3B); Sushi, nidogen and EGF like domains 1 (SNED1); Superoxide dismutase 3 (SOD3); Suppressor of glucose, autophagy associated 1 (SOGA1); Sortilin related receptor 1 (SORL1); Secreted protein acidic and cysteine rich (SPARC); Serine peptidase inhibitor Kazal type 2 (SPINK2); Serine peptidase inhibitor Kazal type 8 (putative) (SPINK8); Serine peptidase inhibitor, Kunitz type 1 (SPINT1); SPARC (osteonectin), cwcv and kazal like domains proteoglycan 1 (SPOCK1); SPARC (osteonectin), cwcv and kazal like domains proteoglycan 2 (SPOCK2); Spondin 1 (SPON1); Spondin 2 (SPON2); Secreted phosphoprotein 1 (SPP1); Secreted phosphoprotein 2 (SPP2); Spexin hormone (SPX); Serglycin (SRGN); Sushi repeat containing protein X-linked 2 (SRPX2); Somatostatin (SST); ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1); Small vasohibin binding protein (SVBP); Tachykinin precursor 1 (TAC1); Tachykinin precursor 4 (TAC4); Transcobalamin 1 (TCN1); Transcobalamin 2 (TCN2); TEK receptor tyrosine kinase (TEK); Transferrin (TF); Trefoil factor 3 (TFF3); Tissue 74110026078 1factor pathway inhibitor (TFPI); Transferrin receptor (TFRC); Transforming growth factor alpha (TGFA); Transforming growth factor beta 1 (TGFB1); Transforming growth factor beta 2 (TGFB2); Transforming growth factor beta 3 (TGFB3); Transforming growth factor beta induced (TGFBI); Transforming growth factor beta receptor 2 (TGFBR2); Transforming growth factor beta receptor 3 (TGFBR3); Thrombopoietin (THPO); Thrombospondin type 1 domain containing 7A (THSD7A); TIMP metallopeptidase inhibitor 1 (TIMP1); Tumor necrosis factor (TNF); TNF alpha induced protein 6 (TNFAIP6); TNF receptor superfamily member 18 (TNFRSF18); TNF receptor superfamily member 1A (TNFRSF1A); TNF receptor superfamily member IB (TNFRSF1B); TNF receptor superfamily member 6b (TNFRSF6B): TNF superfamily member 10 (TNFSF10); TNF superfamily member 11 (TNFSF11); TNF superfamily member 12 (TNFSF12); TNF superfamily member 13 (TNFSF13); TNF superfamily member 13b (TNFSF13B); TNF superfamily member 14 (TNFSF14); TNF superfamily member 15 (TNFSF15); Torsin family 2 member A (TOR2A); Tryptase alpha / beta 1 (TPSAB1); Tryptase beta 2 (TPSB2); Triggering receptor expressed on myeloid cells 1 (TREM1); Thyroid stimulating hormone subunit beta (TSHB); Tsukushi, small leucine rich proteoglycan (TSKU); Thymic stromal lymphopoietin (TSLP); Transthyretin (TTR); Thioredoxin domain containing 16 (TXNDC16); Urocortin (UCN); Urocortin 2 (UCN2); Urocortin 3 (UCN3); Urotensin 2 (UTS2); Vasohibin 1 (VASH1); Vasohibin 2 (VASH2); Vascular cell adhesion molecule 1 (VCAM1); Versican (VCAN); Vascular endothelial growth factor A (VEGFA); Vascular endothelial growth factor B (VEGFB); Vascular endothelial growth factor C (VEGFC); Vascular endothelial growth factor D (VEGFD); VGF nerve growth factor inducible (VGF); Vasoactive intestinal peptide (VIP); Vitelline membrane outer layer 1 homolog (VM01); V-set and transmembrane domain containing 1 (VSTM1); Vitronectin (VTN); Von Willebrand factor (VWF); WD repeat domain 25 (WDR25); X-C motif chemokine ligand 1 (XCL1); X-C motif chemokine ligand 2 (XCL2); Xylosyltransferase 1 (XYLT1); Xylosyltransferase 2 (XYLT2); or Zinc finger BED-type containing 3 (ZBED3).

[0277] In an aspect, a disclosed targeted pre-mRNA can encode a secretable brain-specific peptide or a secretable brain-specific protein. In an aspect, a secretable brain-specific peptide or a secretable brain-specific protein can comprise ADAM metallopeptidase domain 23 (ADAM23); Adhesion G protein-coupled receptor Bl (ADGRB1); Agouti related neuropeptide (AGRP); Anosmin 1 (ANOS1); Beta-1,3-glucuronyltransferase 1 (B3GAT1); Brevican (BCAN); BTB domain containing 17 (BTBD17); Complement Clq like 1 (C1QL1); Complement Clq like 2 (C1QL2); Complement Clq like 3 (C1QL3); Complement Clq like 4 (C1QL4); Clq and TNF related 4 (C1QTNF4); Carbonic anhydrase 10 (CA10); Carbonic anhydrase 11 (CA11); Cerebellin 1 precursor (CBLN1); Cerebellin 2 precursor (CBLN2); Cerebellin 3 precursor (CBLN3); Cerebellin 4 precursor (CBLN4); Cell growth regulator with EF-hand domain 1 (CGREF1); Cell 75110026078 1adhesion molecule LI like (CHL1); C-type lectin domain containing 19A (CLEC19A); Contactin 2 (CNTN2); Cortistatin (CORT); Crumbs cell polarity complex component 1 (CRB1); Cellular repressor of E1A stimulated genes 2 (CREG2); Chondroitin sulfate proteoglycan 5 (CSPG5); Dorsal inhibitory’ axon guidance protein (DRAXIN); Energy homeostasis associated (ENHO); Fibroblast growth factor 17 (FGF 17); Fibroblast growth factor 3 (FGF3); Fibroblast growth factor 5 (FGF5); Fibroblast growth factor binding protein 3 (FGFBP3); Follistatin like 5 (FSTL5); Galanin like peptide (GALP); Hyaluronan and proteoglycan link protein 2 (HAPLN2); Hyaluronan and proteoglycan link protein 4 (HAPLN4); Hydroxysteroid 11-beta dehydrogenase 1 like (HSD11B1L); IgLON family member 5 (IGLON5); KIAA0319 (KIAA0319); Leucine rich glioma inactivated 1 (LGI1); Leucine rich repeat LGI family member 3 (LGI3); Leucine rich repeat LGI family member 4 (LGI4); Leucine zipper protein 2 (LUZP2); Meteorin, glial cell differentiation regulator (METRN); Neurocan (NCAN); Neuropilin and tolloid like 1 (NETO1); Neuromedin S (NMS); Neuropeptide S (NPS); Neuronal pentraxin 1 (NPTX1); Neuregulin 3 (NRG3); Netrin 3 (NTN3); Netrin 5 (NTN5); Neurexophilin 1 (NXPH1); Neurexophilin 2 (NXPH2); Neurexophilin 3 (NXPH3); Neurexophilin 4 (NXPH4); Olfactomedin 1 (OLFM1); Olfactomedin 3 (OLFM3); Protocadherin alpha 6 (PCDHA6); Prodynorphin (PDYN); Prolactin releasing hormone (PRLH); Serine protease 51 (PRSS51); Parathyroid hormone 2 (PTH2); Protein tyrosine phosphatase receptor type Z1 (PTPRZ1); Reelin (RELN); Secretogranin III (SCG3); Stimulator of chondrogenesis 1 (SCRG1); Serpin family I member 1 (SERPINI1); Slit guidance ligand 1 (SLIT1); SLIT and NTRK like family member 1 (SLITRK1); TAFA chemokine like family member 1 (TAFA1); TAFA chemokine like family member 4 (TAFA4); TAFA chemokine like family member 5 (TAFA5); Tenascin R (TNR); or Triggering receptor expressed on myeloid cells 2 (TREM2).

[0278] In an aspect, a disclosed targeted endogenous pre-mRNA can comprise transthyretin and can be expressed by one or more cells in the brain. In an aspect, a disclosed targeted endogenous pre-mRNA can comprise transthyretin and can be expressed by choroid plexus epithelial cells.

[0279] In an aspect, a disclosed targeted pre-mRNA can encode a secretable peptide or a secretable protein specific to the digestive system. In an aspect, a secretable peptide or a secretable protein specific to the digestive system can comprise Aldo-keto reductase family 1 member BIO (AKR1B10); Amylase alpha 1A (AMY1A); Amylase alpha IB (AMY1B); Amylase alpha 1C (AMY1C); Amylase alpha 2A (AMY2A); Amylase alpha 2B (AMY2B); BPI fold containing family A member 2 (BPIFA2); Chromosome 6 open reading frame 58 (C6orf58); Carbonic anhydrase 6 (CA6); Cobalamin binding intrinsic factor (CBLIF); Carboxyl ester lipase (CEL); Chymotrypsin like elastase 2A (CELA2A); Chymotrypsin like elastase 2B (CELA2B); Chymotrypsin like elastase 3A (CELA3A); Chymotrypsin like elastase 3B (CELA3B); Chloride 76110026078 1channel accessory 1 (CLCA1); Colipase (CLPS) Carboxypeptidase Al (CPA1); Carboxypeptidase A2 (CPA2); Carboxypeptidase Bl (CPB1); Cystatin SN (CST1); Cystatin SA (CST2); Cystatin S (CST4); Cystatin D (CST5); Chymotrypsinogen Bl (CTRB1); Chymotrypsinogen B2 (CTRB2); Chymotrypsin C (CTRC); Chymotrypsin like (CTRL); Defensin alpha 5 (DEFA5); Defensin alpha 6 (DEFA6); Dehydrogenase / reductase 11 (DHRS11) Deoxyribonuclease 1 (DNASE1) FAM3 metabolism regulating signaling molecule D (FAM3D); Gastrin (GAST); Gastrokine 1 (GKN1); Gastrokine 2 (GKN2); Glycoprotein 2 (GP2); Histatin 1 (HTN1); Histatin 3 (HTN3); INS-IGF2 readthrough (INS-IGF2); Intelectin 2 (ITLN2); Kallikrein 1 (KLK1); Lacritin (LACRT); Lipase F, gastric type (LIPF); Lactoperoxidase (LPO); LY6 / PLAUR domain containing 8 (LYPD8); Meprin A subunit beta (MEP1B); Mucin 13, cell surface associated (MUC13); Mucin 5AC, oligomeric mucus / gel-forming (MUC5AC); Mucin 6, oligomeric mucus / gel-forming (MUC6); Mucin 7, secreted (MUC7); Neuregulin 4 (NRG4); Neurotensin (NTS); Neurexophilin and PC-esterase domain family member 4 (NXPE4); Olfactomedin 4 (OLFM4); Pepsinogen A3 (PGA3); Pepsinogen A4 (PGA4); Pepsinogen A5 (PGA5); Progastricsin (PGC); Polymeric immunoglobulin receptor (PIGR); Phospholipase A2 group IB (PLA2G1B); Peptidase M20 domain containing 1 (PM20D1); Pancreatic lipase (PNLIP); Pancreatic lipase related protein 1 (PNLIPRP1); Proline rich acidic protein 1 (PRAP1); Proline rich protein BstNI subfamily 1 (PRB1); Proline rich protein BstNI subfamily 2 (PRB2); Proline rich protein BstNI subfamily 3 (PRB3); Proline rich protein BstNI subfamily 4 (PRB4); Proline rich protein Haelll subfamily 2 (PRH2); Proline rich 27 (PRR27); Proline rich 4 (PRR4); Serine protease 1 (PRSS1); Serine protease 2 (PRSS2); Serine protease 27 (PRSS27); Serine protease 3 (PRSS3); Regenerating family member 1 alpha (REG1A); Regenerating family member 1 beta (REG1B); Regenerating family member 3 alpha (REG3A); Regenerating family member 3 gamma (REG3G); Regenerating family member 4 (REG4); Ribonuclease A family member 1, pancreatic (RNASE1); Ribonuclease A family member 8 (RNASE8); Serpin family I member 2 (SERPINI2); Submaxillary gland androgen regulated protein 3A (SMR3A); Submaxillary gland androgen regulated protein 3B (SMR3B); Serine peptidase inhibitor Kazal type 1 (SPINK1); Serine peptidase inhibitor Kazal type 4 (SPINK4); Small proline rich protein 2A (SPRR2A); Statherin (STATH); Trefoil factor 1 (TFF1); Trefoil factor 2 (TFF2); Zymogen granule protein 16 (ZG16); or Zymogen granule protein 16B (ZG16B).

[0280] In an aspect, a disclosed targeted pre-mRNA can encode a secretable peptide or a secretable protein specific to the female reproductive system. In an aspect, a secretable peptide or a secretable protein specific to the female reproductive system can comprise ADAM metallopeptidase domain 12 (ADAM12); Casein alpha si (CSN1S1); Casein beta (CSN2); Casein kappa (CSN3); Cystatin 9 (CST9); Endogenous retrovirus group 48 member 1 (ERVH48-1);77110026078 1Growth differentiation factor 9 (GDF9); HtrA serine peptidase 4 (HTRA4); Isthmin 2 (ISM2); KiSS-1 metastasis suppressor (KISSI); Lactalbumin alpha (LALBA); Notum, palmitoleoyl-protein carboxylesterase (NOTUM); Oviductal glycoprotein 1 (OVGP1); Progestagen associated endometrial protein (PAEP); Pappalysin 1 (PAPP A); Pappalysin 2 (PAPPA2); Placenta enriched 1 (PLAC1); Proteoglycan 2, pro eosinophil major basic protein (PRG2); Serine protease 35 (PRSS35); Pregnancy specific beta- 1 -glycoprotein 1 (PSG1); Pregnancy specific beta-1 -glycoprotein 11 (PSG11); Pregnancy specific beta- 1 -glycoprotein 2 (PSG2); Pregnancy specific beta- 1 -glycoprotein 3 (PSG3); Pregnancy specific beta- 1 -glycoprotein 4 (PSG4); Pregnancy specific beta- 1 -glycoprotein 5 (PSG5); Pregnancy specific beta- 1 -glycoprotein 6 (PSG6); Pregnancy specific beta- 1 -glycoprotein 7 (PSG7); Pregnancy specific beta- 1 -glycoprotein 8 (PSG8); Pregnancy specific beta- 1 -glycoprotein 9 (PSG9); R-spondin 1 (RSPO1); Secretoglobin family 2A member 2 (SCGB2A2); Serpin family E member 2 (SERPINE2); Secreted frizzled related protein 4 (SFRP4); Tachykinin precursor 3 (TAC3); Zona pellucida glycoprotein 1 (ZP1); Zona pellucida glycoprotein 2 (ZP2); Zona pellucida glycoprotein 3 (ZP3); or Zona pellucida glycoprotein 4 (ZP4).

[0281] In an aspect, a disclosed targeted pre-mRNA can encode a secretable peptide or a secretable protein specific to the immune system. In an aspect, a secretable peptide or a secretable protein specific to the immune can comprise Immunoglobulin heavy constant alpha 1 (IGHA1); Immunoglobulin heavy constant alpha 2 (A2m marker) (IGHA2); Immunoglobulin heavy diversity 1-1 (IGHD1-1); Immunoglobulin heavy constant epsilon (IGHE); Immunoglobulin heavy constant gamma 1 (Glm marker) (IGHG1); Immunoglobulin heavy constant gamma 2 (G2m marker) (IGHG2); Immunoglobulin heavy constant gamma 3 (G3m marker) (IGHG3); Immunoglobulin heavy constant gamma 4 (G4m marker) (IGHG4); Immunoglobulin heavy joining 1 (IGHJ1); Immunoglobulin heavy constant mu (IGHM); Immunoglobulin heavy variable 1-18 (IGHV1-18); Immunoglobulin heavy variable 1-2 (IGHV1-2); Immunoglobulin heavy variable 1-24 (IGHV1-24); Immunoglobulin heavy variable 1-3 (IGHV1-3); Immunoglobulin heavy variable 1-45 (IGHV1-45); Immunoglobulin heavy variable 1-46 (IGHV1-46); Immunoglobulin heavy variable 1-58 (IGHV1-58); Immunoglobulin heavy variable 1-69 (IGHV1-69); Immunoglobulin heavy variable 1-69-2 (IGHV 1 -69-2); Immunoglobulin heavy variable 1-69D (IGHV1-69D); Immunoglobulin heavy variable 2-26 (IGHV2-26); Immunoglobulin heavy variable 2-5 (IGHV2-5); Immunoglobulin heavy variable 2-70 (IGHV2-70); Immunoglobulin heavy variable 2-70D (IGHV2-70D); Immunoglobulin heavy variable 3-11 (IGHV3-11); Immunoglobulin heavy variable 3-13 (IGHV3-13); Immunoglobulin heavy variable 3-15 (IGHV3-15); Immunoglobulin heavy variable 3-16 (non-functional) (IGHV3-16); Immunoglobulin heavy variable 3-20 (IGHV3-20); Immunoglobulin heavy variable 3-2178110026078 1(IGHV3-21); Immunoglobulin heavy variable 3-23 (IGHV3-23); Immunoglobulin heavy variable 3-30 (IGHV3-30); Immunoglobulin heavy variable 3-33 (IGHV3-33); Immunoglobulin heavy variable 3-35 (non-functional) (IGHV3-35); Immunoglobulin heavy variable 3-38 (nonfunctional) (IGHV3-38); Immunoglobulin heavy variable 3-43 (IGHV3-43); Immunoglobulin heavy variable 3-48 (IGHV3-48); Immunoglobulin heavy variable 3-49 (IGHV3-49); Immunoglobulin heavy variable 3-53 (IGHV3-53); Immunoglobulin heavy variable 3-64 (IGHV3-64); Immunoglobulin heavy variable 3-64D (IGHV3-64D); Immunoglobulin heavy variable 3-66 (IGHV3-66); Immunoglobulin heavy variable 3-7 (IGHV3-7); Immunoglobulin heavy variable 3-72 (IGHV3-72); Immunoglobulin heavy variable 3-73 (IGHV3-73); Immunoglobulin heavy variable 3-74 (IGHV3-74); Immunoglobulin heavy variable 4-28 (IGHV4-28); Immunoglobulin heavy variable 4-31 (IGHV4-31); Immunoglobulin heavy variable 4-34 (IGHV4-34); Immunoglobulin heavy variable 4-39 (IGHV4-39); Immunoglobulin heavy variable 4-4 (IGHV4-4); Immunoglobulin heavy variable 4-59 (IGHV4-59); Immunoglobulin heavy variable 4-61 (IGHV4-61); Immunoglobulin heavy variable 5-10-1 (IGHV5-10-1); Immunoglobulin heavy variable 5-51 (IGHV5-51); Immunoglobulin heavy variable 6-1 (IGHV6-1); Immunoglobulin heavy variable 7-4-1 (IGHV7-4-1); Immunoglobulin heavy variable 7-81 (non-functional) (IGHV7-81); Immunoglobulin heavy variable IGHV8-51-1 (non-functional) (IGHV8-51-1); Immunoglobulin kappa constant (IGKC); Immunoglobulin kappa joining 1 (IGKJ1); Immunoglobulin kappa variable 1-12 (IGKV1-12); Immunoglobulin kappa variable 1-16 (IGKV1-16); Immunoglobulin kappa variable 1-17 (IGKV1-17); Immunoglobulin kappa variable 1-27 (IGKV1-27); Immunoglobulin kappa variable 1-33 (IGKV1-33); Immunoglobulin kappa variable 1-37 (non-functional) (IGKV1-37); Immunoglobulin kappa variable 1-39 (IGKV1-39); Immunoglobulin kappa variable 1-5 (IGKV1-5); Immunoglobulin kappa variable 1-6 (IGKV1-6); Immunoglobulin kappa variable 1-8 (IGKV1-8); Immunoglobulin kappa variable 1-9 (IGKV1-9); Immunoglobulin kappa variable ID-12 (IGKV1D-12); Immunoglobulin kappa variable ID-13 (IGKV1D-13); Immunoglobulin kappa variable ID-16 (IGKV1D-16); Immunoglobulin kappa variable ID-17 (IGKV1D-17); Immunoglobulin kappa variable ID-33 (IGKV1D-33); Immunoglobulin kappa variable ID-37 (non-functional) (IGKV1D-37); Immunoglobulin kappa variable ID-39 (IGKV1D-39); Immunoglobulin kappa variable ID-42 (non-functional) (IGKV1D-42); Immunoglobulin kappa variable ID-43 (IGKV1D-43); Immunoglobulin kappa variable ID-8 (IGKV1D-8); Immunoglobulin kappa variable 2-24 (IGKV2-24); Immunoglobulin kappa variable 2-28 (IGKV2-28); Immunoglobulin kappa variable 2-30 (IGKV2-30); Immunoglobulin kappa variable 2-40 (IGKV2-40); Immunoglobulin kappa variable 2D-24 (non-functional) (IGKV2D-24); Immunoglobulin kappa variable 2D-26 (IGKV2D-26); Immunoglobulin kappa variable 2D-28 (IGKV2D-28); Immunoglobulin kappa 79110026078 1variable 2D-29 (IGKV2D-29); Immunoglobulin kappa variable 2D-30 (IGKV2D-30); Immunoglobulin kappa variable 2D-40 (IGKV2D-40); Immunoglobulin kappa variable 3-11 (IGKV3-11); Immunoglobulin kappa variable 3-15 (IGKV3-15); Immunoglobulin kappa variable 3-20 (IGKV3-20); Immunoglobulin kappa variable 3-7 (non-functional) (IGKV3-7); Immunoglobulin kappa variable 3D-11 (IGKV3D-11); Immunoglobulin kappa variable 3D-15 (IGKV3D-15); Immunoglobulin kappa variable 3D-20 (IGKV3D-20); Immunoglobulin kappa variable 3D-7 (IGKV3D-7); Immunoglobulin kappa variable 4-1 (IGKV4-1); Immunoglobulin kappa variable 5-2 (IGKV5-2); Immunoglobulin kappa variable 6-21 (non-functional) (IGKV6-21); Immunoglobulin kappa variable 6D-21 (non-functional) (IGKV6D-21): Immunoglobulin kappa variable 6D-41 (non-functional) (IGKV6D-41); Immunoglobulin lambda constant 1 (IGLC1); Immunoglobulin lambda constant 2 (IGLC2); Immunoglobulin lambda constant 3 (Kem-Oz+ marker) (IGLC3); Immunoglobulin lambda constant 7 (IGLC7); Immunoglobulin lambda joining 1 (IGLJ1); Immunoglobulin lambda variable 1-36 (IGLV1-36); Immunoglobulin lambda variable 1-40 (IGLV1-40); Immunoglobulin lambda variable 1-44 (IGLV1-44); Immunoglobulin lambda variable 1-47 (IGLV1-47); Immunoglobulin lambda variable 1-50 (nonfunctional) (IGLV1-50); Immunoglobulin lambda variable 1-51 (IGLV1-51); Immunoglobulin lambda variable 10-54 (IGLV 10-54); Immunoglobulin lambda variable 11-55 (non-functional) (IGLV11-55); Immunoglobulin lambda variable 2-11 (IGLV2-11); Immunoglobulin lambda variable 2-14 (IGLV2-14); Immunoglobulin lambda variable 2-18 (IGLV2-18); Immunoglobulin lambda variable 2-23 (IGLV2-23); Immunoglobulin lambda variable 2-33 (non-functional) (IGLV2-33); Immunoglobulin lambda variable 2-8 (IGLV2-8); Immunoglobulin lambda variable 3-1 (IGLV3-1); Immunoglobulin lambda variable 3-10 (IGLV3-10); Immunoglobulin lambda variable 3-12 (IGLV3-12); Immunoglobulin lambda variable 3-16 (IGLV3-16); Immunoglobulin lambda variable 3-19 (IGLV3-19); Immunoglobulin lambda variable 3-21 (IGLV3-21); Immunoglobulin lambda variable 3-22 (IGLV3-22); Immunoglobulin lambda variable 3-25 (IGLV3-25); Immunoglobulin lambda variable 3-27 (IGLV3-27); Immunoglobulin lambda variable 3-32 (non-functional) (IGLV3-32); Immunoglobulin lambda variable 3-9 (IGLV3-9); Immunoglobulin lambda variable 4-3 (IGLV4-3); Immunoglobulin lambda variable 4-60 (IGLV4-60); Immunoglobulin lambda variable 4-69 (IGLV4-69); Immunoglobulin lambda variable 5-37 (IGLV5-37); Immunoglobulin lambda variable 5-45 (IGLV5-45); Immunoglobulin lambda variable 5-48 (non-functional) (IGLV5-48); Immunoglobulin lambda variable 5-52 (IGLV5-52); Immunoglobulin lambda variable 6-57 (IGLV6-57); Immunoglobulin lambda variable 7-43 (IGLV7-43); Immunoglobulin lambda variable 7-46 (IGLV7-46); Immunoglobulin lambda variable 8-61 (IGLV8-61); or Immunoglobulin lambda variable 9-49 (IGLV9-49).80110026078 1

[0282] In an aspect, a disclosed targeted pre-mRNA can encode a secretable liver specific peptide or a secretable liver specific protein. In an aspect, a secretable liver specific peptide or a secretable liver specific protein can comprise albumin, fibrinogen, transferrin, or a portion thereof. In an aspect, a disclosed targeted endogenous pre-mRNA can comprise albumin and can be expressed by one or more cells in the liver. In an aspect, a disclosed targeted endogenous pre-mRNA can comprise albumin and can be expressed by hepatocytes.

[0283] In an aspect, a disclosed targeted endogenous pre-mRNA can comprise transferrin and can be expressed by one or more cells in the liver. In an aspect, a disclosed targeted endogenous pre-mRNA can comprise transferrin and can be expressed by hepatocytes.

[0284] In an aspect, a targeted portion of intron 1 of human albumin can comprise the sequence of SEQ ID NO:01. In an aspect, one or more guide RNAs can target intron 1 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 1 of human albumin. In an aspect, a targeted portion of intron 1 of human albumin can comprise SEQ ID NO:01. In an aspect, one or more guide RNAs can bind to one or more portions of intron 1 of human albumin.

[0285] In an aspect, a targeted portion of intron 2 of human albumin can comprise the sequence of SEQ ID NO: 02. In an aspect, one or more guide RNAs can target intron 2 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 2 of human albumin. In an aspect, a targeted portion of intron 2 of human albumin can comprise SEQ ID NO: 02. In an aspect, one or more guide RNAs can bind to one or more portions of intron 2 of human albumin.

[0286] In an aspect, a targeted portion of intron 3 of human albumin can comprise the sequence of SEQ ID NO:03. In an aspect, one or more guide RNAs can target intron 3 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 3 of human albumin. In an aspect, a targeted portion of intron 3 of human albumin can comprise SEQ ID NO: 03. In an aspect, one or more guide RNAs can bind to one or more portions of intron 3 of human albumin.

[0287] In an aspect, a targeted portion of intron 4 of human albumin can comprise the sequence of SEQ ID NO: 04. In an aspect, one or more guide RNAs can target intron 4 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 4 of human albumin. In an aspect, a targeted portion of intron 4 of human albumin can comprise SEQ ID NO:04. In an aspect, one or more guide RNAs can bind to one or more portions of intron 4 of human albumin.

[0288] In an aspect, a targeted portion of intron 5 of human albumin can comprise the sequence of SEQ ID NO:05. In an aspect, one or more guide RNAs can target intron 5 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 5 of human albumin. In an aspect, a targeted portion of intron 5 of human albumin can comprise SEQ ID NO:05. In an aspect, one or more guide RNAs can bind to one or more portions of intron 5 of human albumin.81110026078 1

[0289] In an aspect, a targeted portion of intron 6 of human albumin can comprise the sequence of SEQ ID NO: 06. In an aspect, one or more guide RNAs can target intron 6 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 6 of human albumin. In an aspect, a targeted portion of intron 6 of human albumin can comprise SEQ ID NO:06. In an aspect, one or more guide RNAs can bind to one or more portions of intron 6 of human albumin.

[0290] In an aspect, a targeted portion of intron 7 of human albumin can comprise the sequence of SEQ ID NO: 07. In an aspect, one or more guide RNAs can target intron 7 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 7 of human albumin. In an aspect, a targeted portion of intron 7 of human albumin can comprise SEQ ID NO:07. In an aspect, one or more guide RNAs can bind to one or more portions of intron 7 of human albumin.

[0291] In an aspect, a targeted portion of intron 8 of human albumin can comprise the sequence of SEQ ID NO: 08. In an aspect, one or more guide RNAs can target intron 8 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 8 of human albumin. In an aspect, a targeted portion of intron 8 of human albumin can comprise SEQ ID NO:08. In an aspect, one or more guide RNAs can bind to one or more portions of intron 8 of human albumin.

[0292] In an aspect, a targeted portion of intron 9 of human albumin can comprise the sequence of SEQ ID NO: 09. In an aspect, one or more guide RNAs can target intron 9 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 9 of human albumin. In an aspect, a targeted portion of intron 9 of human albumin can comprise SEQ ID NO:09. In an aspect, one or more guide RNAs can bind to one or more portions of the following sequence in intron 9 of human albumin. In an aspect, a targeted portion of intron 10 of human albumin can comprise the sequence of SEQ ID NO: 10. In an aspect, one or more guide RNAs can target intron 10 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 10 of human albumin. In an aspect, a targeted portion of intron 10 of human albumin can comprise SEQ ID NO: 10. In an aspect, one or more guide RNAs can bind to one or more portions of intron 10 of human albumin. In an aspect, a targeted portion of intron 11 of human albumin can comprise the sequence of SEQ ID NO: 11. In an aspect, one or more guide RNAs can target intron 11 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 11 of human albumin. In an aspect, a targeted portion of intron 11 of human albumin can comprise SEQ ID NO: 11. In an aspect, one or more guide RNAs can bind to one or more portions of intron 11 of human albumin. In an aspect, a targeted portion of intron 12 of human albumin can comprise the sequence of SEQ ID NO: 12. In an aspect, one or more guide RNAs can target intron 12 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 12 of human albumin. In an aspect, a targeted portion of intron 12 of human albumin can comprise SEQ ID NO: 12. In an aspect, one or more guide RNAs can bind to one or more portions of intron 12 of 82110026078 1human albumin. In an aspect, a targeted portion of intron 13 of human albumin can comprise the sequence of SEQ ID NO: 13. In an aspect, one or more guide RNAs can target intron 13 of human albumin. In an aspect, one or more guide RNAs can target a portion of intron 13 of human albumin. In an aspect, a targeted portion of intron 13 of human albumin can comprise SEQ ID NO: 13. In an aspect, one or more guide RNAs can bind to one or more portions of intron 13 of human albumin.

[0293] In an aspect, a disclosed targeted pre-mRNA can encode a secretable peptide or a secretable protein specific to the male reproductive system. In an aspect, a peptide or protein specific to the male reproductive system can comprise Acrosin (ACR); Acrosin binding protein (ACRBP); Acrosomal vesicle protein 1 (ACRV1); BPI fold containing family A member 3 (BPIFA3); Binder of sperm protein homolog 1 (BSPH1); Chromosome 18 open reading frame 54 (C18orf54); Cation channel sperm associated auxiliary subunit gamma (CATSPERG); Carboxylesterase 5A (CES5A); Colipase like 1 (CLPSL1); Colipase like 2 (CLPSL2); Carboxypeptidase A5 (CPA5); Cysteine rich secretory protein 1 (CRISP 1); Cysteine rich secretory protein 2 (CRISP2); Cystatin 11 (CST11); Cystatin 8 (CST8); Cystatin 9 like (CST9L); Cystatin like 1 (CSTL1); Defensin beta 104A (DEFBI 04 A); Defensin beta 104B (DEFBI 04B); Defensin beta 105A (DEFB105A); Defensin beta 105B (DEFB105B); Defensin beta 106A (DEFBI 06 A); Defensin beta 106B (DEFBI 06B); Defensin beta 107A (DEFBI 07A); Defensin beta 107B (DEFBI 07B); Defensin beta 108B (DEFBI 08B); Defensin beta 109B (DEFBI 09B); Defensin beta 110 (DEFBI 10); Defensin beta 113 (DEFBI 13); Defensin beta 114 (DEFBI 14); Defensin beta 115 (DEFBI 15); Defensin beta 116 (DEFBI 16); Defensin beta 118 (DEFBI 18); Defensin beta 119 (DEFBI 19); Defensin beta 121 (DEFB121); Defensin beta 125 (DEFBI 25); Defensin beta 126 (DEFBI 26); Defensin beta 127 (DEFBI 27); Defensin beta 128 (DEFB128); Defensin beta 129 (DEFB129); Defensin beta 130 A (DEFB130A); Defensin beta BOB (DEFB130B); Defensin beta 131B (DEFB131B); Defensin beta 132 (DEFB132); Defensin beta 134 (DEFB134); Defensin beta 135 (DEFB135); Defensin beta 136 (DEFBI 36); Desert hedgehog signaling molecule (DHH); Dickkopf like acrosomal protein 1 (DKKL1); Epididymal protein 13 (EDDM13); Epididymal protein 3 A (EDDM3A); Epididymal protein 3B (EDDM3B); Epididymal sperm binding protein 1 (ELSPBP1); Epididymal peptidase inhibitor (EPPIN); EPPIN-WFDC6 readthrough (EPPIN-WFDC6); Equatorin (EQTN); Family with sequence similarity 24 member A (FAM24A); Fibronectin type III domain containing 7 (FNDC7); GLIPR1 like 1 (GLIPR1L1); Glutathione peroxidase 5 (GPX5); Glutathione peroxidase 6 (GPX6); IZUMO family member 4 (IZUM04); Kallikrein related peptidase 2 (KLK2); Kallikrein related peptidase 3 (KLK3); Kallikrein related peptidase 4 (KLK4); Lipocalin 10 (LCN10); Lipocalin 12 (LCN12); Lipocalin 6 (LCN6); Lipocalin 8 (LCN8); Lipocalin 9 (LCN9); Lipase I 83110026078 1(LIPI); LLLL and CFNLAS motif containing 1 (LLCFC1); Leucine rich colipase like 1 (LRCOL1); Lymphocyte antigen 6 family member K (LY6K); Lysozyme like 1 (LYZL1); Lysozyme like 2 (LYZL2); Lysozyme like 4 (LYZL4); Lysozyme like 6 (LYZL6); Microseminoprotein beta (MSMB); Neuropeptide FF-amide peptide precursor (NPFF); Nuclear pore complex interacting protein family member B7 (NPIPB7); Oocyte secreted protein 2 (OOSP2) Ovochymase 2 (0VCH2); Prostate and testis expressed 1 (PATE1); Prostate and testis expressed 2 (PATE2); Prostate and testis expressed 3 (PATE3); Prostate and testis expressed 4 (PATE4); Serine protease 37 (PRSS37); Serine protease 38 (PRSS38); Serine protease 54 (PRSS54); Serine protease 58 (PRSS58); Ribonuclease A family member 11 (inactive) (RNASE11); Ribonuclease A family member 12 (inactive) (RNASE12); Ribonuclease A family member 13 (inactive) (RNASE13); Ribonuclease A family member 9 (inactive) (RNASE9); Semenogelin 1 (SEMG1); Semenogelin 2 (SEMG2); Signal regulatory protein delta (SIRPD); Sperm acrosome associated 3 (SPACA3); Sperm acrosome associated 5 (SPACA5); Sperm acrosome associated 5B (SPACA5B); Sperm acrosome associated 7 (SPACA7); Sperm associated antigen 11A (SPAG11A); Sperm associated antigen 11B (SPAG11B); Spermatogenesis associated 20 (SPATA20); Sperm equatorial segment protein 1 (SPESP1); Serine peptidase inhibitor Kazal type 13 (SPINK13); Serine peptidase inhibitor, Kunitz type 3 (SPINT3); Serine peptidase inhibitor, Kunitz type 4 (SPINT4); Testis expressed 101 (TEX101); Transmembrane protein with EGF like and two follistatin like domains 2 (TMEFF2); TUB like protein 2 (TULP2); Von Willebrand factor A domain containing 5B1 (VWA5B1); WAP four-disulfide core domain 10A (WFDC10A); WAP four-disulfide core domain 10B (WFDC10B); WAP four-disulfide core domain 11 (WFDC11); WAP four-disulfide core domain 13 (WFDC13); WAP four-disulfide core domain 3 (WFDC3); WAP four-disulfide core domain 6 (WFDC6); WAP four-disulfide core domain 8 (WFDC8); WAP four-disulfide core domain 9 (WFDC9); Zona pellucida binding protein (ZPBP); or Zona pellucida binding protein 2 (ZPBP2).

[0294] In an aspect, a disclosed targeted pre-mRNA can encode a secretable peptide or a secretable protein from other tissues. In an aspect, a secretable peptide or a secretable protein from other tissues can comprise Arylacetamide deacetylase like 2 (AADACL2); ADAM like decysin 1 (ADAMDEC1); AD AMTS like 1 (ADAMTSL1); Amine oxidase copper containing 1 (AOC1); Ar lsulfatase F (ARSF); Arylsulfatase family member I (ARSI); Arylsulfatase family member J (ARSJ); Arylsulfatase family member K (ARSK); ADP-ribosyltransferase 5 (ART5); Cell migration inducing hyaluronidase 1 (CEMIP); Carboxypeptidase A4 (CPA4); Carboxy peptidase X, M14 family member 1 (CPXM1); Dermci din (DCD); Dehydrogenase / reductase 7C (DHRS7C); Deoxyribonuclease 1 like 2 (DNASE1L2); Endonuclease, poly(U) specific (ENDOU); FAM20C golgi associated secretory pathway kinase 84110026078 1(FAM20C); Galactosidase beta 1 like 2 (GLB1L2); HtrA serine peptidase 3 (HTRA3); Kallikrein related peptidase 10 (KLK10); Kallikrein related peptidase 11 (KLK11); Kallikrein related peptidase 12 (KLK12); Kallikrein related peptidase 13 (KLK13); Kallikrein related peptidase 14 (KLK14); Kallikrein related peptidase 5 (KLK5); Kallikrein related peptidase 6 (KLK6); Kallikrein related peptidase 7 (KLK7); Kallikrein related peptidase 8 (KLK8); Kallikrein related peptidase 9 (KLK9); Lipase family member K (LIPK); Lipase family member M (LIPM); Lipase family member N (LIPN); Lysozyme gl (LYG1); Lysozyme g2 (LYG2); Napsin A aspartic peptidase (NAPSA); Ovochymase 1 (OVCH1); Peptidylglycine alpha-amidating monooxygenase (PAM); Proprotein convertase subtilisin / kexin tvpe 1 (PCSK1); Proprotein convertase subtilisin / kexin type 2 (PCSK2); Phospholipase Al member A (PLA1 A); Phospholipase A2 group X (PLA2G10); Phospholipase A2 group IID (PLA2G2D); Phospholipase A2 group V (PLA2G5); Serine protease 16 (PRSS16) Serine protease 22 (PRSS22); Serine protease 53 (PRSS53); Ribonuclease A family member 7 (RNASE7); Sulfatase 1 (SULF1); Sulfatase 2 (SULF2); Transmembrane serine protease HE (TMPRSS11E); Transmembrane serine protease 13 (TMPRSS13); Transmembrane serine protease 2 (TMPRSS2); or Transmembrane serine protease 4 (TMPRSS4).

[0295] In an aspect, a disclosed targeted pre-mRNA can encode a secretable pancreas specific peptide or a secretable pancreas specific protein. In an aspect, a secretable pancreas specific peptide or a secretable pancreas specific protein can comprise Serine Protease 1, chymotrypsin Like Elastase 3A, Amylase Alpha 2A, or a portion thereof.

[0296] In an aspect, a disclosed targeted pre-mRNA can encode a secretable salivary gland specific peptide or a secretable salivary gland protein. In an aspect, a secretable salivary gland specific peptide or a secretable salivary gland protein can comprise Proline Rich 4, Statherin, Zymogen Granule Protein 16B, or a portion thereof.

[0297] In an aspect, a disclosed targeted pre-mRNA can encode a secretable stomach specific peptide or a secretable stomach protein. In an aspect, a secretable stomach specific peptide or a secretable stomach specific protein can comprise Pepsinogen A3, Pepsiogen, A4.or a portion thereof.

[0298] In an aspect, a disclosed targeted pre-mRNA can encode a cytokine. In an aspect, a disclosed cytokine can comprise 4-1BBL, adiponectin (AdipoQ), APRIL, BAFF, C3a, C5a, CD27L, CD30L. CD40L, CT-1, decorin. EGF, FasL, FGF, FLT3L. G-CSF, GDNF, GITRL, GM-CSF, HGF, IFNal, IFN|3, IFNy, IFNs, IFNK, IFN / .2. IGF-1, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F, IL-18, IL-19, IL-IRa, IL-la, IL-ip, IL-2, IL-20, IL-21, IL-22, IL-23, IL-24, IL-27, IL-3, IL-30, IL-31, IL-33, IL-34, IL-36Ra, IL-36a, IL-4, IL-5, IL-6, IL-7, IL-9, IL-Y, leptin, LIF, LIGHT, LTal / |32, LTa2 / pi, M-CSF, noggin. NP,85110026078 1OSM, OX40L, persephin (PSPN), prolactin (PRL), RANKL, resistin (ADSF), SCF, TGF01, thrombopoietin (TPO), TL1A, TNF, TRAIL, TSLP, TWEAK, or VEGF.

[0299] In an aspect, a disclosed targeted endogenous pre-mRNA can encode a molecule that is highly expressed in a targeted cell. In an aspect, a disclosed targeted endogenous pre-mRNA can encode a molecule that is highly expressed in a targeted cell but is not part of the secretome.

[0300] In an aspect, a disclosed targeted endogenous pre-mRNA can be highly expressed in a targeted cell. In an aspect, expression of a disclosed targeted endogenous pre-mRNA in a targeted cell can comprise a transcript per million (nTPM) value that is at least 1,000, at least 5,000, at least 10,000. at least 20.000, at least 30,000, at least 40,000, at least 50,000, at least 60,000. at least 70,000, at least 80,000, at least 90,000, at least 100,000, or at least 100,000.

[0301] In an aspect, expression of a disclosed targeted endogenous pre-mRNA in a targeted cell can comprise a transcript per million (nTPM) value that is greater than 1,000, greater than 5,000, greater than 10,000, greater than 20,000, greater than 30,000, greater than 40,000, greater than 50,000, greater than 60,000, greater than 70,000, greater than 80,000, greater than 90,000, at least 100,000, or greater than 100,000.

[0302] In an aspect, expression of a disclosed targeted endogenous pre-mRNA in a targeted cell can comprise a transcript per million (nTPM) value that is between about 1,000 to about 5.000, about 5,000 to about 10.000, about 10,000 to about 20.000, about 20,000 to about 30.000. about 30,000 to about 40,000, about 40,000 to about 50,000, about 50,000 to about 60,000, about 60,000 to about 70,000, about 70,000 to about 80,000, about 80,000 to about 90,000, about 90,000 to about 100,000, or more than about 100,000.

[0303] In an aspect, a disclosed targeted endogenous pre-mRNA can be expressed by one or more immune cells. In an aspect, a disclosed targeted endogenous pre-mRNA can be expressed and secreted by one or more immune cells. In an aspect, a disclosed targeted endogenous pre-mRNA can be expressed and not secreted by one or more immune cells. In an aspect, a disclosed targeted endogenous pre-mRNA can be expressed on the cell surface of one or more immune cells. In an aspect, a disclosed targeted endogenous pre-mRNA can encode a molecule that is highly expressed in one or more immune cells or in a population of immune cells. In an aspect, a disclosed targeted endogenous pre-mRNA can be expressed on the cell surface of an immune cell or in a population of immune cells. In an aspect, a disclosed targeted endogenous pre-mRNA can encode a molecule that is highly expressed in an immune cell or in a population of immune cells.

[0304] In an aspect, a disclosed immune cell can comprise a naive T cell, a central memory T cell, an effector memory T cell, a natural killer (NK) cell, a T helper 17 cell, a B cell, a granulocyte, a regulator}7T cell, a dendritic cell, a macrophage, a T helper 1 cell, a T follicular helper cell, a86110026078 1monocyte, an invariant natural killer T (iNKT) cell, a T helper 2 cell, a cytotoxic T cell, or any combination thereof.

[0305] In an aspect, a disclosed targeted endogenous pre-mRNA can be highly expressed in one or more immune cells. In an aspect, expression of a disclosed targeted endogenous pre-mRNA in an immune cell can comprise a transcript per million (nTPM) value that is at least 1.000, at least 5,000, at least 10,000, at least 20,000, at least 30,000, at least 40,000, at least 50,000, at least 60,000, at least 70,000, at least 80,000, at least 90,000, at least 100,000, or at least 100,000. In an aspect, expression of a disclosed targeted endogenous pre-mRNA in an immune cell can comprise a transcript per million (nTPM) value that is greater than 1,000, greater than 5,000, greater than 10,000, greater than 20,000, greater than 30,000, greater than 40,000, greater than 50,000, greater than 60,000, greater than 70,000, greater than 80,000, greater than 90,000, at least 100,000, or greater than 100,000. In an aspect, expression of a disclosed targeted endogenous pre-mRNA in an immune cell can comprise a transcript per million (nTPM) value that is between about 1,000 to about 5,000, about 5,000 to about 10,000, about 10,000 to about 20,000, about 20,000 to about 30,000, about 30,000 to about 40,000, about 40,000 to about 50,000, about 50,000 to about 60,000, about 60,000 to about 70,000, about 70,000 to about 80,000, about 80,000 to about 90,000, about 90,000 to about 100,000, or more than about 100,000.

[0306] In an aspect, a disclosed population of immune cells can comprise naive T cells, central memory T cells, effector memory T cells, natural killer (NK) cells, T helper 17 cells, B cells, granulocytes, regulatory T cells, dendritic cells, macrophages, T helper 1 cells, T follicular helper cells, monocytes, invariant natural killer T (iNKT) cells, T helper 2 cells, cytotoxic T cells, or any combination thereof.

[0307] In an aspect, a disclosed targeted endogenous pre-mRNA can comprise beta-2-microglobulin and can be expressed by one or more immune cells. In an aspect, a disclosed targeted endogenous pre-mRNA can comprise beta-2 -microglobulin and can be expressed by T cells. In an aspect, a disclosed targeted endogenous pre-mRNA can comprise beta-2-microglobulin and can be expressed by B cells. In an aspect, a disclosed targeted endogenous pre-mRNA can comprise beta-2-microglobulin and can be expressed by NK cells.

[0308] In an aspect, a disclosed targeted endogenous pre-mRNA can be selected based on a number of factors. In an aspect, a disclosed targeted endogenous pre-mRNA can be selected based on a number of factors including, for example, the ability of the encoded molecule to impart upon the cargo one or more characteristics. In an aspect, a disclosed targeted endogenous pre-mRNA can be selected for an ability of the encoded molecule to impart upon the cargo one or more characteristics. In an aspect, a disclosed characteristic imparted upon the cargo can relate to retention and / or redirection of the cargo. In an aspect, retention can relate to the increased half- 87110026078 1life and / or prolonged circulation of the disclosed cargo. In an aspect, redirection can relate to the ability of the targeted endogenous pre-mRNA to deliver and / or funnel the disclosed cargo to a receptor population and / or a cell population.Cargos

[0309] In an aspect, a disclosed cargo can comprise any sequence (encoding any biologically active or biologically relevant molecule) that can be packaged into an AAV capsid. In an aspect, a disclosed cargo can comprise a sequence for a peptide or a protein. In an aspect, a sequence encoding a cargo peptide or protein can comprise a portion of the full-length cargo peptide or full-length cargo protein. In an aspect, for example, a portion of the full-length cargo peptide or full-length cargo protein can comprise one or more exons. In an aspect, a disclosed cargo can be referred to by the resulting translation product (e.g., a protein, a peptide, an enzyme, a hormone, a biosimilar, a monoclonal antibody, a scFv, etc.) or can be referred to by the nucleic acid sequence encoding the disclosed translation product. In an aspect, a sequence encoding a cargo can comprise the open reading frame for an enzyme (or fragment thereof) for enzyme replacement therapy. In an aspect, a disclosed cargo can encode a hormone. In an aspect of a disclosed internal construct, a disclosed cargo can encode an enzyme (or fragment thereof) or a biosimilar (or fragment thereof) for enzyme replacement therapy. In an aspect, a disclosed cargo can encode a monoclonal antibody. In an aspect, a disclosed cargo can encode an antibody fragment such as F(ab’)2, Fab, Fab’, or Fv. In an aspect, a disclosed cargo can encode a scFv. In an aspect, a disclosed cargo can encode a gene or a part of a gene associated with and / or responsible for a genetic disease or genetic disorder.

[0310] In an aspect of a disclosed nucleic acid molecule, a sequence encoding a cargo can comprise the open reading frame for the cargo. In an aspect, a sequence encoding a cargo can comprise the open reading frame for any cargo so long as it can be packaged into an AAV capsid. In an aspect, a sequence encoding a cargo can comprise a portion of the full-length cargo. In an aspect, for example, a portion of the full-length cargo can comprise one or more exons. In an aspect, a disclosed cargo can be referred to by the resulting translation product (e.g.. a protein, a peptide, an enzyme, a hormone, a biosimilar, a monoclonal antibody, a scFv, etc.) or can be referred to by the nucleic acid sequence encoding the disclosed translation product.

[0311] In an aspect, a disclosed cargo can comprise the open reading frame of a gene associated with and / or responsible for a genetic disease or genetic disorder.

[0312] In an aspect, a sequence encoding a cargo can comprise the open reading frame of one of the following genes: Al-AT, ABCA1, ABCA12, ABCA13, ABCA2, ABCA3, ABCA4, ABCA5, ABCD1, ABCC1, ABCC2, ABCC6, ABCC8, ABCC9, AC AN, ACTA1, ACTC1, ACTN2, ADCY10, ADA. ADGRV1, AGA, AGAL, AGL, AGRN. AHDC1, AKAP10, AKAP9, ALK,88110026078 1ALMS1, ALPK3, ALS2, AMPD1, ANAPC1, ANK1, ANK2, ANK3, ANKRD11, ANKRD26, AN05, APC, APC2, APOB, APOE, AR, ARFGEF2, ARHGAP31, ARHGEF10, ARHGEF18, ARID1A, ARID1B, ARID2, ASAHI, ASH1L, ASPM, ASXL1, ASXL2, ASXL3, ATM, ATP2A1, ATP7A, ATP7B. ATPGAP2, ATR, ATRX, ATXN1, ATXN2, ATXN3, ATXN7, B3GALNT2. B4GAT1. BAZ1A. BAZ2B. BCOR, BCORL1, BDP1, BLM, BPTF, BRCA1, BRCA2, BRD4, BRWD3, BRAF, C2CD3, C3, C5, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1S, CALM1, CALM2, CALR3, CAMTAI, CAPN3, CARMIL2, CBS, CC2D2A, CCDC88A, CCDC88C, CCNB3, CDH23, CDK13, CDK5RAP2, CECR1. CELSR1, CEMIP2, CENPE, CENPF. CENPJ, CEP152, CEP164, CEP250, CEP290, CFAP43, CFAP44, CFAP65, CFTR, CFTR / ABCC7, CHD1, CHD2, CHD3, CHD4, CHD7, CHD8, CHAT, CHKB, CHRNA1, CHRNA10, CHRNA2, CHRNA3, CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNA8, CHRNA9, CHRNB1, CHRNB2, CHRNB3, CHRNB4, CHRNE, CHRNE1, CHRNG1, CIC, CIT, CLIP1, CLN3, CLN5, CLN6, CLN8, CLCN1, CLRN1, CLTC, COL11A1, COL11A2, COL12A1, COL17A1, COL18A1, COL1A1, COL1A2, COL27A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL6A1, COL6A2, COL6A3, COL7A1, COLQ, CPAMD8, CPLANE1, CPS1, CPSF1, CRB1. CREBBP, CSRP3, CTNNA3, CTNS. CTSA, CTSK. CUBN, CUL7, CUX1, C90RF72, CYPIB1, DCC, DCHS1, DEPDC5. DES, DFNA1, DICER1, DIP2B, DLC1, DMD, DMXL2, DNA-PKcs, DNAH1, DNAH11, DNAH17, DNAH2, DNAH5, DNAH7, DNAH8, DNAH9, DNMBP, DNMT1, DOCK2, DOCK3, DOCK6, DOCK7, DOCK8, DMPK, DNM2, D0K7, DSC2, DSCAM, DSG2, DSP, DST, DTNA, DUOX2, DUX4, DYNC1H1, DYNC2H1, DYSF, DYSF / TTN, EMD, EP300, EPG5. EPO, ERCC6. ERCC6L2, EXPH5, EYA4, EYS, F5, F8, FANCA, FANCD2, FANCM, FATE FAT4, FBN1, FBN2, FGF14, FGF2, FGF4, FHL1, FKRP, FKTN, FLG, FLG2, FLNA, FLNB, FLNC, FLT4, FMN2, FN1, FOXG1, FRAS1, FREM1, FREM2, FSIP2, FUCA1, FUS, FXN, FYCO1, GALC, GALNS, GBA, GBE1, GJB2, GJB6, GLB1, GLA, GLI2, GLI3, GNAI2, GNPTA, GNPTB, GNPTG, GNS, GM2A, GPR179, GREB1L, GRIN2A. GRIN2B, GRIN2D, GUSB, GYSI, GYS2, HBA1, HBA2, HBB, HCFC1, HCN4, HECW2, HERC1, HERC2, HEXA, HEXB, HFM1, HGSNAT, HGD, HIVEP1, HIVEP2, HMCN1, HSPG2, HTT, HTRA1, HYAL1, HYDIN, IDUA, IDS, IGF-1, IGF1R, IGF2R, IGTA7, IGTA9, IGSF1, IL2RG, INSR, INTS1, IQSEC2, ISPD, ITGB4, ITPR1, ITPR2. JPH2, JMJD1C, JUP, K14, KALRN, KANK1, KAT6A. KAT6B. KCNC3, KCND1, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, KCNQ2, KCNQ3, KDR, KIAA0586, KIAA1109, KIAA1549, KIDINS220, KIF14, KIF1A, KIF1B, KIF21A, KIF26B, KIF7, KMT2A, KMT2B, KMT2C, KMT2D, KMT2E, KNL1, LAMA1, LAMA2, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMC3, LAMP2, LARGE1, LDB3, LCT, LDHA. LDLR, LHDB, LIPA,89110026078 1LMNA, LMNB, LBR, L0XHD1, LPA, LRBA, LRP1, LRP2, LRP4, LRP5, LRP6, LRPPRC, LRRK1, LRRK2, LTBP2, LTBP4, LYST, MACF1, MADD, MAGI2, MAP IB, MAP2K1, MAP3K1, MAPK8IP3, MAPKBP1, MAPT, MAST1, MATR3, MBD5, MCM3AP, MCOLN1, MDX, MECP2, MED12, MED12L, MED13, MED13L, MED23. MEGF8, MET, MFSD8. ML2, ML3, MLH3, MPDZ. MSH6. MSTN, MTM, MT-NDE MT-ND5, MT-TE, MT-TH, MT-TK, MT-TL1, MT-TS1, MT-TV, MTHFR, MTOR, MTR, MTRR, MTTP, MYBPC3, MYH10, MYH11, MYH14, MYH2, MYH3, MYH6, MYH7, MYH7B, MYH8, MYH9, MYLK, MYLK2, MYO 15 A, MYO18B, MYO3A, MYO5A, MYO5B, MYO7A, MYO9A, MYOC, MYOZ2, MYPN, NAGA. NAGLU, NALCN. NBAS, NBEA, NBEAL2, NCAPD2, NCAPD3, NEB, NEXMIF, NEXN, NEU1, NF1, NFASC, NHS, NIN, NIPBL, NKX2-5, NLRP1, NOTCH1, NOTCH2, NOTCH3, NPC1, NPC2, NPHP4, NRXN1, NRXN3, NSD1, NSD2, NUP155, NUP188, NUP205, OBSCN, OBSL1, OPTN, OTOF, OTOG, OTOGL, PABPN1, PARD3, PBRM1, PCDH15, PCLO, PCNT, PCSK9, PGAM2, PGK1, PHIP. PHKA1. PHKA2. PHKB, PHKG2, PHOX2A, PIEZO1, PIEZO2, PIK3C2A, PIKFYVE, PKD1, PKD1L1, PKD2, PKHD1, PLEC, PLEKHG2, PLCE1, PLN, PLOD1, POMGNT1, POMGNT2, POMK, POMT1, POMT2, POU3F3, PPP2R2B, PRG4, PRKAG2, PRKCG, PRKDC, PRNP, PRPF3, PRPF31, PRPF6, PRPF8, PRR12, PRRT2, PRX. PTCHI, PTEN, PTN11, PTPN23, PTPRF, PTPRJ, PTPRQ, PXDN. PYGL, PYGM. QRICH2, RAFI, RAH, RAPSN, RALGAPA1. RANBP2, RB1CC1, RELN, RERE, REV3L, RHO, RHOA, RIC1, RIMS1, RIMS2, RNF213, ROBO1, ROBO2, ROBO3, ROS1, RP1, RP1L1, RP2, RPGR, RUSC2, RYR1, RYR2, SACS, SAMD9, SAMD9L, SBF2, SCAPER, SCN10A, SCN11A, SCN1A, SCN2A, SCN3A, SCN4A, SCN4B, SCN5A, SCN8A, SCN9A, SECISBP2. SELENON, SERCA2A, SETBP1, SETD1A, SETD1B, SETD2, SETD5, SETX, SGCA, SGCB, SGCD, SGCG, SGSH, SHANK2, SHANK3, SHROOM4, SI, SIPA1L3, SLIT2, SLX4, SMARCA2, SMARCA4, SMCHD1, SMN2, SMPD1, SNRNP200, SOD1, SON, SPEF2, SPEG, SPG11, SPTA1, SPTAN1, SPTB, SPTBN2, SPTBN4, SRCAP, STARD7, STIM1, STRC, SUMFI, SVIL, SYNE1, SYNGAP1, SYNJ1, SZT2, TAF1, TANC2, TARDBP, TAZ. TCF20, TCOF1, TCAP, TDRD9, TECPR2. TECTA, TENM3, TENM4, TET3, TEX14, TEX15, TG, TGF03, TGF R1, TGF0R2, THOC2, TMEM94, TNC, TNIK, TNNI3, TNNC1, TNNT2, TNR, TNRC6B, TNXB, TOGARAMI, TONSL, TPM1, TPM3, TRIM32, TRIO, TRIOBP, TRIP11, TRIP12, TRPM1, TRPM6, TRPM7, TRRAP, TSC2, TTC37, TTBK2, TEN. TTPA, TUBGCP6. U2AF1. UBE3A. UNC80. USH1F. USH2A, USHA2A, USP9X, VC AN, VCL, VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGFR1, VEGFR2, VPS 13 A, VPS13B, VPS13C, VPS13D, VWF, WDFY3, WDR19, WDR25, WDR62, WDR81, WFS1, WNK1, WRN, XYLT1, XYLT2, ZFHX2, ZFYVE26, ZMPSTE24, ZNF142, ZNF292, ZNF335, ZNF407, ZNF462, and ZNF469.90110026078 1

[0313] In an aspect a sequence encoding a cargo can comprise the open reading frame for a hormone. In an aspect, a disclosed cargo can comprise a hormone for hormone replacement therapy. In an aspect, a disclosed hormone can comprise Aldosterone, Calcitonin, Cholecystokinin, Chorionic gonadotropin, Corticotropin (also called adrenocorticotropic hormone [ACTH]), Corticotropin-releasing hormone, Cortisol, Dehydroepiandrosterone (DHEA), Epinephrine and norepinephrine. Erythropoietin, Estrogen, Estrogen and progesterone, Ghrelin, Glucagon, Glucagon-like peptide, Gonadotropin-releasing hormone, Growth hormone, Growth hormone-releasing hormone, Insulin, Leptin, Luteinizing hormone and follicle-stimulating hormone, Oxytocin, Parathyroid hormone. Progesterone, Prolactin, Renin, Resistin. Somatostatin, Testosterone, Thyroid hormones (thyroxine and triiodothyronine). Thyroid-stimulating hormone. Thyrotropin-releasing hormone, Vasopressin (antidiuretic hormone), or Vasoactive intestinal polypeptide.

[0314] In an aspect, a sequence encoding a cargo can comprise the open reading frame for an enzyme (or fragment thereof) for enzyme replacement therapy. In an aspect, a disclosed cargo can comprise an enzyme (or fragment thereof) for enzyme replacement therapy. In an aspect, a disclosed cargo can comprise an enzyme (or fragment thereof) for enzyme replacement therapy in connection with one or more lysosomal storage diseases (LSDs).

[0315] In an aspect, a disclosed cargo can comprise a sequence for Acid Alpha-Glucosidase, Acid Beta-Galactosidase, Acid Ceramidase, Acid Sphingomyelinase, Alpha-Galactosidase A, Alpha-Glucosaminide Acetyltransferase, Alpha-L-Iduronidase, Alpha-N-Acetylglucosaminidase, Arylsulfatase A, Beta-Galactosidase, Beta-Glucuronidase, Beta-Hexosaminidase, Galactocerebrosidase, Hyaluronidase. Iduronate Sulfate Sulfatase, Lysosomal Acid Glucosyl ceramidase. Lysosomal Acid Lipase, N-Acetylgalactosamine-4-Sulfatase, N-Acetylgalactosamine-6-sulfatase, N-Acetylglucosaminine-6-Sulfatase, N-Sulphoglucosamine Sulphohydrolase, Sialidase, or a fragment thereof.

[0316] In an aspect, a disclosed cargo can comprise an enzyme (or fragment thereof) or a biosimilar (or fragment thereof) for enzyme replacement therapy. In an aspect, a disclosed enzyme (or fragment thereof) or a disclosed biosimilar (or fragment thereof) for enzyme replacement therapy can comprise Aldurazyme (laronidase), Elaprase (idursulfase), Elfabrio (pegunigalsidase alfa-iwxj), Fabrazyme (agalsidase beta), Kanuma (sebelipase alfa). Lamzede (velmanase alfa-tycv), Lumizyme (al glucosidase alfa), Mepsevii (vestronidase alfa-vjbk), Naglazyme (galsulfase), Nexviazyme (avalglucosidase alfa-ngpt), Nulibry (fosdenopterin), Pombiliti (cipaglucosidase alfa-atga), Revcovi (elapegademase-lvlr), Vimizim (elosulfase alfa), or Xenpozyme (olipudase alfa-rpcp).91110026078 1

[0317] In an aspect a disclosed cargo can comprise a sequence for Acid Alpha-Glucosidase (P10253) or fragment thereof for treating Pompe Disease. In an aspect, a disclosed cargo can comprise a sequence for Alpha-Galactosidase A (P06280) or fragment thereof for treating Fabry Disease. In an aspect, a disclosed cargo can comprise a sequence for Lysosomal Acid Gucosylceramidase (P04062) or fragment thereof for treating Gaucher Disease. In an aspect, a disclosed cargo can comprise a sequence for Acid Sphingomyelinase (P17405) or fragment thereof for treating Niemann-Pick Disease. In an aspect, a disclosed cargo can comprise a sequence for Acid Ceramidase (Q13510) or fragment thereof for treating Farber Disease. In an aspect, a disclosed cargo can comprise a sequence for Galactocerebrosidase (P54803) or fragment thereof for treating Krabbe Disease. In an aspect, a disclosed cargo can comprise a sequence for Lysosomal Acid Lipase (P38571) or fragment thereof for treating Lysosomal Acid Lipase Deficiency. In an aspect, a disclosed cargo can comprise a sequence for Acid Beta-Galactosidase (P16278) or fragment thereof for treating Gangliosidosis (GM1). In an aspect, a disclosed cargo can comprise a sequence for Beta-Hexosaminidase (P07686) or fragment thereof for treating Gangliosidosis (GM2). In an aspect, a disclosed cargo can comprise a sequence for Sialidase-1 (Q99519) or fragment thereof for treating mucolipidosis Type I (ML1). In an aspect, a disclosed cargo can comprise a sequence for Arylsulfatase A (P15289) or fragment thereof for treating Metachromatic Leukodystrophy. In an aspect, a disclosed cargo can comprise a sequence for Alpha-L-Iduronidase (P35475) or fragment thereof for treating Mucopolysaccharidosis type I (MPS I). In an aspect, a disclosed cargo can comprise a sequence for Iduronate Sulfate Sulfatase (P22304) or fragment thereof for treating Mucopolysaccharidosis type II (MPS II). In an aspect, a disclosed cargo can comprise a sequence for N-Sulphoglucosamine sulphohydrolase (P51688) or fragment thereof for treating Mucopolysaccharidosis type III A (MPS III A). In an aspect, a disclosed cargo can comprise a sequence for Alpha-N-Acetylglucosaminidase (P54802) or fragment thereof for treating Mucopolysaccharidosis type IIIB (MPS IIIB). In an aspect, a disclosed cargo can comprise a sequence for Alpha-Alucosaminide Acetyltransferase (Q68CP4) or fragment thereof for treating Mucopolysaccharidosis type IIIC (MPS IIIC). In an aspect, a disclosed cargo can comprise a sequence for N-Acetylglucosaminine-6-Sulfatase (P15586) or fragment thereof for treating Mucopolysaccharidosis type IIID (MPS IIID). In an aspect, a disclosed cargo can comprise a sequence for N-Acetylgalactosamine-6-sulfatase (P34059.1) or fragment thereof for treating Mucopolysaccharidosis type IVA (MPS IVA). In an aspect, a disclosed cargo can comprise a sequence for Beta-Galactosidase (P16278) or fragment thereof for treating Mucopolysaccharidosis type IVB (MPS IVB). In an aspect, a disclosed cargo can comprise a sequence for N-Acetylgalactosamine-4-Sulfatase (P15848) or fragment thereof for treating Mucopolysaccharidosis type VI (MPS VI). In an aspect, a disclosed cargo can comprise 92110026078 1a sequence for Beta-Glucuronidase (P08236) or fragment thereof for treating Mucopolysaccharidosis type VII (MPS VII). In an aspect, a disclosed cargo can comprise a sequence for Hyaluronidase (Q12794.2) or fragment thereof for treating Mucopolysaccharidosis type IX (MPS IX).

[0318] In an aspect, a disclosed cargo can comprise a biosimilar. In an aspect, a disclosed biosimilar can comprise an FDA approved biosimilar. In an aspect, a sequence encoding a cargo can comprise the open reading frame for a biosimilar. In an aspect, a sequence encoding a cargo can comprise the open reading frame for an FDA approved biosimilar.

[0319] In an aspect, a disclosed biosimilar can comprise Bkemv (eculizumab-aeeb), Yesafili (aflibercept-jbvf), Opuviz (aflibercept-yszy), Hercessi (trastuzumab-strf), Selarsdi (ustekinumab-aekn), Tyenne (tocilizumab-aazg), Jubbonti (denosumab-bbdz), Wyost (denosumab-bbdz), Simlandi (adalimumab-ryvk), Avzivi (bevacizumab-tnjn), Wezlana (ustekinumab-auub), Tofidence (tocilizumab-bavi), Tyruko (natalizumab-sztn), Yuflyma (adalimumab-aaty), Idacio (adalimumab-aacf), Vegzelma (bevacizumab-adcd), Stimufend (pegfilgrastim-fpgk), Cimerh (ranibizumab-eqm), Fylnetra (pegfilgrastim-pbbk), Alymsys (bevacizumab-maly), Releuko (filgrastim-ayow), Yusimry (adalimumab-aqvh), Rezvoglar (insulin glargine-aglr), Byooviz (ranibizumab-nuna), Semglee (insulin glargine-yfgn). Riabni (rituximab-arrx), Hulio (adalimumab-fkjp), Nyvepria (pegfilgrastim-apgf), Avsola (infliximab-axxq), Abrilada (adalimumab-afzb), Ziextenzo (pegfilgrastim-bmez), Hadlima (adalimumab-bwwd), Ruxience (rituximab-pvvr), Zirabev (bevacizumab-bvzr), Kanjinti (trastuzumab-anns), Eticovo (etanercept-ykro), Trazimera (trastuzumab-qyyp), Ontruzant (trastuzumab-dttb), Herzuma (trastuzumab-pkrb), Truxima (rituximab-abbs), Udenyca (pegfilgrastim-cbqv), Hyrimoz (adalimumab-adaz), Nivestym (filgrastim-aafi), Fulphila (pegfilgrastim-jmdb), Retacrit (epoetin alfa-epbx), Ixifi (infliximab-qbtx), Ogivri (trastuzumab-dkst), Mvasi (bevacizumab-awwb), Cyltezo (adalimumab-adbm), Renflexis (infliximab-abda), Amjevita (adalimumab-atto), Erelzi (etanercept-szzs), Inflectra (infliximab-dyyb), or Zarxio (filgrastim-sndz).

[0320] In an aspect, a disclosed cargo can comprise a monoclonal antibody. In an aspect, a sequence encoding a cargo can comprise the open reading frame for a monoclonal antibody. In an aspect, a sequence encoding a cargo can comprise the open reading frame for an FDA-approved monoclonal antibody.

[0321] In an aspect, a disclosed monoclonal antibody cargo can comprise 3F8, Abagovomab, Abciximab, Abituzumab, Abrezekimab, Abrilumab, Actoxumab, Adalimumab, Adecatumumab, Aducanumab, Afasevikumab, Afelimomab, Alacizumab pegol, Alemtuzumab, Alirocumab, Altumomab pentetate, Amatuximab, Amivantamab, Anatumomab mafenatox, Andecaliximab, Anetumab ravtansine. Anifrolumab, Ansuvimab. Anrukinzumab. Apolizumab, Aprutumab 93110026078 1ixadotin, Arcitumomab, Ascrinvacumab, Aselizumab, Atezolizumab, Atidortoxumab, Atinumab, Atoltivimab, Atoltivimab / maftivimab / odesivimab, Atorolimumab, Avelumab, Axatilimab, Azintuxizumab vedotin, Bamlanivimab, Bapineuzumab, Basiliximab, Bavituximab, BCD- 100, Bebtelovimab, Bectumomab, Bedinvetmab, Begelomab, Belantamab mafodotin, Belimumab, Bemarituzumab. Benralizumab. Berlimatoxumab. Bermekimab, Bersanlimab. Bertilimumab, Besilesomab, Bevacizumab, Bezlotoxumab, Biciromab, Bimagrumab, Bimekizumab, Birtamimab, Bivatuzumab, Bleselumab, Blinatumomab, Blontuvetmab, Blosozumab, Bococizumab, Brazikumab, Brentuximab vedotin, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab. Burosumab, Cabiralizumab. Camidanlumab tesirine. Camrelizumab, Canakinumab, Cantuzumab mertansine, Cantuzumab ravtansine, Caplacizumab, Casirivimab, Capromab, Carlumab, Carotuximab, Catumaxomab, cBR96-doxorubicin immunoconjugate, Cedelizumab, Cemiplimab, Cergutuzumab amunaleukin, Certolizumab pegol, Cetrelimab, Cetuximab, Cibisatamab, Cilgavimab, Cirmtuzumab, Citatuzumab bogatox, Cixutumumab, Clazakizumab, Clenoliximab, Clesrovimab, Clivatuzumab tetraxetan, Codrituzumab, Cofetuzumab pelidotin, Coltuximab ravtansine, Conatumumab, Concizumab, Cosfroviximab, Cosibelimab, Crenezumab, Crizanlizumab, Crotedumab, Crovalimab, CR6261, Cusatuzumab, Dacetuzumab, Daclizumab, Dalotuzumab, Dapirolizumab pegol, Daratumumab, Dectrekumab, Demcizumab, Denintuzumab mafodotin, Denosumab, Depatuxizumab mafodotin, Depemokimab, Derlotuximab biotin, Detumomab, Dezamizumab, Dinutuximab, Dinutuximab beta, Diridavumab, Divozilimab, Domagrozumab, Donanemab, Dorlimomab aritox, Dostarlimab, Drozitumab, DS-8201, Duligotuzumab, Dupilumab, Durvalumab, Dusigitumab, Duvortuxizumab, Ecromeximab, Eculizumab. Edobacomab, Edrecolomab, Efalizumab, Efungumab, Eldelumab, Elezanumab, Elgemtumab, Elotuzumab, Elsilimomab, Emactuzumab, Emapalumab, Emibetuzumab, Emicizumab, Enapotamab vedotin, Enavatuzumab, Enfortumab vedotin, Enlimomab pegol, Enoblituzumab, Enokizumab, Enoticumab, Ensituximab, Epcoritamab, Epitumomab cituxetan, Epratuzumab, Eptinezumab. Erenumab, Erlizumab, Ertumaxomab. Etaracizumab, Etesevimab, Etigilimab, Etrolizumab. Evinacumab. Evolocumab, Exbivirumab, Fanolesomab, Faralimomab, Faricimab, Farletuzumab, Fasinumab, FBTA05, Felvizumab, Fezakinumab, Fibatuzumab, Ficlatuzumab, Figitumumab, Firivumab, Flanvotumab, Fletikumab, Flotetuzumab, Fontolizumab, Foralumab, Foravirumab, Fremanezumab, Fresolimumab. Frovocimab. Frunevetmab, Fulranumab, Futuximab, Galcanezumab, Galiximab, Gancotamab, Ganitumab, Gantenerumab, Garadacimab, Gatipotuzumab, Gavilimomab, Gedivumab, Gemtuzumab ozogamicin, Gevokizumab, Gilvetmab, Gimsilumab, Girentuximab, Glembatumumab vedotin, Glofitamab, Golimumab, Gomiliximab, Gosuranemab, Guselkumab, lanalumab. Ibalizumab, Sintilimab, Ibritumomab tiuxetan, Icrucumab, Idarucizumab,94110026078 1Ifabotuzumab, Igovomab, Iladatuzumab vedotin, Imalumab, Imaprelimab, Imciromab, Imdevimab, Imgatuzumab, Inclacumab, Indatuximab ravtansine, Indusatumab vedotin, Inebilizumab, Infliximab, Intetumumab, Inolimomab, Inotuzumab ozogamicin, Ipilimumab, lomab-B, Iratumumab. Isatuximab, Iscalimab, Istiratumab, Itolizumab, Ixekizumab, Izenivetmab, KappaMAB. Keliximab. Labetuzumab, Lacnotuzumab, Ladiratuzumab vedotin. Lampalizumab, Lanadelumab, Landogrozumab, Laprituximab emtansine, Larcaviximab, Lebrikizumab, Lecanemab, Lemalesomab, Lendalizumab, Lenvervimab, Lenzilumab, Lerdelimumab, Leronlimab, Lesofavumab, Letolizumab, Lexatumumab, Libivirumab, Lifastuzumab vedotin, Ligelizumab. Loncastuximab tesirine, Losatuxizumab vedotin. Lilotomab satetraxetan, Lintuzumab, Linvoseltamab, Lirilumab, Lodelcizumab, Lokivetmab, Lorvotuzumab mertansine, Lucatumumab, Lulizumab pegol, Lumiliximab, Lumretuzumab, Lupartumab, Lupartumab amadotin, Lutikizumab, Maftivimab, Mapatumumab, Margetuximab, Marstacimab, Maslimomab, Mavrilimumab, Matuzumab, Mepolizumab. Metelimumab, Milatuzumab, Minretumomab, Mirikizumab, Mirvetuximab soravtansine, Mitumomab, Modotuximab, Mogamulizumab, Monalizumab, Morolimumab, Mosunetuzumab, Motavizumab, Moxetumomab pasudotox, Muromonab-CD3, Nacolomab tafenatox, Namilumab, Naptumomab estafenatox, Naratuximab emtansine, Narnatumab. Narsoplimab, Natalizumab, Navicixizumab, Navivumab, Naxitamab, Nebacumab. Necitumumab. Nemolizumab. NEOD001, Nerelimomab. Nesvacumab, Netakimab, Nimotuzumab, Nipocalimab, Nirsevimab, Nivolumab, Nofetumomab merpentan, Obiltoxaximab, Obinutuzumab, Ocaratuzumab, Ocrelizumab, Odesivimab, Odulimomab, Ofatumumab, Olaratumab, Oleclumab, Olendalizumab, Olokizumab, Omalizumab, Omburtamab, OMS721, Onartuzumab, Ontuxizumab, Onvatilimab, Opicinumab, Oportuzumab monatox, Oregovomab, Orticumab, Otelixizumab, Otilimab, Otlertuzumab, Oxelumab, Ozanezumab, Ozoralizumab, Pagibaximab, Palivizumab, Pamrevlumab, Panitumumab, Pankomab, Panobacumab, Parsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab, Patritumab, PDR001, Pembrolizumab. Pemivibart, Pemtumomab, Penpulimab, Perakizumab, Pertuzumab, Pexelizumab, Pidilizumab. Pinatuzumab vedotin. Pintumomab. Placulumab, Pozelimab, Prezalumab, Plozalizumab, Pogalizumab, Polatuzumab vedotin, Ponezumab, Porgaviximab, Prasinezumab, Prezalizumab, Priliximab, Pritoxaximab, Pritumumab, PRO 140, Quilizumab, Racotumomab, Radretumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranevetmab, Ranibizumab, Raxibacumab, Ravagalimab, Ravulizumab. Refanezumab, Regavirumab, Regdanvimab, Relatlimab, Relfovetmab, Remtolumab, Reslizumab, Retifanlimab, Rilotumumab, Rinucumab, Risankizumab, Rituximab, Rivabazumab pegol, Robatumumab, Rmab, Roledumab, Romilkimab, Romosozumab, Rontalizumab, Rosmantuzumab, Rovalpituzumab tesirine, Rovelizumab, Rozanolixizumab, Ruplizumab, SA237, Sacituzumab govitecan, Samalizumab,95110026078 1Samrotamab vedotin, Sarilumab, Satralizumab, Satumomab pendetide, Secukinumab, Selicrelumab, Seribantumab, Setoxaximab, Setrusumab, Sevirumab, Sibrotuzumab, SGN-CD19A, SHP647, Sibeprenlimab, Sifalimumab, Siltuximab, Simtuzumab, Sipavibart, Siplizumab, Sirtratumab vedotin, Sirukumab, Sofituzumab vedotin, Solanezumab, Solitomab, Sonepcizumab, Sontuzumab, Sotrovimab, Spartalizumab. Spesolimab. Stamulumab, Sugemalimab, Sulesomab, Suptavumab, Sutimlimab, Suvizumab, Suvratoxumab, Tabalumab, Tacatuzumab tetraxetan, Tadocizumab, Tafasitamab, Talacotuzumab, Talizumab, Talquetamab, Tamtuvetmab, Tanezumab. Taplitumomab paptox, Tarextumab, Tarlatamab, Tavolimab, Teclistamab, Tefibazumab, Telimomab aritox. Telisotuzumab. Telisotuzumab vedotin, Tenatumomab, Teneliximab, Teplizumab, Tepoditamab, Teprotumumab, Tesidolumab, Tetulomab, Tezepelumab, TGN1412, Tibulizumab, Tildrakizumab, Tigatuzumab, Timigutuzumab, Timolumab, tiragolumab, Tiragotumab, Tislelizumab, Tisotumab vedotin, Tixagevimab, TNX-650, Tocilizumab, Tomuzotuximab. Toralizumab, Tosatoxumab, Tositumomab, Tovetumab, Tralokinumab, Trastuzumab, Trastuzumab duocarmazine, Trastuzumab emtansine, TRBS07, Tregalizumab, Tremelimumab, Trevogrumab, Tucotuzumab celmoleukin, Tuvirumab, Ublituximab, Ulocuplumab, Urelumab, Urtoxazumab, Ustekinumab, Utomilumab. Vadastuximab talirine, Vanalimab, Vandortuzumab vedotin, Vantictumab, Vanucizumab, Vapaliximab. Varisacumab, Varlilumab, Vatelizumab. Vedolizumab, Veltuzumab, Vepalimomab, Vesencumab, Vilobelimab, Visilizumab, Vobarilizumab, Volociximab, Vonlerolizumab, Vopratelimab, Vorsetuzumab mafodotin, Votumumab, Vunakizumab, Xentuzumab, XMAB-5574, Zalutumumab, Zanidatamab, Zanolimumab, Zatuximab, Zenocutuzumab, Ziralimumab, Zolbetuximab, or Zolimomab aritox.

[0322] In an aspect, a sequence encoding a cargo can comprise the open reading frame for an antibody fragment. In an aspect, a sequence encoding a cargo can comprise the open reading frame for an FDA-approved antibody fragment.

[0323] In an aspect, a disclosed cargo can comprise antibody fragment. In an aspect, a disclosed cargo can comprise a Fab fragment, a Fab' fragment, a F(ab)'2 fragment, a F(ab)3 fragment, a Fv, a single-chain variable fragment (scFv), a bis-scFv, a (scFv)2, a minibody, a diabody, a triabody, a tetrabody, a disulfide stabilized Fv protein (dsFv), or a single-domain antibody (sdAb). In an aspect, a disclosed cargo can comprise a Fab fragment (-55 kDa), a Fab' fragment, a F(ab)'2 fragment, a F(ab)3 fragment, a Fv, a scFv (~ 25 kDa), a bis-scFv (~50 kDa), a (scFv)2. a scFv-CH (—80 kDa), a minibody (~75 kDa), a diabody (—55 kDa), a triabody (—75 kDa), a tetrabody (-100 kDa), a disulfide stabilized Fv protein (dsFv), or a single-domain antibody (sdAb).

[0324] As known to the art, F(ab’)2, Fab, Fab’ and Fv are antigen-binding fragments that can be generated from the variable region of IgG and IgM. These antigen-binding fragments vary in size 96110026078 1(MW), valency, and Fc content. Fc fragments are generated entirely from the heavy chain constant region of an immunoglobulin. These and several additional unique fragment structures can be generated from pentameric IgM, including an “IgG’'-type fragment, an inverted “IgG”-type fragment, and a pentameric Fc fragment.

[0325] In an aspect, a F(ab’)2 fragment can comprise two antigen-binding regions joined at the hinge through disulfides. In an aspect, a F(ab’)2 fragment can comprise about 110,000 daltons. This fragment is void of most, but not all, of the Fc region.

[0326] In an aspect, a Fab’ fragment can be formed by the reduction of F(ab’)2 fragments. In an aspect, a disclosed Fab' fragment can comprise about 55,000 daltons. The Fab’ fragment contains a free sulfhydryl group that may be alkylated or utilized in conjugation with an enzyme, toxin or other protein of interest. Fab’ is derived from F(ab’)2; therefore, it may contain a small portion of Fc.

[0327] In an aspect, a Fab fragment is a monovalent fragment that can be produced from IgG and IgM. In an aspect, a Fab fragment can comprise about 50,000 daltons. In an aspect, a Fab fragment can comprise the VH, CHI and VL, CL regions, linked by an intramolecular disulfide bond. In an aspect, a Fv fragment is the smallest fragment produced from IgG and IgM that contains a complete antigen-binding site. In an aspect, a Fv fragment can comprise about 25,000 daltons. In an aspect, a Fv fragment can have the same binding properties and similar three-dimensional binding characteristics as Fab. The VH and VL chains of the Fv fragments are held together by non-covalent interactions. These chains tend to dissociate upon dilution, so methods have been developed to cross-link the chains through glutaraldehyde, intermolecular disulfides or a peptide linker.

[0328] In an aspect, a rlgG can refer to a half-IgG. In an aspect, a rlgG can be the product of selectively reducing just the hinge-region disulfide bonds, and can comprise about 75,000 datlons. Although several disulfide bonds occur in IgG, those in the hinge-region are most accessible and easiest to reduce, especially with mild reducing agents like 2-mercaptoethyl amine (2-MEA). In an aspect, a disclosed Fc fragment can comprise the CH2 and CH3 region and part of the hinge region held together by one or more disulfides and noncovalent interactions. In an aspect, Fc and Fc5p fragments can be produced from fragmentation of IgG and IgM, respectively. The term Fc is derived from the ability of these antibody fragments to crystallize. In an aspect, a Fc fragment can comprise about 50,000 daltons, and can be generated entirely from the heavy chain constant region of an immunoglobulin. In an aspect, a Fc fragment cannot bind antigen, but it is responsible for the effector functions of antibodies, such as complement fixation.

[0329] In an aspect, a disclosed cargo can comprise a scFv. In an aspect, a sequence encoding a cargo can comprise the open reading frame for a scFv. In an aspect, a sequence encoding a cargo 97110026078 1can comprise the open reading frame for an FDA-approved scFv. In an aspect, a sequence encoding a cargo can comprise the open reading frame for a dimeric-scFv. In an aspect, a sequence encoding a cargo can comprise the open reading frame for an FDA-approved dimeric scFv.

[0330] In an aspect, a disclosed scFv can comprise Alpha-fetoprotein (AFP), CAI 25, CD 123, CD176, CD22, Cholecystokinin-2 / gastrin receptor (CCKR2), Cyclin DI, Cyclin E, Epidermal growth factor receptor III (EGFRvIII), Epithelial cell adhesion molecule (EpCAM), fAChR scFv / ETA, Frizzled class receptor 7 (Fzd7), Integrin alphavbeta3 (ITG αvβ3). Insulin-like growth factor binding protein-2 (IGFBP2), Lidamidine apoprotein (LDP). MG7-scFv / SEB, MUC18, p21Ras, p53, Prostate-specific membrane antigen (PSMA), Reg4, scFv / Mesothelin, STEAP-1, or Transferrin receptor 1 (TfRl).

[0331] In an aspect, a disclosed scFv or a disclosed dimeric scFv can target a tumor-cell surface antigen. In an aspect, a disclosed scFv comprises a single polypeptide comprising the variable light chain (VL) and variable heavy chain (VH) of a traditional antibody. In a scFv, the VL and the VH are connected by a flexible linker peptide (generally, for example, about 15 to about 20 amino acids long-mostly comprising glycines and serines).

[0332] In an aspect, a disclosed dimeric scFv comprises a polypeptide comprising 2 copies of the variable light chain (VL) and variable heavy chain (VH) of a traditional antibody. In a dimeric scFv, the VL and the VH are connected by a flexible linker peptide (generally, for example, about 15 to about 20 amino acids long-mostly comprising glycines and serines). In a dimeric scFv, two copies of the polypeptide are connected by a linker peptide.

[0333] In an aspect, a disclosed scFv cargo can provide advantages over a disclosed monoclonal antibody cargo including rapid blood clearance, better tissue penetration, and reduced immunogenicity (due to lack of Fc region). In an aspect, a disclosed scFv can be a building block for bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapies.

[0334] In an aspect, a peptide or protein can be involved with and / or related to fibrosis and / or kidney disease. In an aspect, a peptide or protein involved with and / or related to fibrosis and / or kidney disease can comprise Apelin-13, ELA-32, ELA-21, or ELA-11. In an aspect, apeptide or protein can be involved with and / or related to diabetes and / or metabolic dysfunction. In an aspect, a peptide or protein involved with and / or related to diabetes and / or metabolic dysfunction can comprise Amylin, Cagrilintide, BRP. or Avexitide. In an aspect, a peptide or protein can be involved with and / or related to acute and / or chronic pain. In an aspect, a peptide or protein involved with and / or related to acute and / or chronic pain can comprise Ziconotide. In an aspect, a peptide or protein can be involved with and / or related to HIV infection and / or HIV re-infection and / or HIV persistence. In an aspect, a peptide or protein involved with and / or related to HIV 98110026078 1infection and / or HIV re-infection and / or HIV persistence can comprise Enfuvirtide or Egrifta. In an aspect, a peptide or protein can be involved with and / or related to short bowel syndrome. In an aspect, a peptide or protein involved with and / or related to short bowel syndrome can comprise Teduglutide. In an aspect, a peptide or protein can be involved with and / or related to cardiac function and / or cardiac dysfunction. In an aspect, a peptide or protein involved with and / or related to cardiac function and / or cardiac dysfunction can comprise DWORF. In an aspect, a peptide or protein can be involved with and / or related to epilepsy and / or seizures. In an aspect, a peptide or protein involved with and / or related to epilepsy and / or seizures can comprise Galanin. In an aspect, a peptide or protein can be involved with and / or related to beta-thalassemia and / or myelodysplastic syndrome. In an aspect, a peptide or protein involved with and / or related to betathalassemia and / or myelodysplastic syndrome can comprise Luspatercept. In an aspect, a peptide or protein can be involved with and / or related to heart failure and / or cardiac fibrosis. In an aspect, a peptide or protein involved with and / or related to heart failure and / or cardiac fibrosis can comprise FAM3C. In an aspect, a peptide or protein can be involved with and / or related to sarcopenia. In an aspect, a peptide or protein involved with and / or related to sarcopenia can comprise GDF 11. In an aspect, a peptide or protein can be involved with and / or related to fibrosis and / or fibrotic tissue. In an aspect, a peptide or protein involved with and / or related to fibrosis and / or fibrotic tissue can comprise FGF21. In an aspect, a peptide or protein can be involved with and / or related to Pompe disease and / or muscle wasting. In an aspect, a peptide or protein involved with and / or related to Pompe disease and / or muscle wasting can comprise GAA. In an aspect, a peptide or protein can be involved with and / or related to Gaucher's Disease. In an aspect, a peptide or protein involved with and / or related to Gaucher’s Disease can comprise GBA1.Table 2 - Exemplary CargosProtein / Peptide / Gene SEQ ID # Protein / Peptide / Gene SEQ ID #Apelin-13 38 Avexitide 50ELA-32 39 Galanin 51ELA-21 40 Luspatercept 52EL A- 11 41 GLP-1 Receptor Agonist 53Amylin 42 FAM3C 54Cagnlintide 43 GDF 11 55BRP 44 FGF21 56Ziconotide 45 GAA 57Enfuvirtide 46 GBA1 58Egrifta 47 3xHA 5999110026078 1Protein / Peptide / Gene SEQ ID # Protein / Peptide / Gene SEQ ID # Teduglutide 48 EGFP 60DWORF 49Targeting Guide Sequences

[0335] In an aspect, one or more disclosed targeting guide sequences can bind to a complementary sequence in a targeted endogenous pre-mRNA. In an aspect, one or more disclosed targeting guide sequences can bind to a complementary sequence in a disclosed targeted endogenous pre-mRNA. In an aspect, one or more disclosed targeting guide sequences can bind to a complementary’ sequence in an intron of a targeted endogenous pre-mRNA. In an aspect, one or more disclosed targeting guide sequences can bind to different complementary sequences in one intron of a targeted endogenous pre-mRNA. In an aspect, one or more disclosed targeting guide sequences can bind to different complementary sequences in two separate introns of a targeted endogenous pre-mRNA. In an aspect, one or more disclosed targeting guide sequences can bind to a complementary sequence in an exon of a targeted endogenous pre-mRNA. In an aspect, one or more disclosed targeting guide sequences can bind to different complementary sequences in one exon of a targeted endogenous pre-mRNA. In an aspect, one or more disclosed targeting guide sequences can bind t...

Claims

VIII. CLAIMSWhat is claimed is:

1. A nucleic acid molecule, comprising:two or more targeting guide sequences;a 3 ’ hemi intron;an exogenous RNA to be trans-spliced to a targeted endogenous pre-mRNA, wherein the exogenous RNA to be trans-spliced comprises a sequence encoding a carboxy terminus of a targeted endogenous pre-mRNA, a linker, and a sequence encoding a cargo.

2. The nucleic acid molecule of Claim 1, wherein the two or more targeting guide sequences bind to an intron within the targeted endogenous pre-mRNA.

3. The nucleic acid molecule of Claim 1, wherein the 3’ hemi intron is linked to the exogenous RNA to be trans-spliced with the targeted endogenous mRNA.

4. The nucleic acid molecule of Claim 1, wherein the 3’ hemi intron comprises (i) a 3’ splice region comprising a branch point, (ii) a polypyrimidine tract, and (iii) a 3’ splice acceptor site, and is recognized by nuclear splicing components in one or more cells.

5. The nucleic acid molecule of Claim 1, wherein the carboxy terminus of a targeted endogenous pre-mRNA comprises the last exon.

6. The nucleic acid molecule of Claim 1, wherein the targeted endogenous pre-mRNA encodes albumin, transferrin, transthyretin, beta-2-microglobulin, apolipoprotein E, or apolipoprotein B.

7. The nucleic acid molecule of Claim 6, wherein the targeted endogenous pre-mRNA encodes albumin, and wherein each of the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:26–SEQ ID NO:37.

8. The nucleic acid molecule of Claim 6, wherein the targeted endogenous pre-mRNA encodes transferrin, and wherein each of the targeting guide sequences comprise a sequence set forth in any one of SEQ ID NO:68–SEQ ID NO:73.

9. The nucleic acid molecule of Claim 6, wherein the targeted endogenous pre-mRNA encodes transthyretin, and wherein each of the targeting guide sequences bind to a complementary sequence in any one of SEQ ID NO:96–SEQ ID NO:98.

10. The nucleic acid molecule of Claim 6. wherein the targeted endogenous pre-mRNA encodes beta-2-microglobulin, and wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:99 or SEQ ID NO: 100.172110026078 111. The nucleic acid molecule of Claim 6, wherein the targeted endogenous pre-mRNA encodes apolipoprotein E, and wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO: 101 or SEQ ID NO: 102.

12. The nucleic acid molecule of Claim 6. wherein the targeted endogenous pre-mRNA encodes apolipoprotein B, and wherein each of the targeting guide sequences bind to a complementary sequence in SEQ ID NO:103.

13. The nucleic acid molecule of any preceding claim, wherein the cargo encodes a hormone, an enzyme, a monoclonal antibody, or a scFv.

14. An adeno-associated virus (AAV) vector, comprising: the nucleic acid molecule of any- preceding claim.

15. A pharmaceutical formulation, comprising:the AAV vector of Claim 14; andone or more pharmaceutically acceptable carriers.

16. A method of generating a chimeric RNA molecule, the method comprising:contacting a targeted endogenous pre-mRNA in one or more cells with the nucleic acid molecule of any one of Claims 1 - 13 or the vector of Claim 14, wherein the resulting chimeric RNA molecule encodes a fusion product.

17. The method of Claim 16, wherein the fusion product conveys a therapeutic benefit.

18. The method of Claim 16, wherein the one or more cells are in a subject, and wherein the subject has been diagnosed with having a disease or a disorder.

19. A method of treating, preventing, and or minimizing progression of disease or a disorder, the method comprising:generating a chimeric RNA molecule in one or more cells by administering to a subject in need thereof a therapeutically effective amount of the vector of Claim 14 or the pharmaceutical formulation of Claim 15;wherein the resulting chimeric RNA molecule encodes a fusion product; and wherein the resulting fusion product restores one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation.

20. The method of Claim 19, wherein restoring one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation comprises restoring the functionality and / or structural integrity- of a missing, deficient, and / or mutant protein or enzyme.

21. The method of Claim 19, wherein restoring one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysfunction comprises (i) correcting cell starvation in one or more cells; (ii) correcting, preventing, reducing, and / or ameliorating autophagy; (hi) improving, enhancing, restoring, and / or preserving mitochondrial functionality and / or 173110026078 1structural integrity; (iv) improving, enhancing, restoring, and / or preserving organelle functionality and / or structural integrity; (v) correcting enzyme dysregulation; (vi) reversing, inhibiting, preventing, stabilizing, and / or slowing the rate of progression of the multi-systemic manifestations of the genetic disease or disorder; (vii) reversing, inhibiting, preventing, stabilizing, and / or slowing the rate of progression of a disease or disorder, or (viii) any combination thereof.

22. The method of any one of Claims 19 - 21, wherein the therapeutically effective amount of the AAV vector comprises about 1 x 1010vg to about 2 x 1014vg.

23. The method of any one of Claims 19 - 22, further comprising administering to the subject a therapeutically effective amount of one or more therapeutic agents.174110026078 1

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