Compositions for and methods of modulating trans-splicing efficiency

Abstract

Disclosed herein are compositions for and methods of modulating RNA trans-splicing and methods of using disclosed compositions in methods treating and / or preventing a genetic disease or disorder with the mRNA generated via trans-splicing.

Description

COMPOSITIONS FOR AND METHODS OF MODULATING TRANS-SPLICING EFFICIENCY I. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 704,264 filed 7 October 2024, which is incorporated by reference herein in its entirety. II. REFERENCE TO THE SEQUENCE LISTING

[0002] The Sequence Listing submitted 7 October 2025 as an XML file named “24-3023- WO_SL”, created on 6 October 2025 and having a size of 7,053,312 bytes, is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5). III. BACKGROUND

[0003] In eukaryotes, a large ribonucleoprotein complex called the spliceosome cuts out non- coding introns from protein-coding genes. In most cases, constituents of the spliceosome recognize exon-intron boundaries at the 5’ and 3’ splice sites, remove the intron and ligate adjacent exons within the same pre-mRNA molecule, a process referred to as ‘cis-splicing’. Pre-mRNA ‘trans-splicing’, a less common form of natural RNA splicing, occurs when splice sites from two separate pre-mRNAs are recombined due to interactions between their introns. Although endogenous trans-splicing is rare in mammals, several types of trans-splicing have been documented in various eukaryotic species. Multiple groups leveraged the splicing machinery to drive mRNA trans-splicing, whereby recombinant exons are incorporated into a pre-mRNA transcript. In its simplest form, a pre-trans-splicing RNA molecule is composed of an anti-sense sequence connected to a hemi-intron and one or more exons. After nuclear delivery, the antisense binding domain base pairs with the target mRNA, enabling the intronic sequence to merge the recombinant exons in trans by utilizing the splicing machinery. Despite its potential as a novel RNA rewriting technique, low efficiency prevents this approach from being implemented for therapeutic applications.

[0004] Thus, there remains a need for compositions and methods directed at modulating and / or regulating RNA trans-splicing efficiency. The compositions and methods disclosed herein meet this need. IV. BRIEF DESCRIPTION OF THE FIGURES

[0005] FIG.1A - FIG.1D shows the experimental workflow for the work described herein. FIG. 1A shows the non-coding regions in RNA viruses that infect humans were collected from Genbank sequences. Segments of 50 nucleotide length in 10 nucleotide tiling steps were linked with an FP mutation barcode preceded by a hemi-intron and guide. Generated constructs were cloned into a plasmid backbone. FIG.1B shows the library plasmid was transfected into HEK293 cells stably expressing a splitGFP reporter. RNA was extracted 48 hours post-transfection. After reversetranscription, cDNA and gDNA were indexed and sent to Illumina sequencing. A custom analysis Python pipeline was written for analyzing sequencing results. FIG.1C shows that after a repeat experiment, highest ranking 200 sequences in both datasets were compared. Viral sequences in the intersection and a few unique sequences were cloned individually into the same plasmid backbone. A splitGFP construct with a mutation in the second GFP exon and the individual candidate plasmids were double-transfected into HEK293 cells. FIG 1D shows that EGFP expression as quantified by flow cytometry 48 hours after transfection. Diagram is created with BioRender.com.

[0006] FIG. 2 shows that the input plasmid library distribution is a histogram representing 390,314 sequences gathered after data filtering.

[0007] FIG.3 shows RNA to DNA ratio from the first NextSeq sequencing experiment. 500 ng plasmid library was transfected into HEK293 cells. 48 hours later, RNA was collected, converted to cDNA, and amplified for Illumina sequencing. Unique barcodes were paired with viral RNA sequences of interest to determine trans-spliced mRNA abundance for each candidate. Trans- spliced transcript counts were normalized by input counts in the gDNA pool to quantify trans- splicing efficiency.

[0008] FIG.4 shows RNA to DNA ratio from the first NextSeq sequencing experiment. 1000 ng plasmid library was transfected into HEK293 cells.48 hours later, RNA was collected, converted to cDNA, and amplified for Illumina sequencing. Unique barcodes were paired with viral RNA sequences of interest to determine trans-spliced mRNA abundance for each candidate. Trans- spliced transcript counts were normalized by input counts in the gDNA pool to quantify trans- splicing efficiency. ‘Second NextSeq Data Table_62424’ contains the full dataset.

[0009] FIG. 5 shows the percent GFP positive cells for individual RNA sequence candidates enabling trans-splicing using a GFP assay. Flow cytometry was utilized to quantify the number of percent GFP positive cells for each viral RNA construct. Results were normalized by a pre- trans-splicing RNA without a viral segment.

[0010] FIG.6 shows the mean Fluorescence Intensity of GFP positive cells for individual RNA sequence candidates enabling trans-splicing using a GFP assay. Flow cytometry was utilized to calculate the mean fluorescence intensity for GFP positive cells for each viral RNA construct. Results were normalized by a pre-trans-splicing RNA without a viral segment.

[0011] FIG. 7 shows distribution after data re-analysis by averaging across replicates in the second experiment. Negative Binomial distribution was used to obtain the p-value for each variant. Benjamini-Hochberg was applied to adjust for multiple testing. The variants that were enriched were shown in the right side of the plot with log2 fold change greater than zero. Red colored dots indicate top performing candidates from the original data analysis.V. BRIEF SUMMARY

[0012] Disclosed herein is a non-coding viral RNA sequence, comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a non-coding viral RNA sequence, comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a non-coding viral RNA sequence, comprising a structure set forth in Table 1. Disclosed herein is a non-coding viral RNA sequence, comprising the structure of any one of Candidate 25 – Candidate 48.

[0013] Disclosed herein a 3’ replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0014] Disclosed herein a 5’ replacement construct comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre- mRNA and the 5’ portion of the exogenous RNA.

[0015] Disclosed herein a 3’ replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0016] Disclosed herein a 5’ replacement construct comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ IDNO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0017] Disclosed herein is a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731.

[0018] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, and one or more pharmaceutically acceptable carriers and / or excipients.

[0019] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a nucleic acid molecule, comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0020] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0021] . Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a disclosed a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the resulting trans-spliced RNA transcript comprises the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0022] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule comprising one or more non- coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre- mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0023] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0024] Disclosed herein is a method of treating a genetic disease or disorder, the method comprising generating a trans-spliced RNA molecule in one or more cells by administering to a subject in need thereof a therapeutically effective amount of a disclosed non-viral vector or a disclosed viral vector or a pharmaceutical formulation thereof, wherein the resulting trans-spliced RNA molecule can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation.

[0025] Disclosed herein is a method of treating a genetic disease or disorder, the method comprising generating a trans-spliced RNA molecule in one or more cells by administering to a subject in need thereof a therapeutically effective amount of a disclosed non-viral vector or a disclosed viral vector or a pharmaceutical formulation thereof, wherein the resulting trans-spliced RNA molecule can restore the functionality and / or structural integrity of a missing, deficient, and / or mutant protein or enzyme (such as those, for example, encoded by one of the genes provided supra).VI. DETAILED DESCRIPTION

[0026] 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.

[0027] 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 construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. A. Definitions

[0028] 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.

[0029] 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.

[0030] 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.

[0031] The phrase “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.

[0032] 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.

[0033] 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 “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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] In an aspect, the term “subject” refers to the target of administration, e.g., a human being. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). Thus, the subject of the disclosed methods can be a vertebrate, such as a mammal,a fish, a bird, a reptile, or an amphibian. Alternatively, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex, and thus, adult and child subjects, as well as fetuses, whether male or female, are intended to be covered. In an aspect, a subject can be a human patient. In an aspect, a subject can have a disease or disorder, be suspected of having a disease or disorder, or be at risk of developing a disease or disorder (e.g., a genetic disease or disorder). In an aspect, a subject can be treatment-naïve.

[0038] 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 trans-splicing constructs, disclosed replacement constructs, 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 (such as a genetic disease or disorder) that can be treated by one or more of the disclosed trans-splicing constructs, disclosed replacement constructs, 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 (such as a genetic disease or disorder) that can likely be treated by one or more of by one or more of the disclosed trans- splicing constructs, disclosed replacement constructs, 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, can involve various tests (e.g., blood tests, genotyping, biopsies, etc.) and assays (e.g., enzymatic assay), or a combination thereof.

[0039] A “patient” refers to a subject afflicted with a disease or disorder (e.g., a genetic disease or disorder). In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having a disease or disorder. In an aspect, a patient can refer to a subject that has been diagnosed with or is suspected of having a disease or disorder and is seeking treatment or receiving treatment for a disease or disorder.

[0040] In an aspect, the phrase “identified to be in need of treatment for a disease or disorder,” or the like, refers to selection of a subject based upon need for treatment of the disease or disorder. For example, a subject can be identified as having a need for treatment of a disease or disorder (e.g., a genetic disease or disorder) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the genetic disease or disorder. In an aspect, the identificationcan be performed by a person different from the person making the diagnosis. In an aspect, the administration can be performed by one who performed the diagnosis.

[0041] The words “treat” or “treating” or “treatment” include palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In an aspect, the terms cover any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the undesired physiological change, disease, pathological condition, or disorder from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the physiological change, disease, pathological condition, or disorder, i.e., arresting its development; or (iii) relieving the physiological change, disease, pathological condition, or disorder, i.e., causing regression of the disease. For example, in an aspect, treating a disease or disorder can reduce the severity of an established a disease or disorder in a subject by 1%-100% as compared to a control (such as, for example, an individual not having a genetic disease or disorder). In an aspect, treating can refer to a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of a disease or disorder (such as a genetic disease or disorder). For example, treating a disease or disorder can reduce one or more symptoms of a disease or disorder in a subject by 1%-100% as compared to a control (such as, for example, an individual not having a genetic disease or disorder). In an aspect, treating can refer to 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% reduction of one or more symptoms of an established a disease or disorder. It is understood that treatment does not necessarily refer to a cure or complete ablation or eradication of a disease or disorder. However, in an aspect, treatment can refer to a cure or complete ablation or eradication of a disease or disorder.

[0042] 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 (such as a genetic disease or disorder) or related complication from progressing to that complication.

[0043] 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 trans-splicing constructs, disclosed replacement constructs, disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof to treat or prevent a disease or disorder (such as genetic 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 trans-splicing constructs, disclosed replacement constructs, disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof.

[0044] 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.

[0045] In an aspect, “modifying the method” can comprise modifying or changing one or more features or aspects of one or more steps of a disclosed method. For example, in an aspect, a method can be altered by changing the amount of one or more of the disclosed trans-splicing constructs, disclosed replacement constructs, disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof administered to a subject, or by changing the frequency of administration of one or more of the disclosed trans-splicing constructs, disclosed replacement constructs, disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination thereof to a subject, by changing the duration of time one or more of the disclosed trans-splicing constructs, disclosed replacement constructs, disclosed nucleic acid molecules, disclosed vectors, disclosed pharmaceutical formulations, or a combination are administered to a subject, or by substituting for one or more of the disclosed components and / or reagents with a similar or equivalent component and / or reagent. The same applies to all disclosed therapeutic agents, immune modulators, immunosuppressive agents, proteosome inhibitors, etc.

[0046] 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 suchas 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 form, 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.

[0047] In an aspect, the term “excipient” 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 entirety.

[0048] In an aspect, “concurrently” means (1) simultaneously in time, or (2) at different times during the course of a common treatment schedule.

[0049] In an aspect, the term “contacting” can refer to bringing one or more of the disclosed trans- splicing constructs, disclosed replacement constructs, 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 trans-splicing constructs, disclosed replacement constructs, 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 (such as a genetic 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 (such as a genetic disease or disorder).

[0050] In an aspect, “determining” can refer to measuring or ascertaining the presence and severity of a disease or disorder, such as, for example, a genetic disease or disorder. Methods and techniques used to determine the presence and / or severity of a disease or disorder are typically known to the medical arts. For example, the art is familiar with the ways to identify and / or diagnose the presence, severity, or both of a disease or disorder (such as, for example, a genetic disease or disorder).

[0051] 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 (e.g., a genetic 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 (e.g., a disease or disorder). 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 trans-splicing construct, a disclosed replacement construct, a disclosed nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation; that (i) treatsthe particular disease, condition, or disorder (e.g., a genetic disease or disorder), (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder e.g., a genetic disease or disorder), or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein (e.g., a genetic disease or disorder). 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 trans- splicing constructs, the disclosed replacement constructs, 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 trans-splicing constructs, disclosed replacement constructs, disclosed nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations employed; the duration of the treatment; drugs used in combination or coincidental with the disclosed trans-splicing constructs, the disclosed replacement constructs, the disclosed nucleic acid molecules, the disclosed vectors, or the disclosed pharmaceutical formulations employed, and other like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the disclosed trans-splicing constructs, disclosed replacement constructs, 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 trans-splicing constructs, disclosed replacement constructs, 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.

[0052] In an aspect, the term “ex vivo” can refer generally to activities that take place outside an organism or subject such as experimentation, modification, differentiation, manipulation, and / or measurement done in or on living tissue in an artificial environment outside the organism. In an aspect, ex vivo experimentation, ex vivo modification, ex vivo differentiation, ex vivo manipulation, and / or ex vivo measurement can occur with a minimum alteration of the naturalconditions. In an aspect, “ex vivo” can comprise living cells, tissues, or organs (e.g., cells in need of trans-splicing for one or more protein coding genes) taken from a subject in need thereof or a donor subject and cultured and / or maintained and / or perfused in a laboratory apparatus, usually under sterile conditions, and typically for a limited duration of time (e.g., a few hours or up to about 24 hours, up to about 48 hours, up to about 72 hours, up to about 96 hours, up to about 120 hours, up to about 144 hours, up to about 168 hours, or more depending on the circumstances and / or the desired characteristics. In an aspect, tissues, cells, or organs can be collected, frozen, and later thawed for ex vivo treatment.

[0053] 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 deoxyribo- and ribo-nucleotides, and combinations of bases including uracil, adenine, thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine and isoguanine. 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.

[0054] A “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).

[0055] A “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.

[0056] A “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 the disclosure can be, where appropriate, included in a larger amino acid sequence of which it is a constituent.

[0057] A “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.

[0058] In an aspect, a “recombinant viral vector” can refer to a recombinant polynucleotide vector comprising one or more heterologous sequences (i.e., a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced).

[0059] In an aspect, a “recombinant AAV vector (rAAV vector)” can refer to a polynucleotide vector comprising one or more heterologous sequences (i.e., a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced) that are flanked by at least one, and in some embodiments two, AAV inverted terminal repeat sequences (ITRs). Such rAAV vectors can be replicated andpackaged into infectious viral particles when present in a host cell that has been infected with a suitable helper virus (or that is expressing suitable helper functions) and that is expressing AAV rep and cap gene products (i.e. AAV Rep and Cap proteins). In an aspect, rAAV vector can exist in several forms, including, but not limited to, plasmids, linear artificial chromosomes, complexed with lipids, encapsulated within liposomes, and encapsidated in a viral particle, particularly an AAV particle. In an aspect, an rAAV vector can be packaged into an AAV virus capsid to generate a “recombinant adeno-associated viral particle (rAAV particle)”.

[0060] In an aspect, “complement” or “complementary” means a nucleic acid can mean Watson- Crick (e.g., A-T / U and C-G) or Hoogsteen base pairing between nucleotides or nucleotide analogs of nucleic acid molecules. “Complementarity” refers to a property shared between two nucleic acid sequences, such that when they are aligned antiparallel to each other, the nucleotide bases at each position will be complementary.

[0061] In an aspect, the terms “genome particles (gp),” “genome equivalents,” or “genome copies” can refer to a viral titer or refer to the number of virions containing the recombinant AAV DNA genome, regardless of infectivity or functionality. In an aspect, the term “vector genome (vg)” can refer to one or more polynucleotides comprising a set of the polynucleotide sequences of a vector, e.g., a viral vector. A vector genome can be encapsidated in a viral particle. In an aspect, a vector genome can comprise single-stranded DNA, double-stranded DNA, or single- stranded RNA, or double-stranded RNA. In an aspect, a nucleic acid titer of a viral vector can be measured in terms of vg / mL. Methods suitable for measuring this titer are known in the art (e.g., quantitative PCR).

[0062] In an aspect, the term “serotype” is a distinction used to refer to an AAV having a capsid that is serologically distinct from other AAV serotypes. Serologic distinctiveness can be determined by the lack of cross-reactivity between antibodies to one AAV as compared to another AAV. Such cross-reactivity differences are usually due to differences in capsid protein sequences / antigenic determinants (e.g., due to VP1, VP2, and / or VP3 sequence differences of AAV serotypes).

[0063] In an aspect, “tropism” refers to the specificity of an AAV capsid protein present in an AAV viral particle, for infecting a particular type of cell or tissue. The tropism of an AAV capsid for a particular type of cell or tissue may be determined by measuring the ability of AAV vector particles comprising the hybrid AAV capsid protein to infect or to transduce a particular type of cell or tissue, using standard assays that are well-known in the art such as those disclosed in the examples of the present application. In an aspect, the term “liver tropism” or “hepatic tropism” refers to the tropism for liver or hepatic tissue and cells, including hepatocytes.

[0064] “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.

[0065] In an aspect, “codon optimization” can refer to a process of modifying a nucleic acid sequence for enhanced expression in the host cells of interest by replacing one or more codons or more of the native sequence with codons that are more frequently or most frequently used in the genes of that host cell while maintaining the native amino acid sequence. Various species exhibit particular bias for certain codons of a particular amino acid. As contemplated herein, genes can be tailored for optimal gene expression in a given organism based on codon optimization. Codon usage tables are readily available, for example, at the “Codon Usage Database.” Many methods and software tools for codon optimization have been reported previously. (See, for example, genomes.urv.es / OPTIMIZER / ).

[0066] 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 trypanosomes, 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.

[0067] 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.

[0068] In an aspect, “immune-modulating” refers to the ability of a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed nucleic acid molecules, a disclosedvector, a disclosed pharmaceutical formulation, or a disclosed agent to alter (modulate) one or more aspects of the immune system. The immune system functions to protect the organism from infection and from foreign antigens by cellular and humoral mechanisms involving lymphocytes, macrophages, and other antigen-presenting cells that regulate each other by means of multiple cell-cell interactions and by elaborating soluble factors, including lymphokines and antibodies, that have autocrine, paracrine, and endocrine effects on immune cells.

[0069] In an aspect, the term “immunotolerant” refers to unresponsiveness to an antigen (e.g., a vector, a therapeutic protein, a transgene product, etc.). An immunotolerant promoter can reduce, ameliorate, or prevent transgene-induced immune responses that can be associated with gene therapy. Assays known in the art to measure immune responses, such as immunohistochemical detection of cytotoxic T cell responses, can be used to determine whether one or more promoters can confer immunotolerant properties.

[0070] 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.

[0071] Disclosed are the components to be used to prepare the disclosed trans-splicing constructs, disclosed replacement constructs, disclosed nucleic acid molecules, disclosed vectors, or disclosed pharmaceutical formulations as well as the disclosed trans-splicing constructs, disclosed replacement constructs, 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 every 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 theinvention. 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. Compositions for Trans-Splicing 1. Non-Coding Viral RNA Sequences

[0072] Disclosed herein is a non-coding viral RNA sequence, comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698.

[0073] Disclosed herein is a non-coding viral RNA sequence, comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the non-coding viral RNA sequence modulates RNA trans-splicing efficiency. In an aspect, a disclosed non-coding viral RNA sequence comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 can modulate RNA trans-splicing efficiency. In an aspect, a disclosed non-coding viral RNA sequence comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 can modulate RNA trans-splicing efficiency.

[0074] In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans- splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0075] In an aspect, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0076] Disclosed herein is a non-coding viral RNA sequence, comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. In an aspect, a disclosed RNA sequence can comprise the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705. Disclosed herein is a non-coding viral RNA sequence, comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the non-coding viral RNA sequence modulates RNA trans-splicing efficiency. In an aspect, a disclosed non-coding viral RNA sequence comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0077] Disclosed herein is a non-coding viral RNA sequence, comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a non-coding viral RNA sequence, comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the non-coding viral RNA sequence modulates RNA trans-splicing efficiency. In an aspect, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans- splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0078] In an aspect, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372,SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0079] Disclosed herein is a non-coding viral RNA sequence, comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a non-coding viral RNA sequence, comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the non-coding viral RNA sequence modulates RNA trans-splicing efficiency. In an aspect, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 can modulate RNA trans-splicing efficiency. In an aspect, a disclosed RNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0080] In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans- splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0081] Disclosed herein is a non-coding viral RNA sequence, comprising a structure set forth in Table 1. Disclosed herein is a non-coding viral RNA sequence, comprising the structure of any one of Candidate 25 – Candidate 48. In an aspect, a disclosed non-coding viral RNA sequencecan be obtained from and / or associated with Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, or Filo_Bundibugyo7_40. In an aspect, a disclosed non- coding viral RNA sequence can comprise Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, Filo_Bundibugyo7_40, or any combination thereof.

[0082] In an aspect, a disclosed non-coding viral RNA sequence can comprise the sequence of any one of SEQ ID NO:7706 – SEQ ID NO:7731. In an aspect, a disclosed non-coding viral RNA sequence can comprise the sequence of any one of SEQ ID NO:7699 – SEQ ID NO:7705. In an aspect, a disclosed non-coding viral RNA sequence can be described by its cDNA sequence or by its RNA sequence. In an aspect, a cDNA sequence describing a disclosed non-coding viral RNA sequence can be converted into a corresponding RNA sequence by substituting “t” with “u”. In an aspect, an RNA sequence describing a disclosed non-coding viral RNA sequence can be converted into a corresponding cDNA sequence by substituting “u” with “t”.

[0083] In an aspect, a disclosed non-coding Paramyxo_Measles_4_42 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:2413 or the corresponding RNA sequence set forth in SEQ ID NO:7706. In an aspect, a disclosed non-coding Corona_MERS_4_20 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:656 or the corresponding RNA sequence set forth in SEQ ID NO:7707. In an aspect, a disclosed non-coding Filo_Tai Forest_8_34 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1763 or the corresponding RNA sequence set forth in SEQ ID NO:7708. In an aspect, a disclosed non-coding Filo_Bundibugyo_8_50 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1372 or the corresponding RNA sequence set forth in SEQ ID NO:7709. In an aspect, a disclosed non-coding Paramyxo_RSV_3_4 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:2525 or the corresponding RNA sequence set forth in SEQ ID NO:7710. In an aspect, a disclosed non-coding Flavi_MVV_2_48 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1956 or the corresponding RNA sequence set forth in SEQ ID NO:7711. In an aspect, a disclosed non-coding Retro_HIV2_1_87 viral RNA sequence can comprise the cDNA sequence set forth in SEQ IDNO:3406 or the corresponding RNA sequence set forth in SEQ ID NO:7712. In an aspect, a disclosed non-coding Filo_Tai Forest_2_22 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1456 or the corresponding RNA sequence set forth in SEQ ID NO:7713. In an aspect, a disclosed non-coding Filo_Bundibugyo_8_53 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1375 or the corresponding RNA sequence set forth in SEQ ID NO:7714. In an aspect, a disclosed non-coding Filo_Bundibugyo_8_49 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO: 1371 or the corresponding RNA sequence set forth in SEQ ID NO:7715. In an aspect, a disclosed non-coding Flavi_Dengue type 2_2_28 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1831 or the corresponding RNA sequence set forth in SEQ ID NO:7716. In an aspect, a disclosed non-coding Picorna_EnterovirusD_1_28 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:2891 or the corresponding RNA sequence set forth in SEQ ID NO:7717. In an aspect, a disclosed non-coding Toga_Chik_3_29 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:3755 or the corresponding RNA sequence set forth in SEQ ID NO:7718. In an aspect, a disclosed non-coding Filo_Tai Forest_2_33 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1467 or the corresponding RNA sequence set forth in SEQ ID NO:7719. In an aspect, a disclosed non-coding Toga_Chik_3_14 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:3740 or the corresponding RNA sequence set forth in SEQ ID NO:7720. In an aspect, a disclosed non-coding Paramyxo_Measles_3_6 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:2371 or the corresponding RNA sequence set forth in SEQ ID NO:7721. In an aspect, a disclosed non-coding Flavi_Dengue type 2_2_12 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1815 or the corresponding RNA sequence set forth in SEQ ID NO:7722. In an aspect, a disclosed non-coding Filo_Tai Forest_6_33 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1627 or the corresponding RNA sequence set forth in SEQ ID NO:7723. In an aspect, a disclosed non- coding Filo_Tai Forest_7_8 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1694 or the corresponding RNA sequence set forth in SEQ ID NO:7724. In an aspect, a disclosed non-coding Picorna_HepA_2_1 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:3004 or the corresponding RNA sequence set forth in SEQ ID NO:7725. In an aspect, a disclosed non-coding Flavi_MVV_2_2 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1910 or the corresponding RNA sequence set forth in SEQ ID NO:7726. In an aspect, a disclosed non-coding Corona_HKU1_2_3 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:520 or the corresponding RNA sequence set forth in SEQ ID NO:7727. In an aspect, a disclosed non-codingFilo_Bundibugyo_6_38 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1225 or the corresponding RNA sequence set forth in SEQ ID NO:7728. In an aspect, a disclosed non-coding Retro_Human T1_3_17 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:3543 or the corresponding RNA sequence set forth in SEQ ID NO:7729. In an aspect, a disclosed non-coding Rfx_Cas13_DR viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:7697 or the corresponding RNA sequence set forth in SEQ ID NO:7730. In an aspect, a disclosed non-coding Tar_hairpin viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:7698 or the corresponding RNA sequence set forth in SEQ ID NO:7731.

[0084] In an aspect, a disclosed non-coding Retro_HIV1_2_31 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:3299 or the corresponding RNA sequence set forth in SEQ ID NO:7699. In an aspect, a disclosed non-coding Arena_LCMV_2_2 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:55 or the corresponding RNA sequence set forth in SEQ ID NO:7700. In an aspect, a disclosed non-coding Picorna_HepA_1_17 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:2951 or the corresponding RNA sequence set forth in SEQ ID NO:7701. In an aspect, a disclosed non-coding Corona_NL63_2_3 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:760 or the corresponding RNA sequence set forth in SEQ ID NO:7702. In an aspect, a disclosed non-coding Flavi_Zika_2_26 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:2214 or the corresponding RNA sequence set forth in SEQ ID NO:7703. In an aspect, a disclosed non-coding Flavi_MVV_2_36 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1944 or the corresponding RNA sequence set forth in SEQ ID NO:7704. In an aspect, a disclosed non-coding Filo_Bundibugyo_7_40 viral RNA sequence can comprise the cDNA sequence set forth in SEQ ID NO:1319 or the corresponding RNA sequence set forth in SEQ ID NO:7705. Here, the sequences are the same but for the “t” in the cDNA sequence and the “u” in the RNA sequence. In an aspect, the skilled person can convert a disclosed cDNA sequence into an RNA sequence without undue burden and / or undue experimentation. In an aspect, the skilled person can convert a disclosed RNA sequence into a cDNA sequence without undue burden and / or undue experimentation. Table 1 – List of Viral Non-Coding Viral RNA Sequences (Candidates 25 - 48)

[0085] In an aspect, a disclosed non-coding viral RNA sequence can be interrogated and / or validated. In an aspect, a disclosed non-coding viral RNA sequence can be interrogated and / or validated for its ability to modulate RNA trans-splicing efficiency. In an aspect, the trans-splicing efficiency can be measured using flow cytometry. In an aspect, flow cytometry can measure mean fluorescence intensity of the trans-spliced RNA molecule and / or the percent of cells expressing the trans-spliced RNA molecule. In an aspect, trans-splicing efficiency can be measured using a barcode analysis. In an aspect, a disclosed barcode analysis can comprise one or more nucleic acid barcode sequences. In an aspect, a disclosed nucleic acid barcode sequences can comprise the sequence set forth in any one of SEQ ID NO:3849 - SEQ ID NO:7696. 2. Trans-Splicing Constructs & Replacement Constructs

[0086] Disclosed herein is a trans-splicing construct, comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a trans-splicing construct, comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a trans-splicing construct, comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698.

[0087] In an aspect, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ IDNO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0088] In an aspect, a disclosed non-coding viral RNA sequence comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a trans-splicing construct can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans- splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0089] Disclosed herein is a trans-splicing construct, comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a trans-splicing construct, comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a trans-splicing construct, comprising an exogenous sequence to be trans- spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. In an aspect, a disclosed RNA sequence can comprise the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0090] In an aspect, a disclosed non-coding viral RNA sequence comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a trans-splicing construct can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre- mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans- splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0091] Disclosed herein is a trans-splicing construct, comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a trans-splicing construct, comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a trans-splicing construct, comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non- coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698.

[0092] In an aspect, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0093] In an aspect, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a trans-splicing construct can modulate RNA trans- splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i)improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0094] Disclosed herein is a trans-splicing construct, comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a trans-splicing construct, comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a trans-splicing construct, comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non- coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. In an aspect, a disclosed non-coding viral RNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0095] In an aspect, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a trans-splicing construct can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans- splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0096] Disclosed herein is a trans-splicing construct, comprising a non-coding viral RNA sequence comprising a structure set forth in Table 1. Disclosed herein is a trans-splicing construct, comprising a non-coding viral RNA sequence comprising the structure of any one of Candidate25 – Candidate 48. In an aspect, a disclosed non-coding viral RNA sequence can be obtained from and / or associated with Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, or Filo_Bundibugyo7_40. In an aspect, a disclosed non- coding viral RNA sequence can comprise Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, Filo_Bundibugyo7_40, or any combination thereof.

[0097] Disclosed herein is a replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans- spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0098] Disclosed herein a 3’ replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein a 5’ replacement construct comprising a nucleic acid molecule comprising an exogenous sequence to be trans- spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specificfor a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0099] In an aspect, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0100] In an aspect, a disclosed non-coding viral RNA sequence comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans- splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0101] Disclosed herein is a replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resultingtrans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0102] Disclosed herein a 3’ replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein a 5’ replacement construct comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non- coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA. In an aspect, a disclosed RNA sequence can comprise the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0103] In an aspect, a disclosed non-coding viral RNA sequence comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans- splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0104] Disclosed herein is a replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNAsequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0105] Disclosed herein a 3’ replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre- mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein a 5’ replacement construct comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans- spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0106] In an aspect, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ IDNO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0107] In an aspect, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans- splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0108] Disclosed herein is a replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0109] Disclosed herein a 3’ replacement construct comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans- spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein a 5’ replacement construct comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targetedendogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre- mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0110] In an aspect, a disclosed non-coding viral RNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0111] In an aspect, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de- stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0112] Disclosed herein is a replacement construct comprising a nucleic acid molecule comprising a non-coding viral RNA sequence comprising a structure set forth in Table 1. Disclosed herein is a replacement construct comprising a nucleic acid molecule comprising a non-coding viral RNA sequence comprising the structure of any one of Candidate 25 – Candidate 48. In an aspect, a disclosed non-coding viral RNA sequence can be obtained from and / or associated with Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, or Filo_Bundibugyo7_40. In an aspect, a disclosed non-coding viral RNA sequence can comprise Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6,Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, Filo_Bundibugyo7_40, or any combination thereof. 3. Nucleic Acid Molecules

[0113] Disclosed herein is a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a nucleic acid molecule, comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. In an aspect, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0114] In an aspect, a disclosed non-coding viral RNA sequence comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans- splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / ordiminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0115] Disclosed herein is a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a nucleic acid molecule, comprising an exogenous sequence to be trans- spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731.

[0116] In an aspect, a disclosed RNA sequence can comprise the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705. In an aspect, a disclosed non-coding viral RNA sequence comrpising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre- trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre- mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans- splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0117] Disclosed herein is a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a nucleic acid molecule, comprising anexogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non- coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698.

[0118] In an aspect, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0119] In an aspect, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans- splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0120] Disclosed herein is a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a nucleic acid molecule, comprising anexogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. In an aspect, a disclosed non-coding viral RNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0121] In an aspect, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de- stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0122] In an aspect, a disclosed non-coding viral RNA sequence can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0123] In an aspect, one or more non-coding viral RNA sequences can improve and / or can enhance trans-splicing efficiency. In an aspect, one or more disclosed non-coding viral RNA sequences can stabilize the pre-mRNA. In an aspect, one or more disclosed non-coding viral RNA sequences can localize the RNA to the nucleus. In an aspect, one or more disclosed non-coding viral RNA sequences can stabilize the interaction between the targeted endogenous pre-mRNA molecule and the exogenous RNA to be trans-spliced. In an aspect, a disclosed nucleic acid molecule can lack a CRISPR-associated protein.

[0124] In an aspect, one or more disclosed non-coding viral RNA sequences can bind to one or more RNA binding proteins. In an aspect, one or more disclosed non-coding viral RNA sequences can bind to one or more double-stranded RNA binding proteins (dsRBP). In an aspect, dsRBPs are known to the skilled person in the art and include, but are not limited to, ADAR1, ADAR2, DICER, NFAR, PACT, PKR, RHA RNaseIII, Stauffen, TRBP, TSEN, or any combination thereof.

[0125] In an aspect, a disclosed targeted endogenous pre-mRNA can comprise one or more mutations. In an aspect of a disclosed targeted endogenous pre-mRNA, one or more disclosed mutations can be in the 5’ portion of the pre-mRNA. In an aspect, one or more disclosed mutations can be in the 5’ portion of the one or more exons of the pre-mRNA. In an aspect of a disclosed targeted endogenous pre-mRNA, one or more disclosed mutations can be in the 3’ portion of the pre-mRNA. In an aspect, one or more disclosed mutations can be in the 3’ portion of the one or more exons of the pre-mRNA. In an aspect, one or more disclosed mutations in one or more exons can contribute to pathogenesis of one or more cells.

[0126] In an aspect, a disclosed targeted endogenous pre-mRNA can comprise one or more mutations in one or more exons. In an aspect, a disclosed targeted endogenous pre-mRNA can comprise one or more mutations in one or more introns. In an aspect, one or more disclosed mutations can inhibit translation of the encoded protein. In an aspect, one or more disclosed mutations can modify translation of the encoded protein. In an aspect, one or more disclosed mutations can generate an encoded protein having a non-sense mutation or a missense mutation. In an aspect, the one or more disclosed exonic mutations can contribute to pathogenesis in one or more cells. In an aspect, the one or more disclosed intronic mutations can contribute to pathogenesis in one or more cells. In an aspect, a disclosed targeted endogenous pre-mRNA can encode a protein coding gene (including those disclosed herein and including those large genes disclosed herein).

[0127] In an aspect, the disclosed cells can be in a subject. In an aspect, a subject can be a human patient and can be male or female. In an aspect, a subject can have a genetic disease or disorder. In an aspect, a subject can be treatment-naïve.

[0128] In an aspect, a disclosed targeted endogenous pre-mRNA can be a primary transcript of a protein coding gene. In an aspect of a disclosed targeted endogenous pre-mRNA, a disclosed protein coding gene can comprise one or more coding regions or one or more exons of ABCA1, ABCA12, ABCA13, ABCA2, ABCA3, ABCA4, ABCA5, ABCC1, ABCC2, ABCC6, ABCC8, ABCC9, ACAN, ADAMTS13, ADCY10, ADGRV1, AGL, AGRN, AHDC1, ALK, ALMS1, ALPK3, ALS2, ANAPC1, ANK1, ANK2, ANK3, ANKRD11, ANKRD26, APC, APC2, APOB, ARFGEF2, ARHGAP31, ARHGEF10, ARHGEF18, ARID1A, ARID1B, ARID2, ASH1L, ASPM, ASXL1,ASXL2, ASXL3, ATM, ATP7A, ATP7B, ATR, ATRX, BAZ1A, BAZ2B, BCOR, BCORL1, BDP1, BLM, BPTF, BRCA1, BRCA2, BRD4, BRWD3, C2CD3, C3, C5, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1S, CAD, CAMTA1, CARMIL2, CC2D2A, CCDC88A, CCDC88C, CCNB3, CDH23, CDK13, CDK5RAP2, CELSR1, CEMIP2, CENPE, CENPF, CENPJ, CEP152, CEP164, CEP250, CEP290, CFAP43, CFAP44, CFAP65, CFTR / ABCC7, CHD1, CHD2, CHD3, CHD4, CHD7, CHD8, CIC, CIT, CLIP1, CLTC, CNOT1, CNTNAP1, COL11A1, COL11A2, COL12A1, COL17A1, COL18A1, COL1A1, COL1A2, COL27A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL6A3, COL7A1, CPAMD8, CPLANE1, CPS1, CPSF1, CRB1, CREBBP, CUBN, CUL7, CUX1, DCC, DCHS1, DEPDC5, DICER1, DIP2B, DLC1, DMD, DMXL2, DNAH1, DNAH11, DNAH17, DNAH2, DNAH5, DNAH7, DNAH8, DNAH9, DNMBP, DNMT1, DOCK2, DOCK3, DOCK6, DOCK7, DOCK8, DSCAM, DSP, DST, DUOX2, DYNC1H1, DYNC2H1, DYSF, EIF2AK4, EP300, EPG5, ERCC6, ERCC6L2, EXPH5, EYS, F5, F8, FANCA, FANCD2, FANCM, FAT1, FAT4, FBN1, FBN2, FLG, FLG2, FLNA, FLNB, FLNC, FLT4, FMN2, FN1, FRAS1, FREM1, FREM2, FSIP2, FXN, FYCO1, GLI2, GLI3, GPR179, GREB1L, GRIN2A, GRIN2B, GRIN2D, HCFC1, HECW2, HERC1, HERC2, HFM1, HIVEP1, HIVEP2, HMCN1, HSPG2, HTT, HUWE1, HYDIN, IFT140, IFT172, IGF1R, IGF2R, IGSF1, INSR, INTS1, IQSEC2, ITGB4, ITPR1, ITPR2, JMJD1C, KALRN, KANK1, KAT6A, KAT6B, KDM3B, KDM5B, KDM5C, KDM6A, KDM6B, 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, LCT, LMNA, LOXHD1, LPA, LRBA, LRP1, LRP2, LRP4, LRP5, LRP6, LRPPRC, LRRK1, LRRK2, LTBP2, LTBP4, LYST, MACF1, MADD, MAGI2, MAP1B, MAP3K1, MAPK8IP3, MAPKBP1, MAST1, MBD5, MCM3AP, MED12, MED12L, MED13, MED13L, MED23, MEGF8, MET, MLH3, MPDZ, MSH6, MTOR, MYH10, MYH11, MYH14, MYH2, MYH3, MYH6, MYH7, MYH7B, MYH8, MYH9, MYLK, MYO15A, MYO18B, MYO3A, MYO5A, MYO5B, MYO7A, MYO9A, NALCN, NBAS, NBEA, NBEAL2, NCAPD2, NCAPD3, NEB, NEXMIF, NEXMIF, NF1, NFASC, NHS, NIN, NIPBL, NLRP1, NOTCH1, NOTCH2, NOTCH3, NPHP4, NRXN1, NRXN3, NSD1, NSD2, NUP155, NUP188, NUP205, OBSCN, OBSL1, OTOF, OTOG, OTOGL, PARD3, PBRM1, PCDH15, PCLO, PCNT, PHIP, PI4KA, PIEZO1, PIEZO2, PIK3C2A, PIKFYVE, PKD1, PKD1L1, PKHD1, PLCE1, PLEC, PLEKHG2, PNPLA6, POGZ, POLA1, POLE, POLR1A, POLR2A, POLR3A, PRG4, PRKDC, PRPF8, PRR12, PRX, PTCH1, PTPN23, PTPRF, PTPRJ, PTPRQ, PXDN, QRICH2, RAB3GAP2, RAI1, RALGAPA1, RANBP2, RB1CC1, RELN, RERE, REV3L, RIC1, RIMS1, RIMS2, RNF213, ROBO1, ROBO2, ROBO3, ROS1, RP1, RP1L1, RTTN, RUSC2, RYR1, RYR2, SACS, SAMD9, SAMD9L, SBF2, SCAPER, SCN10A, SCN11A, SCN1A,SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SETBP1, SETD1A, SETD1B, SETD2, SETD5, SETX, SHANK2, SHANK3, SHROOM4, SI, SIPA1L3, SLIT2, SLX4, SMARCA2, SMARCA4, SMCHD1, SNRNP200, SON, SPEF2, SPEG, SPG11, SPTA1, SPTAN1, SPTB, SPTBN2, SPTBN4, SRCAP, STRC, SVIL, SYNE1, SYNGAP1, SYNJ1, SZT2, TAF1, TANC2, TCF20, TCOF1, TDRD9, TECPR2, TECTA, TENM3, TENM4, TET3, TEX14, TEX15, TG, THOC2, TMEM94, TNC, TNIK, TNR, TNRC6B, TNXB, TOGARAM1, TONSL, TRIO, TRIOBP, TRIP11, TRIP12, TRPM1, TRPM6, TRPM7, TRRAP, TSC2, TTC37, TTN, TUBGCP6, UBR1, UNC80, USH2A, USP9X, VCAN, VPS13A, VPS13B, VPS13C, VPS13D, VWF, WDFY3, WDR19, WDR62, WDR81, WNK1, WRN, ZFHX2, ZFYVE26, ZNF142, ZNF292, ZNF335, ZNF407, ZNF462, or ZNF469. In an aspect, a disclosed protein coding gene can comprise one or more coding regions of CFTR, MDX, DYSF / TTN, DMPK, COL7A1, K14, MAPT, FVIII, HTT, RHO, DNA-PKcs, SMN2, or CD40L. In an aspect, a disclosed protein coding gene can comprise one or more coding regions of FXN, LMNA, or RYR2. In an aspect, a disclosed protein coding gene can comprise a portion of a disclosed protein coding gene (such as, for example, Exon 1 or Exon 4, etc.) In an aspect, a disclosed targeted endogenous pre-mRNA and a disclosed exogenous RNA can encode the same protein coding gene. In an aspect, a disclosed targeted endogenous pre-mRNA and a disclosed exogenous RNA can comprise one or more exons of the same protein coding gene.

[0129] In an aspect, a disclosed 5’ portion of the targeted endogenous pre-mRNA can be trans- spliced with the exogenous RNA. In an aspect, a disclosed RNA targeting motif can bind to the targeted endogenous pre-mRNA. In an aspect, a disclosed RNA targeting motif can bind to the 3’ end of the targeted endogenous pre-mRNA. In an aspect, a disclosed 3’ portion of the targeted endogenous pre-mRNA can be trans-spliced with the exogenous RNA. In an aspect, a disclosed RNA targeting motif can bind to the targeted endogenous pre-mRNA. In an aspect, a disclosed RNA targeting motif can bind to the 5’ end of the targeted endogenous pre-mRNA.

[0130] In an aspect, a disclosed targeted endogenous pre-mRNA and a disclosed exogenous RNA can encode the same protein coding gene. In an aspect, a disclosed targeted endogenous pre- mRNA and a disclosed exogenous RNA can comprise one or more exons of the same protein coding gene. In an aspect, a disclosed resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. In an aspect, a disclosed resulting trans-spliced RNA transcript can comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0131] In an aspect, a disclosed exogenous RNA to be trans-spliced to the targeted endogenous pre-mRNA can comprise one or more exons of the protein coding gene. In an aspect, a disclosed exogenous RNA to be trans-spliced to the targeted endogenous pre-mRNA can comprise the primary sequence of the coding sequence of one or more exons having the one or more mutations.

[0132] In an aspect, a disclosed exogenous RNA and a disclosed targeted endogenous pre-mRNA can encode the same protein coding gene. In an aspect, a disclosed exogenous RNA and a disclosed targeted endogenous pre-mRNA can comprise one or more exons of the same protein coding gene.

[0133] In an aspect of a disclosed exogenous RNA, a disclosed protein coding gene can comprise one or more coding regions of ABCA1, ABCA12, ABCA13, ABCA2, ABCA3, ABCA4, ABCA5, ABCC1, ABCC2, ABCC6, ABCC8, ABCC9, ACAN, ADAMTS13, ADCY10, ADGRV1, AGL, AGRN, AHDC1, ALK, ALMS1, ALPK3, ALS2, ANAPC1, ANK1, ANK2, ANK3, ANKRD11, ANKRD26, APC, APC2, APOB, ARFGEF2, ARHGAP31, ARHGEF10, ARHGEF18, ARID1A, ARID1B, ARID2, ASH1L, ASPM, ASXL1, ASXL2, ASXL3, ATM, ATP7A, ATP7B, ATR, ATRX, BAZ1A, BAZ2B, BCOR, BCORL1, BDP1, BLM, BPTF, BRCA1, BRCA2, BRD4, BRWD3, C2CD3, C3, C5, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1S, CAD, CAMTA1, CARMIL2, CC2D2A, CCDC88A, CCDC88C, CCNB3, CDH23, CDK13, CDK5RAP2, CELSR1, CEMIP2, CENPE, CENPF, CENPJ, CEP152, CEP164, CEP250, CEP290, CFAP43, CFAP44, CFAP65, CFTR / ABCC7, CHD1, CHD2, CHD3, CHD4, CHD7, CHD8, CIC, CIT, CLIP1, CLTC, CNOT1, CNTNAP1, COL11A1, COL11A2, COL12A1, COL17A1, COL18A1, COL1A1, COL1A2, COL27A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL6A3, COL7A1, CPAMD8, CPLANE1, CPS1, CPSF1, CRB1, CREBBP, CUBN, CUL7, CUX1, DCC, DCHS1, DEPDC5, DICER1, DIP2B, DLC1, DMD, DMXL2, DNAH1, DNAH11, DNAH17, DNAH2, DNAH5, DNAH7, DNAH8, DNAH9, DNMBP, DNMT1, DOCK2, DOCK3, DOCK6, DOCK7, DOCK8, DSCAM, DSP, DST, DUOX2, DYNC1H1, DYNC2H1, DYSF, EIF2AK4, EP300, EPG5, ERCC6, ERCC6L2, EXPH5, EYS, F5, F8, FANCA, FANCD2, FANCM, FAT1, FAT4, FBN1, FBN2, FLG, FLG2, FLNA, FLNB, FLNC, FLT4, FMN2, FN1, FRAS1, FREM1, FREM2, FSIP2, FXN, FYCO1, GLI2, GLI3, GPR179, GREB1L, GRIN2A, GRIN2B, GRIN2D, HCFC1, HECW2, HERC1, HERC2, HFM1, HIVEP1, HIVEP2, HMCN1, HSPG2, HTT, HUWE1, HYDIN, IFT140, IFT172, IGF1R, IGF2R, IGSF1, INSR, INTS1, IQSEC2, ITGB4, ITPR1, ITPR2, JMJD1C, KALRN, KANK1, KAT6A, KAT6B, KDM3B, KDM5B, KDM5C, KDM6A, KDM6B, 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, LCT, LMNA, LOXHD1, LPA, LRBA, LRP1, LRP2, LRP4, LRP5, LRP6, LRPPRC, LRRK1, LRRK2, LTBP2, LTBP4, LYST, MACF1, MADD, MAGI2, MAP1B, MAP3K1, MAPK8IP3, MAPKBP1, MAST1, MBD5, MCM3AP, MED12, MED12L, MED13, MED13L, MED23, MEGF8, MET, MLH3, MPDZ, MSH6, MTOR, MYH10, MYH11, MYH14, MYH2, MYH3, MYH6, MYH7, MYH7B, MYH8, MYH9, MYLK, MYO15A, MYO18B, MYO3A, MYO5A, MYO5B,MYO7A, MYO9A, NALCN, NBAS, NBEA, NBEAL2, NCAPD2, NCAPD3, NEB, NEXMIF, NEXMIF, NF1, NFASC, NHS, NIN, NIPBL, NLRP1, NOTCH1, NOTCH2, NOTCH3, NPHP4, NRXN1, NRXN3, NSD1, NSD2, NUP155, NUP188, NUP205, OBSCN, OBSL1, OTOF, OTOG, OTOGL, PARD3, PBRM1, PCDH15, PCLO, PCNT, PHIP, PI4KA, PIEZO1, PIEZO2, PIK3C2A, PIKFYVE, PKD1, PKD1L1, PKHD1, PLCE1, PLEC, PLEKHG2, PNPLA6, POGZ, POLA1, POLE, POLR1A, POLR2A, POLR3A, PRG4, PRKDC, PRPF8, PRR12, PRX, PTCH1, PTPN23, PTPRF, PTPRJ, PTPRQ, PXDN, QRICH2, RAB3GAP2, RAI1, RALGAPA1, RANBP2, RB1CC1, RELN, RERE, REV3L, RIC1, RIMS1, RIMS2, RNF213, ROBO1, ROBO2, ROBO3, ROS1, RP1, RP1L1, RTTN, RUSC2, RYR1, RYR2, SACS, SAMD9, SAMD9L, SBF2, SCAPER, SCN10A, SCN11A, SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SETBP1, SETD1A, SETD1B, SETD2, SETD5, SETX, SHANK2, SHANK3, SHROOM4, SI, SIPA1L3, SLIT2, SLX4, SMARCA2, SMARCA4, SMCHD1, SNRNP200, SON, SPEF2, SPEG, SPG11, SPTA1, SPTAN1, SPTB, SPTBN2, SPTBN4, SRCAP, STRC, SVIL, SYNE1, SYNGAP1, SYNJ1, SZT2, TAF1, TANC2, TCF20, TCOF1, TDRD9, TECPR2, TECTA, TENM3, TENM4, TET3, TEX14, TEX15, TG, THOC2, TMEM94, TNC, TNIK, TNR, TNRC6B, TNXB, TOGARAM1, TONSL, TRIO, TRIOBP, TRIP11, TRIP12, TRPM1, TRPM6, TRPM7, TRRAP, TSC2, TTC37, TTN, TUBGCP6, UBR1, UNC80, USH2A, USP9X, VCAN, VPS13A, VPS13B, VPS13C, VPS13D, VWF, WDFY3, WDR19, WDR62, WDR81, WNK1, WRN, ZFHX2, ZFYVE26, ZNF142, ZNF292, ZNF335, ZNF407, ZNF462, or ZNF469. In an aspect, a disclosed protein coding gene can comprise one or more coding regions of CFTR, MDX, DYSF / TTN, DMPK, COL7A1, K14, MAPT, FVIII, HTT, RHO, DNA-PKcs, SMN2, or CD40L. In an aspect, a disclosed protein coding gene can comprise one or more coding regions of FXN, LMNA, or RYR2.

[0134] In an aspect, a disclosed exogenous RNA to be trans-spliced can further comprise a UTR.

[0135] In an aspect, a disclosed exogenous RNA and a disclosed targeted endogenous pre-mRNA can encode the same protein coding gene. In an aspect, a disclosed exogenous RNA and a disclosed targeted endogenous pre-mRNA can comprise one or more exons of the same protein coding gene.

[0136] In an aspect, a disclosed 5’ hemi intron can comprise a 5’ splice site. In an aspect, a disclosed 5’ splice site can comprise a consensus 5’ splice site. In an aspect, a disclosed consequence 5’ splice site can comprise MAG | GURAGU, wherein | denotes the exon intron junction, wherein M = A or C, and wherein R = A or G (SEQ ID NO:7732). In an aspect, a disclosed 5’ hemi intron can be recognized by nuclear splicing components in a host cell. In an aspect, a disclosed 5’ hemi intron can be recognized by the spliceosome in a host cell. In an aspect, a disclosed 5’ hemi intron can facilitate the trans-splicing of the exogenous RNA to theexon immediately 3’ to the targeted intron in the endogenous pre-mRNA. In an aspect, a disclosed 5’ hemi intron can be recognized by nuclear splicing components within a host cell.

[0137] In an aspect, a disclosed 3’ hemi intron can comprise (i) a 3’ splice region comprising a branch point, (ii) a polypyrimidine tract, and (iii) a 3’ splice acceptor site. In an aspect, a disclosed 3’ splice acceptor site can comprise the sequence YAG, where Y is a pyrimidine. In an aspect, a disclosed 3’ hemi intron can be recognized by nuclear splicing components in a host cell. In an aspect, a disclosed 3’ hemi intron can be recognized by the spliceosome in a host cell. In an aspect, a disclosed 3’ hemi intron can facilitate the trans-splicing of the exogenous RNA to the exon immediately 5’ to the targeted intron in the endogenous pre-mRNA. In an aspect, a disclosed 3’ hemi intron can be recognized by nuclear splicing components within a host cell. In an aspect, a disclosed exogenous RNA can induce a splice event.

[0138] In an aspect, a disclosed RNA targeting motif can be specific for an endogenous pre- mRNA having one or more mutations. In an aspect, a disclosed RNA targeting motif can be specific for an endogenous pre-mRNA having one or more exonic mutations. In an aspect, a disclosed RNA targeting motif can be specific for an endogenous pre-mRNA having one or more intronic mutations.

[0139] In an aspect, a disclosed RNA targeting motif can comprise an antisense oligonucleotide. In an aspect, a disclosed antisense oligonucleotide can comprise about 15 nucleotides to about 50 nucleotides. In an aspect, a disclosed antisense oligonucleotide can comprise about 30 nucleotides. In an aspect, a disclosed RNA targeting motif can be directed to the intron immediately 5’ to the exon of the targeted endogenous pre-mRNA with which it is to be spliced. In an aspect, a disclosed RNA targeting motif can be directed to the intron immediately 3’ to the exon of the targeted endogenous pre-mRNA with which it is to be spliced.

[0140] In an aspect, a disclosed RNA targeting motif can bind to the targeted endogenous pre- mRNA. In an aspect, a disclosed RNA targeting motif can bind to the 3’ end of the targeted endogenous pre-mRNA.

[0141] In an aspect, a disclosed RNA targeting motif can target an endogenous pre-mRNA for one or more coding regions or one or more exons of ABCA1, ABCA12, ABCA13, ABCA2, ABCA3, ABCA4, ABCA5, ABCC1, ABCC2, ABCC6, ABCC8, ABCC9, ACAN, ADAMTS13, ADCY10, ADGRV1, AGL, AGRN, AHDC1, ALK, ALMS1, ALPK3, ALS2, ANAPC1, ANK1, ANK2, ANK3, ANKRD11, ANKRD26, APC, APC2, APOB, ARFGEF2, ARHGAP31, ARHGEF10, ARHGEF18, ARID1A, ARID1B, ARID2, ASH1L, ASPM, ASXL1, ASXL2, ASXL3, ATM, ATP7A, ATP7B, ATR, ATRX, BAZ1A, BAZ2B, BCOR, BCORL1, BDP1, BLM, BPTF, BRCA1, BRCA2, BRD4, BRWD3, C2CD3, C3, C5, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1S, CAD, CAMTA1, CARMIL2, CC2D2A, CCDC88A,CCDC88C, CCNB3, CDH23, CDK13, CDK5RAP2, CELSR1, CEMIP2, CENPE, CENPF, CENPJ, CEP152, CEP164, CEP250, CEP290, CFAP43, CFAP44, CFAP65, CFTR / ABCC7, CHD1, CHD2, CHD3, CHD4, CHD7, CHD8, CIC, CIT, CLIP1, CLTC, CNOT1, CNTNAP1, COL11A1, COL11A2, COL12A1, COL17A1, COL18A1, COL1A1, COL1A2, COL27A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL6A3, COL7A1, CPAMD8, CPLANE1, CPS1, CPSF1, CRB1, CREBBP, CUBN, CUL7, CUX1, DCC, DCHS1, DEPDC5, DICER1, DIP2B, DLC1, DMD, DMXL2, DNAH1, DNAH11, DNAH17, DNAH2, DNAH5, DNAH7, DNAH8, DNAH9, DNMBP, DNMT1, DOCK2, DOCK3, DOCK6, DOCK7, DOCK8, DSCAM, DSP, DST, DUOX2, DYNC1H1, DYNC2H1, DYSF, EIF2AK4, EP300, EPG5, ERCC6, ERCC6L2, EXPH5, EYS, F5, F8, FANCA, FANCD2, FANCM, FAT1, FAT4, FBN1, FBN2, FLG, FLG2, FLNA, FLNB, FLNC, FLT4, FMN2, FN1, FRAS1, FREM1, FREM2, FSIP2, FXN, FYCO1, GLI2, GLI3, GPR179, GREB1L, GRIN2A, GRIN2B, GRIN2D, HCFC1, HECW2, HERC1, HERC2, HFM1, HIVEP1, HIVEP2, HMCN1, HSPG2, HTT, HUWE1, HYDIN, IFT140, IFT172, IGF1R, IGF2R, IGSF1, INSR, INTS1, IQSEC2, ITGB4, ITPR1, ITPR2, JMJD1C, KALRN, KANK1, KAT6A, KAT6B, KDM3B, KDM5B, KDM5C, KDM6A, KDM6B, 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, LCT, LMNA, LOXHD1, LPA, LRBA, LRP1, LRP2, LRP4, LRP5, LRP6, LRPPRC, LRRK1, LRRK2, LTBP2, LTBP4, LYST, MACF1, MADD, MAGI2, MAP1B, MAP3K1, MAPK8IP3, MAPKBP1, MAST1, MBD5, MCM3AP, MED12, MED12L, MED13, MED13L, MED23, MEGF8, MET, MLH3, MPDZ, MSH6, MTOR, MYH10, MYH11, MYH14, MYH2, MYH3, MYH6, MYH7, MYH7B, MYH8, MYH9, MYLK, MYO15A, MYO18B, MYO3A, MYO5A, MYO5B, MYO7A, MYO9A, NALCN, NBAS, NBEA, NBEAL2, NCAPD2, NCAPD3, NEB, NEXMIF, NEXMIF, NF1, NFASC, NHS, NIN, NIPBL, NLRP1, NOTCH1, NOTCH2, NOTCH3, NPHP4, NRXN1, NRXN3, NSD1, NSD2, NUP155, NUP188, NUP205, OBSCN, OBSL1, OTOF, OTOG, OTOGL, PARD3, PBRM1, PCDH15, PCLO, PCNT, PHIP, PI4KA, PIEZO1, PIEZO2, PIK3C2A, PIKFYVE, PKD1, PKD1L1, PKHD1, PLCE1, PLEC, PLEKHG2, PNPLA6, POGZ, POLA1, POLE, POLR1A, POLR2A, POLR3A, PRG4, PRKDC, PRPF8, PRR12, PRX, PTCH1, PTPN23, PTPRF, PTPRJ, PTPRQ, PXDN, QRICH2, RAB3GAP2, RAI1, RALGAPA1, RANBP2, RB1CC1, RELN, RERE, REV3L, RIC1, RIMS1, RIMS2, RNF213, ROBO1, ROBO2, ROBO3, ROS1, RP1, RP1L1, RTTN, RUSC2, RYR1, RYR2, SACS, SAMD9, SAMD9L, SBF2, SCAPER, SCN10A, SCN11A, SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SETBP1, SETD1A, SETD1B, SETD2, SETD5, SETX, SHANK2, SHANK3, SHROOM4, SI, SIPA1L3, SLIT2, SLX4, SMARCA2, SMARCA4, SMCHD1, SNRNP200, SON, SPEF2, SPEG, SPG11, SPTA1, SPTAN1, SPTB, SPTBN2, SPTBN4, SRCAP, STRC, SVIL, SYNE1, SYNGAP1,SYNJ1, SZT2, TAF1, TANC2, TCF20, TCOF1, TDRD9, TECPR2, TECTA, TENM3, TENM4, TET3, TEX14, TEX15, TG, THOC2, TMEM94, TNC, TNIK, TNR, TNRC6B, TNXB, TOGARAM1, TONSL, TRIO, TRIOBP, TRIP11, TRIP12, TRPM1, TRPM6, TRPM7, TRRAP, TSC2, TTC37, TTN, TUBGCP6, UBR1, UNC80, USH2A, USP9X, VCAN, VPS13A, VPS13B, VPS13C, VPS13D, VWF, WDFY3, WDR19, WDR62, WDR81, WNK1, WRN, ZFHX2, ZFYVE26, ZNF142, ZNF292, ZNF335, ZNF407, ZNF462, or ZNF469. In an aspect, a disclosed RNA targeting motif can target an endogenous pre-mRNA for one or more coding regions or one or more exons of CFTR, MDX, DYSF / TTN, DMPK, COL7A1, K14, MAPT, FVIII, HTT, RHO, DNA-PKcs, SMN2, or CD40L In an aspect, a disclosed RNA targeting motif can target an endogenous pre-mRNA for one or more coding regions or one or more exons of FXN, LMNA, or RYR2. In an aspect, a disclosed protein coding gene can comprise a portion of a disclosed protein coding gene (such as, for example, Exon 1 or Exon 4, etc.)

[0142] In an aspect, a disclosed nucleic acid molecule can modulate RNA trans-splicing efficiency and / or can modulate expression and / or activity of one or more genes of interest. In an aspect, modulating can comprise increasing and / or decreasing RNA trans-splicing efficiency and / or increasing and / or decreasing expression and / or activity of one or more genes of interest (e.g., targeted genes). In an aspect, a disclosed nucleic acid molecule can be particularly useful in a method of treating a subject having an autosomal dominant genetic disease or disorder (such as, for example, progeria, achondroplasia, antithrombin III deficiency, Ehlers-Danlos syndrome, Gilbert’s disease, hereditary hemorrhagic telangiectasia, hereditary elliptosis, hereditary spherocytosis, Huntington’s disease, idiopathic hypoparathyroidism, intestinal polyposis, marble bone disease, Marfan’s syndrome, neurofibromatosis, polycystic kidney disease (adult), protein C deficiency, osteogenesis imperfecta, Treacher Collins syndrome, tuberous sclerosis, Von Willebrand’s disease, etc.).

[0143] In an aspect, expression of a disclosed protein coding gene can be restored and / or returned to a wild-type, normal, or control expression level. In an aspect, a disclosed nucleic acid molecule can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation. In an aspect, a disclosed nucleic acid molecule can restore the functionality and / or structural integrity of a missing, deficient, and / or mutant protein or enzyme (such as those, for example, encoded by one of the genes provided supra).

[0144] In an aspect, restoring one or more aspects of cellular homeostasis and / or cellular functionality can comprise one or more of the following: (i) correcting cell starvation in one or more cell types; (ii) normalizing aspects of the autophagy pathway (such as, for example, correcting, preventing, reducing, and / or ameliorating autophagy); (iii) improving, enhancing, restoring, and / or preserving mitochondrial functionality and / or structural 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 a genetic disease or disorder; (vii) reversing, inhibiting, preventing, stabilizing, and / or slowing the rate of progression of a genetic disease or disorder, or (viii) any combination thereof. In an aspect, restoring one or more aspects of cellular homeostasis can comprise improving, enhancing, restoring, and / or preserving one or more aspects of cellular structural and / or functional integrity.

[0145] In an aspect, restoring the activity and / or functionality of a missing, deficient, and / or mutant protein or enzyme can comprise a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of restoration when compared to a pre-existing level such as, for example, a pre-treatment level. In an aspect, the amount of restoration can be 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% more than a pre-existing level such as, for example, a pre-treatment level. In an aspect, restoration can be measured against a control level or a reference level (e.g., determined, for example, using one or more subjects not having a missing, deficient, and / or mutant protein or enzyme). In an aspect, restoration can be a partial or incomplete restoration. In an aspect, restoration can be complete or near complete restoration such that the level of expression, activity, and / or functionality is similar to that of a wild-type or control level.

[0146] In an aspect, a disclosed nucleic acid molecule can further comprise a polyadenylation sequence. In an aspect, a disclosed nucleic acid molecule can further comprise a sequence for a promoter. In an aspect, a disclosed nucleic acid molecule can further comprise a spacer region. In an aspect, a disclosed spacer region can separate the 5’ splice region from the one or more non- coding viral RNA sequences. In an aspect, a disclosed spacer region can comprise any known spacer. In an aspect, a disclosed spacer region can comprise a consensus splicing motif (e.g., such as U1 or U2). In an aspect, a disclosed spacer region can comprise a limited number of consensus splicing motifs (e.g., such as U1 or U2).

[0147] In an aspect, a disclosed nucleic acid molecule can further comprise stuffer nucleic acid. In an aspect, a disclosed nucleic acid molecule can further comprise one or more nuclear localization signals (NLS). NLS are known to the skilled person in the art. In an aspect, a disclosed NLS can comprise any NLS known to the art. As known to the art (see, e.g., Lu J, et al. (2021) Cell Commun Signal.19:60, which is incorporated herein by reference for its teachings of NLS), nuclear localization signals (NLS) are generally short peptides that act as a signal fragment that mediates the transport of proteins from the cytoplasm into the nucleus. In an aspect, a disclosed nucleic acid molecule can further comprise one or more nuclear retention elements(NRE). NRE are known to the skilled person in the art. In an aspect, a disclosed NRE can comprise SIRLOIN or BORG.

[0148] In an aspect, a disclosed nucleic acid molecule can further comprise one or more Flavivirus genetic elements. In an aspect, Flavivirus genetic elements can comprise one or more Flavivirus 3’ untranslated region (3’ UTR), one or more subgenomic Flavivirus RNA (sfRNA) elements, one or more Flavivirus XRN1-resistant RNA (xrRNA) elements, one or more Flavivirus dumbbell (DB) RNA elements, one or more Flavivirus 3’ stem loop (3’ SL) elements, or any combination thereof. (See WO 2022 / 182835 for a description of Flavivirus gene elements).

[0149] In an aspect, a disclosed nucleic acid molecule can comprise the sequence for one or more regulatory elements (e.g., Woodchuck Hepatitis Virus (WHV) Posttranscriptional Regulator Element (WPRE), triplex from MALAT1, the PRE of Hepatitis B virus (HPRE), and an iron response element). For example, a disclosed regulatory element can comprise a promoter operably linked to a disclosed nucleic acid molecule, wherein the promoter drives the expression of a disclosed variant capsid protein, a disclosed encoded polypeptide, a disclosed encoded therapeutic agent, or both. In an aspect, regulatory elements can refer to promoters, enhancers, internal ribosomal entry sites (IRES), and other expression control elements (e.g., transcription termination signals, such as polyadenylation signals and poly-U sequences). Regulatory elements can include those that direct constitutive expression of a nucleotide sequence in many types of host cells and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences).

[0150] 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. In an aspect, an operably linked 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.

[0151] n an aspect, a disclosed promoter can be tissue-specific or ubiquitous and can be constitutive or inducible, depending on the pattern of the expression desired. A promoter can be native or foreign and can be a natural or a synthetic sequence. By foreign, it is intended that the transcriptional initiation region is not found in the wild-type host into which the transcriptional initiation region is introduced. In an aspect, a disclosed promoter can be a promoter / enhancer. In an aspect, a disclosed promoter for the disclosed nucleic acid molecule can be an endogenous promoter. In an aspect, a disclosed endogenous promoter can be an endogenous promoter / enhancer. In an aspect, a disclosed endogenous promoter or a disclosed endogenous promoter / enhancer can generally be obtained from a non-coding region upstream of a transcriptioninitiation site of a gene of interest. In an aspect, a disclosed endogenous promoter or a disclosed endogenous promoter / enhancer can be used for constitutive and efficient expression of a disclosed protein coding gene (see, e.g., those in Table 2). In an aspect, a disclosed promoter for the one or more disclosed guide RNA sequences can be a CMV promoter or a CMV promoter / enhancer. CMV promoters and CMV promoters / enhancers are well known to the art. In an aspect, a disclosed promoter for the one or more disclosed guide RNA sequences can be any eukaryotic RNA polymerase II promoter.

[0152] In an aspect, a disclosed nucleic acid molecule can be packaged into a viral vector. In an aspect, a disclosed viral vector can comprise a lentiviral vector. In an aspect, a disclosed viral vector can comprise an AAV vector. In an aspect, a disclosed nucleic acid molecule can be packaged into a non-viral carrier. In an aspect, a disclosed nucleic acid molecule can be incorporated into a plasmid. In an aspect, a disclosed nucleic acid molecule can be incorporated into lipid nanoparticles.

[0153] In an aspect, a disclosed promoter can be tissue-specific or ubiquitous and can be constitutive or inducible, depending on the pattern of the expression desired. A promoter can be native or foreign and can be a natural or a synthetic sequence. By foreign, it is intended that the transcriptional initiation region is not found in the wild-type host into which the transcriptional initiation region is introduced. In an aspect, a disclosed promoter can be a promoter / enhancer. In an aspect, a disclosed promoter for the disclosed nucleic acid molecule can be an endogenous promoter. In an aspect, a disclosed endogenous promoter can be an endogenous promoter / enhancer. In an aspect, a disclosed endogenous promoter or a disclosed endogenous promoter / enhancer can generally be obtained from a non-coding region upstream of a transcription initiation site of a gene of interest. In an aspect, a disclosed endogenous promoter or a disclosed endogenous promoter / enhancer can be used for constitutive and efficient expression of a disclosed gene. In an aspect, a disclosed promoter for the one or more disclosed guide RNA sequences can be a CMV promoter or a CMV promoter / enhancer. CMV promoters and CMV promoters / enhancers are well known to the art. In an aspect, a disclosed promoter for the one or more disclosed guide RNA sequences can be any eukaryotic RNA polymerase II promoter.

[0154] In an aspect, a targeted endogenous mRNA can be related to a large gene. Large genes are known to the skilled person and include, but are not limited to, the following: ABCA1, ABCA12, ABCA13, ABCA2, ABCA3, ABCA4, ABCA5, ABCC1, ABCC2, ABCC6, ABCC8, ABCC9, ACAN, ADAMTS13, ADCY10, ADGRV1, AGL, AGRN, AHDC1, ALK, ALMS1, ALPK3, ALS2, ANAPC1, ANK1, ANK2, ANK3, ANKRD11, ANKRD26, APC, APC2, APOB, ARFGEF2, ARHGAP31, ARHGEF10, ARHGEF18, ARID1A, ARID1B, ARID2, ASH1L, ASPM, ASXL1, ASXL2, ASXL3, ATM, ATP7A, ATP7B, ATR, ATRX, BAZ1A, BAZ2B, BCOR, BCORL1, BDP1, BLM, BPTF,BRCA1, BRCA2, BRD4, BRWD3, C2CD3, C3, C5, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1S, CAD, CAMTA1, CARMIL2, CC2D2A, CCDC88A, CCDC88C, CCNB3, CDH23, CDK13, CDK5RAP2, CELSR1, CEMIP2, CENPE, CENPF, CENPJ, CEP152, CEP164, CEP250, CEP290, CFAP43, CFAP44, CFAP65, CFTR / ABCC7, CHD1, CHD2, CHD3, CHD4, CHD7, CHD8, CIC, CIT, CLIP1, CLTC, CNOT1, CNTNAP1, COL11A1, COL11A2, COL12A1, COL17A1, COL18A1, COL1A1, COL1A2, COL27A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL6A3, COL7A1, CPAMD8, CPLANE1, CPS1, CPSF1, CRB1, CREBBP, CUBN, CUL7, CUX1, DCC, DCHS1, DEPDC5, DICER1, DIP2B, DLC1, DMD, DMXL2, DNAH1, DNAH11, DNAH17, DNAH2, DNAH5, DNAH7, DNAH8, DNAH9, DNMBP, DNMT1, DOCK2, DOCK3, DOCK6, DOCK7, DOCK8, DSCAM, DSP, DST, DUOX2, DYNC1H1, DYNC2H1, DYSF, EIF2AK4, EP300, EPG5, ERCC6, ERCC6L2, EXPH5, EYS, F5, F8, FANCA, FANCD2, FANCM, FAT1, FAT4, FBN1, FBN2, FLG, FLG2, FLNA, FLNB, FLNC, FLT4, FMN2, FN1, FRAS1, FREM1, FREM2, FSIP2, FYCO1, GLI2, GLI3, GPR179, GREB1L, GRIN2A, GRIN2B, GRIN2D, HCFC1, HECW2, HERC1, HERC2, HFM1, HIVEP1, HIVEP2, HMCN1, HSPG2, HTT, HUWE1, HYDIN, IFT140, IFT172, IGF1R, IGF2R, IGSF1, INSR, INTS1, IQSEC2, ITGB4, ITPR1, ITPR2, JMJD1C, KALRN, KANK1, KAT6A, KAT6B, KDM3B, KDM5B, KDM5C, KDM6A, KDM6B, 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, LCT, LOXHD1, LPA, LRBA, LRP1, LRP2, LRP4, LRP5, LRP6, LRPPRC, LRRK1, LRRK2, LTBP2, LTBP4, LYST, MACF1, MADD, MAGI2, MAP1B, MAP3K1, MAPK8IP3, MAPKBP1, MAST1, MBD5, MCM3AP, MED12, MED12L, MED13, MED13L, MED23, MEGF8, MET, MLH3, MPDZ, MSH6, MTOR, MYH10, MYH11, MYH14, MYH2, MYH3, MYH6, MYH7, MYH7B, MYH8, MYH9, MYLK, MYO15A, MYO18B, MYO3A, MYO5A, MYO5B, MYO7A, MYO9A, NALCN, NBAS, NBEA, NBEAL2, NCAPD2, NCAPD3, NEB, NEXMIF, NEXMIF, NF1, NFASC, NHS, NIN, NIPBL, NLRP1, NOTCH1, NOTCH2, NOTCH3, NPHP4, NRXN1, NRXN3, NSD1, NSD2, NUP155, NUP188, NUP205, OBSCN, OBSL1, OTOF, OTOG, OTOGL, PARD3, PBRM1, PCDH15, PCLO, PCNT, PHIP, PI4KA, PIEZO1, PIEZO2, PIK3C2A, PIKFYVE, PKD1, PKD1L1, PKHD1, PLCE1, PLEC, PLEKHG2, PNPLA6, POGZ, POLA1, POLE, POLR1A, POLR2A, POLR3A, PRG4, PRKDC, PRPF8, PRR12, PRX, PTCH1, PTPN23, PTPRF, PTPRJ, PTPRQ, PXDN, QRICH2, RAB3GAP2, RAI1, RALGAPA1, RANBP2, RB1CC1, RELN, RERE, REV3L, RIC1, RIMS1, RIMS2, RNF213, ROBO1, ROBO2, ROBO3, ROS1, RP1, RP1L1, RTTN, RUSC2, RYR1, RYR2, SACS, SAMD9, SAMD9L, SBF2, SCAPER, SCN10A, SCN11A, SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SETBP1, SETD1A, SETD1B, SETD2, SETD5, SETX, SHANK2, SHANK3, SHROOM4,SI, SIPA1L3, SLIT2, SLX4, SMARCA2, SMARCA4, SMCHD1, SNRNP200, SON, SPEF2, SPEG, SPG11, SPTA1, SPTAN1, SPTB, SPTBN2, SPTBN4, SRCAP, STRC, SVIL, SYNE1, SYNGAP1, SYNJ1, SZT2, TAF1, TANC2, TCF20, TCOF1, TDRD9, TECPR2, TECTA, TENM3, TENM4, TET3, TEX14, TEX15, TG, THOC2, TMEM94, TNC, TNIK, TNR, TNRC6B, TNXB, TOGARAM1, TONSL, TRIO, TRIOBP, TRIP11, TRIP12, TRPM1, TRPM6, TRPM7, TRRAP, TSC2, TTC37, TTN, TUBGCP6, UBR1, UNC80, USH2A, USP9X, VCAN, VPS13A, VPS13B, VPS13C, VPS13D, VWF, WDFY3, WDR19, WDR62, WDR81, WNK1, WRN, ZFHX2, ZFYVE26, ZNF142, ZNF292, ZNF335, ZNF407, ZNF462, and ZNF469.

[0155] In an aspect, a disclosed method can be particularly useful in treating a subject having an autosomal dominant genetic disease or disorder (such as, for example, progeria, achondroplasia, antithrombin III deficiency, Ehlers-Danlos syndrome, Gilbert’s disease, hereditary hemorrhagic telangiectasia, hereditary elliptosis, hereditary spherocytosis, Huntington’s disease, idiopathic hypoparathyroidism, intestinal polyposis, marble bone disease, Marfan’s syndrome, neurofibromatosis, polycystic kidney disease (adult), protein C deficiency, osteogenesis imperfecta, Treacher Collins syndrome, tuberous sclerosis, Von Willebrand’s disease, etc.) 4. Expression Cassettes

[0156] Disclosed herein is an expression cassette comprising a disclosed nucleic acid sequence and one or more regulatory elements. Disclosed herein is an expression cassette comprising a disclosed nucleic acid sequence comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, and one or more regulatory elements. Disclosed herein is an expression cassette comprising a disclosed nucleic acid sequence comprising one or more non- coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, and one or more regulatory elements. Disclosed herein is an expression cassette comprising a disclosed nucleic acid sequence comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, and one or more regulatory elements.

[0157] In an aspect of a disclosed expression cassette, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ IDNO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect of a disclosed expression cassette, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0158] In an aspect of a disclosed expression cassette, a disclosed non-coding viral RNA sequence comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0159] Disclosed herein is an expression cassette comprising a disclosed nucleic acid sequence comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, and one or more regulatory elements. Disclosed herein is an expression cassette comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, and one or more regulatory elements. Disclosed herein is an expression cassette comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, and one or more regulatory elements. In an aspect of a disclosed expression cassette, a disclosed RNA sequence can comprise the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ IDNO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0160] In an aspect of a disclosed expression cassette, a disclosed non-coding viral RNA sequence comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans- splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de- stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0161] Disclosed herein is an expression cassette comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, and one or more regulatory elements. Disclosed herein is an expression cassette comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, and one or more regulatory elements. Disclosed herein is an expression cassette comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, and one or more regulatory elements.

[0162] In an aspect of a disclosed expression cassette, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect of a disclosed expression cassette, a disclosed cDNA sequence cancomprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0163] In an aspect of a disclosed expression cassette, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre- mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans- splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0164] Disclosed herein is an expression cassette comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, and one or more regulatory elements. Disclosed herein is an expression cassette comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, and one or more regulatory elements. Disclosed herein is an expression cassette comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, and one or more regulatory elements

[0165] In an aspect of a disclosed expression cassette, a disclosed non-coding viral RNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0166] In an aspect of a disclosed expression cassette, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 –SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0167] Disclosed herein is an expression cassette comprising a non-coding viral RNA sequence comprising a structure set forth in Table 1, and one or more regulatory elements. Disclosed herein is an expression cassette comprising a non-coding viral RNA sequence comprising the structure of any one of Candidate 25 – Candidate 48, and one or more regulatory elements. In an aspect, a disclosed non-coding viral RNA sequence can be obtained from and / or associated with Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, or Filo_Bundibugyo7_40. In an aspect, a disclosed non-coding viral RNA sequence can comprise Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, Filo_Bundibugyo7_40, or any combination thereof. 5. Transcriptome Engineering Systems

[0168] Disclosed herein is a transcriptome engineering system comprising one or more of (i) a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; (ii) a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; or (iii) a nucleic acid molecule, comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNAtargeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; wherein the nucleic acid molecule enables the 3’ replacement or the 5’ replacement of the targeted endogenous pre-mRNA.

[0169] In an aspect of a disclosed transcriptome engineering system, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect of a disclosed transcriptome engineering system, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0170] In an aspect of a disclosed transcriptome engineering system, a disclosed non-coding viral RNA sequence comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans- splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0171] Disclosed herein is a transcriptome engineering system comprising one or more of (i) a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; (ii) a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; or (iii) a nucleic acid molecule, comprising an exogenoussequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 3’ replacement or the 5’ replacement of the targeted endogenous pre-mRNA. In an aspect of a disclosed transcriptome engineering system, a disclosed RNA sequence can comprise the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0172] In an aspect of a disclosed transcriptome engineering system, a disclosed non-coding viral RNA sequence comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0173] Disclosed herein is a transcriptome engineering system comprising one or more of (i) a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; (ii) a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; or (iii) a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre- mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the nucleic acid molecule enables the 3’ replacement or the 5’ replacement of the targeted endogenous pre-mRNA.

[0174] In an aspect of a disclosed transcriptome engineering system, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect of a disclosed transcriptome engineering system, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0175] In an aspect of a disclosed transcriptome engineering system, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans- splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de- stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0176] Disclosed herein is a transcriptome engineering system comprising one or more of (i) a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; (ii) a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; or (iii) a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targetedendogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 3’ replacement or the 5’ replacement of the targeted endogenous pre-mRNA.

[0177] In an aspect of a disclosed transcriptome engineering system, a disclosed non-coding viral RNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0178] In an aspect of a disclosed transcriptome engineering system, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. Overall, described herein is a transcriptome engineering system for modulating RNA editing and / or the efficiency of RNA editing. For example, disclosed herein are composition and methods for modulating mRNA trans- splicing efficiency of pre-trans-splicing RNA.

[0179] Disclosed herein is a transcriptome engineering system comprising one or more non- coding viral RNA sequences comprising a structure set forth in Table 1. Disclosed herein is a transcriptome engineering system comprising one or more non-coding viral RNA sequences comprising the structure of any one of Candidate 25 – Candidate 48. In an aspect, a disclosed non-coding viral RNA sequence can be obtained from and / or associated with Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, or Filo_Bundibugyo7_40. In an aspect, a disclosed non-coding viral RNA sequence can comprise Paramyxo_Measles_4_42,Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, Filo_Bundibugyo7_40, or any combination thereof. 6. Vectors

[0180] Disclosed herein is a vector comprising a disclosed nucleic acid molecule. Disclosed herein is a non-viral vector comprising a disclosed nucleic acid molecule. Disclosed herein is a non-viral vector comprising one or more disclosed nucleic acid molecules. Disclosed herein is a non-viral vector comprising one or more 5’ replacement constructs. Disclosed herein is a non- viral vector comprising one or more 3’ replacement constructs. Disclosed herein is a non-viral comprising one or more 5’ replacement constructs and / or one or more 3’ replacement constructs. Disclosed herein is a viral vector comprising a disclosed nucleic acid molecule. Disclosed herein is a viral vector comprising one or more disclosed nucleic acid molecules. Disclosed herein is a viral vector comprising one or more 5’ replacement constructs. Disclosed herein is a viral vector comprising one or more 3’ replacement constructs. Disclosed herein is a viral comprising one or more 5’ replacement constructs and / or one or more 3’ replacement constructs. Disclosed herein is a non-viral vector comprising a disclosed expression cassette. Disclosed herein is a non-viral vector comprising one or more disclosed expression cassettes. Disclosed herein is a viral vector comprising a disclosed expression cassette. Disclosed herein is a viral vector comprising one or more disclosed expression cassettes.

[0181] Disclosed herein is a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a vector comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698.

[0182] In an aspect of a disclosed vector, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ IDNO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect of a disclosed vector, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0183] In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0184] Disclosed herein is a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a vector comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. In an aspect of a disclosed vector, a disclosed RNA sequence can comprise the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0185] In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence comrpising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0186] Disclosed herein is a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a vector comprising a nucleic acid molecule comprising one or more non- coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a vector comprising a nucleic acid molecule comprising an exogenous sequence to be trans- spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698.

[0187] In an aspect of a disclosed vector, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect of a disclosed vector, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ IDNO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0188] In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0189] Disclosed herein is a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA. Disclosed herein is a vector comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0190] In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect ofa disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0191] Disclosed herein is a vector comprising a nucleic acid molecule comprising a non-coding viral RNA sequence comprising a structure set forth in Table 1. Disclosed herein is a vector comprising a nucleic acid molecule comprising a non-coding viral RNA sequence comprising the structure of any one of Candidate 25 – Candidate 48. In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence can be obtained from and / or associated with Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, or Filo_Bundibugyo7_40. In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence can comprise Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, Filo_Bundibugyo7_40, or any combination thereof.

[0192] Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0193] Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre- mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non- coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0194] In an aspect of a disclosed vector, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect of a disclosed vector, a disclosed cDNA sequence can comprise the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0195] In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i)improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0196] Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre- mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0197] Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre- mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0198] In an aspect of a disclosed vector, a disclosed RNA sequence can comprise the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ IDNO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0199] In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0200] Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans- spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0201] Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacementconstruct comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre- mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0202] In an aspect of a disclosed vector, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect of a disclosed vector, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0203] In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0204] Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731.Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans- spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0205] Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0206] In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0207] In an aspect of a disclosed vector, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 in a nucleic acid molecule can modulate RNA trans-splicing efficiency. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii)stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect of a disclosed vector, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0208] Disclosed herein is a vector comprising a nucleic acid molecule encoding a replacement construct comprising a non-coding viral RNA sequence comprising a structure set forth in Table 1. Disclosed herein is a replacement construct comprising a nucleic acid molecule comprising a non-coding viral RNA sequence comprising the structure of any one of Candidate 25 – Candidate 48. In an aspect, a disclosed non-coding viral RNA sequence can be obtained from and / or associated with Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, or Filo_Bundibugyo7_40. In an aspect, a disclosed non-coding viral RNA sequence can comprise Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, Filo_Bundibugyo7_40, or any combination thereof.

[0209] In an aspect, a disclosed vector can comprise one or more replacement constructs. In an aspect, a disclosed vector can comprise one or more 5’ replacement constructs and / or 3’ replacement constructs. In an aspect, a disclosed 3’ replacement construct to be used in combination with one or more other 3’ replacement constructs. In an aspect, a disclosed 5’ replacement construct to be used in combination with one or more other 5’ replacement constructs. In an aspect, one or more disclosed 3’ replacement constructs can be used in combination with one or more disclosed 5’ replacement constructs.

[0210] In an aspect, a disclosed non-viral vector can be a polymer-based vector, a peptide-based vector, a lipid nanoparticle, a solid lipid nanoparticle, or a cationic lipid-based vector. In an aspect, a disclosed vector can comprise exosomes, extracellular vesicles, and virus like particles.

[0211] In an aspect, a disclosed viral vector can be an adenovirus vector, an AAV vector, a herpes simplex virus vector, a retrovirus vector, a lentivirus vector, and alphavirus vector, a Flavivirus vector, a rhabdovirus vector, a measles virus vector, a Newcastle disease viral vector, a poxvirusvector, or a picornavirus vector. In an aspect, a disclosed nucleic acid sequence can have a coding sequence that is less than about 4.5 kilobases.

[0212] In an aspect, a disclosed recombinant viral vector can be a recombinant adenovirus vector, a recombinant AAV vector, a recombinant herpes simplex virus vector, a recombinant retrovirus vector, a recombinant lentivirus vector, and a recombinant alphavirus vector, a recombinant Flavivirus vector, a recombinant rhabdovirus vector, a recombinant measles virus vector, a recombinant Newcastle disease viral vector, a recombinant poxvirus vector, or a recombinant picornavirus vector. In an aspect, a disclosed nucleic acid sequence can have a coding sequence that is less than about 4.5 kilobases.

[0213] In an aspect, a disclosed AAV vector can include naturally isolated serotypes including, but not limited to, AAV1, AAV2, AAV3 (including 3a and 3b), AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAV9, AAV10, AAVrh10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV17, AAV18, AAV19, AAV20, AAV21, AAV22, AAV23, AAV24-30, AAV31,AAV37, AAV40, AAV41, AdHu2, AdHu 3, AdHu4, AdHu24, AdHu26, AdHu34, AdHu35, AdHu36, AdHu37, AdHu41, AdHu48, AdHu49, AdHu50, AdC6, AdC7, AdC69, AAVrh39, AAVrh43, AAVcy.7 as well as bovine AAV, caprine AAV, canine AAV, equine AAV, ovine AAV, avian AAV, primate AAV, non-primate AAV, and any other virus classified by the International Committee on Taxonomy of Viruses (ICTV) as an AAV. In an aspect, an AAV capsid can be a chimera either created by capsid evolution or by rational capsid engineering from a naturally isolated AAV variants to capture desirable serotype features such as enhanced or specific tissue tropism and / or a host immune response escape. Naturally isolated AAV variants include, but not limited to, AAV-DJ, AAV-DJ / 8, AAV-MG, AAV2.7m8, AAV2-QuadYF, AAV- HAE1, AAV-HAE2, AAVM41, AAV-BI30, AAV-1829, AAV2 Y / F, AAV2 T / V, AAV2i8, AAV2.5, AAV9.45, AAV9.61, AAV-B1, AAV-AS, AAV9.45A-String (e.g., AAV9.45-AS), AAV9.45Angiopep, AAV9.47-Angiopep, and AAV9.47-AS, AAV-PHP.B, AAV-PHP.eB, AAV-PHP.S, AAV-F, AAVcc.47, and AAVcc.81. In an aspect, a disclosed AAV vector can be AAV-Rh74 or a related variant (e.g., capsid variants like RHM4-1). In an aspect, a disclosed AAV vector can be a self-complementary AAV.

[0214] In an aspect, a disclosed vector can comprise one or more ITRs. In an aspect of a disclosed vector, a disclosed nucleic acid molecule or a disclosed expression cassette can be flanked by one or more AAV inverted terminal repeat (ITR) sequences. In an aspect, disclosed ITRs can be ITRs from any disclosed AAV. In an aspect, disclosed AAV ITRs can be ITRs from AAV1, AAV2, AAV3 (including 3a and 3b), AAV4, AAV5, AAV6, AAV7, AAV8, AAVrh8, AAV9, AAV10, AAVrh10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV17, AAV18, AAV19, AAV20, AAV21, AAV22, AAV23, AAV24-30, AAV31,AAV37, AAV40, AAV41, AdHu2,AdHu 3, AdHu4, AdHu24, AdHu26, AdHu34, AdHu35, AdHu36, AdHu37, AdHu41, AdHu48, AdHu49, AdHu50, AdC6, AdC7, AdC69, AAVrh39, AAVrh43, AAVcy.7 as well as bovine AAV, caprine AAV, canine AAV, equine AAV, ovine AAV, avian AAV, primate AAV, non- primate AAV, and any other virus classified by the International Committee on Taxonomy of Viruses (ICTV) as an AAV. In an aspect, disclosed AAV ITRs can be ITRs from AAV-DJ, AAV- DJ / 8, AAV-MG, AAV2.7m8, AAV2-QuadYF, AAV-HAE1, AAV-HAE2, AAVM41, AAV- BI30, AAV-1829, AAV2 Y / F, AAV2 T / V, AAV2i8, AAV2.5, AAV9.45, AAV9.61, AAV-B1, AAV-AS, AAV9.45A-String (e.g., AAV9.45-AS), AAV9.45Angiopep, AAV9.47-Angiopep, and AAV9.47-AS, AAV-PHP.B, AAV-PHP.eB, AAV-PHP.S, AAV-F, AAVcc.47, and AAVcc.81

[0215] In an aspect, a disclosed vector can further comprise stuffer nucleic acid.

[0216] In an aspect, a disclosed vector can further comprise one or more nuclear localization signals (NLS). NLS are known to the skilled person in the art. In an aspect, a disclosed NLS can comprise any NLS known to the art. As known to the art (see, e.g., Lu J, et al. (2021) Cell Commun Signal. 19:60, which is incorporated herein by reference for its teachings of NLS), nuclear localization signals (NLS) are generally short peptides that act as a signal fragment that mediates the transport of proteins from the cytoplasm into the nucleus.

[0217] In an aspect, a disclosed vector can further comprise one or more nuclear retention elements (NRE). NRE are known to the skilled person in the art. In an aspect, a disclosed NRE can comprise SIRLOIN or BORG.

[0218] In an aspect, a disclosed vector can further comprise one or more Flavivirus genetic elements. In an aspect, Flavivirus genetic elements can comprise one or more Flavivirus 3’ untranslated region (3’ UTR), one or more subgenomic Flavivirus RNA (sfRNA) elements, one or more Flavivirus XRN1-resistant RNA (xrRNA) elements, one or more Flavivirus dumbbell (DB) RNA elements, one or more Flavivirus 3’ stem loop (3’ SL) elements, or any combination thereof. (See WO 2022 / 182835 for a description of Flavivirus gene elements).

[0219] In an aspect, a disclosed vector can further comprise a nucleic acid sequence encoding a therapeutic protein, a therapeutic agent, and / or a therapeutic RNA. In an aspect, a disclosed therapeutic protein can comprise a polypeptide and / or a glycopeptide. In an aspect, a disclosed therapeutic agent can comprise an oligonucleotide therapeutic agent. In an aspect, a disclosed oligonucleotide therapeutic agent can be a single-stranded or double-stranded DNA, iRNA, shRNA, siRNA, mRNA, non-coding RNA (ncRNA), an antisense molecule, miRNA, a morpholino, a peptide-nucleic acid (PNA), or an analog or conjugate thereof. In an aspect, a disclosed therapeutic agent can be an ASO or an RNAi. In an aspect, a disclosed therapeutic agent can comprise a CRISPR-based endonuclease (e.g., Cas9). In an aspect, a disclosed CRISPR-based endonuclease can be derived from a CRISPR / Cas type I, type II, or type III system.

[0220] In an aspect, a disclosed therapeutic RNA can comprise ribosomal RNA (rRNA), transfer RNA (tRNA), heterogeneous nuclear RNA (hnRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), micro RNA (miRNA), Piwi-interacting RNA (piRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), singe guide RNA (sgRNA), non-coding RNA (ncRNA), long non-coding RNA (lncRNA), 7SL, Xist, short enhancer RNA (eRNA), circular RNA, intergenic RNA, or any combination thereof. In an aspect, a disclosed RNA can comprise lncRNA, siRNA, shRNA, sgRNA, circular RNA, snoRNA, miRNA, or any combination thereof. In an aspect, a disclosed encoded RNA can comprise a functional non-coding RNA element.

[0221] In an aspect, a disclosed vector can comprise one or more promoters operably linked to a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans- splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced. In an aspect of a disclosed vector, a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced can be operably linked to one or more transcription regulatory elements. In an aspect, the one or more transcription regulatory elements (e.g., Woodchuck Hepatitis Virus (WHV) Posttranscriptional Regulator Element (WPRE), triplex from MALAT1, the PRE of Hepatitis B virus (HPRE), and an iron response element) can increase the transcription and / or expression of a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced. In an aspect, a disclosed promoter can be positioned 5’ (upstream) or 3’ (downstream) of a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans- spliced under its control. The distance between a disclosed promoter and a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced can be approximately the same as the distance between that promoter and to the disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced under its control. As is known in the art, variation in this distance can be accommodated without loss of promoter function.

[0222] In an aspect of a disclosed vector, a disclosed promoter can be tissue-specific or ubiquitous and can be constitutive or inducible, depending on the pattern of the expression desired. A disclosed promoter can be native or foreign and can be a natural or a synthetic sequence. By foreign, it is intended that the transcriptional initiation region is not found in the wild-type host into which the transcriptional initiation region is introduced. In an aspect, a disclosed promoter can be a promoter / enhancer. In an aspect, a disclosed promoter for a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced can be an endogenous promoter. In an aspect, a disclosed endogenous promoter can be an endogenous promoter / enhancer. In an aspect, a disclosed endogenous promoter or a disclosed endogenous promoter / enhancer can generally be obtained from a non-coding region upstream of a transcription initiation site of a gene of interest. In an aspect, a disclosed endogenous promoter or a disclosed endogenous promoter / enhancer can be used for constitutive and efficient expression of a disclosed protein coding gene (including those disclosed herein and including those large genes disclosed herein). In an aspect, a disclosed promoter for a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced can be a CMV promoter or a CMV promoter / enhancer. CMV promoters and CMV promoters / enhancers are well known to the art. In an aspect, a disclosed promoter for a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced can be any eukaryotic RNA polymerase II promoter.

[0223] In an aspect, a disclosed tissue-specific promoter can comprise a neuron-specific promoter, a muscle-specific promoter, a liver-specific promoter, a skeletal muscle-specific promoter, and a heart-specific promoter. In an aspect, a disclosed liver-specific promoter can comprise the thyroxin binding globulin (TBG) promoter, the α1-microglobulin / bikunin enhancer / thyroid hormone-binding globulin promoter, the human albumin (hALB) promoter, the thyroid hormone- binding globulin promoter, the α-1-anti-trypsin promoter, the bovine albumin (bAlb) promoter, the murine albumin (mAlb) promoter, the human α1-antitrypsin (hAAT) promoter, the ApoEhAAT promoter comprising the ApoE enhancer and the hAAT promoter, the transthyretin (TTR) promoter, the liver fatty acid binding protein promoter, the hepatitis B virus (HBV) promoter, the DC172 promoter comprising the hAAT promoter and the α1-microglobulin enhancer, the DC190 promoter comprising the human albumin promoter and the prothrombin enhancer, or any other natural or synthetic liver-specific promoter. In an aspect, a disclosed liverspecific promoter can comprise about 845-bp and comprise the thyroid hormone-binding globulin promoter sequences (2382 to 13), two copies of α1-microglobulin / bikunin enhancer sequences (22,804 through 22,704), and a 71-bp leader sequence as described by Ill CR, et al. (1997). In an aspect, a disclosed ubiquitous / constitutive promoters can comprise a CMV major immediate-early enhancer / chicken beta-actin promoter, a cytomegalovirus (CMV) major immediate-early promoter, an Elongation Factor 1-α (EF1-α) promoter, a simian vacuolating virus 40 (SV40) promoter, an AmpR promoter, a PγK promoter, a human ubiquitin C gene (Ubc) promoter, a MFG promoter, a human beta actin promoter, a CAG promoter, a EGR1 promoter, a FerH promoter, a FerL promoter, a GRP78 promoter, a GRP94 promoter, a HSP70 promoter, a β-kin promoter, a murine phosphoglycerate kinase (mPGK) or human PGK (hPGK) promoter, a ROSA promoter, human Ubiquitin B promoter, a Rous sarcoma virus promoter, or any other natural or synthetic ubiquitous / constitutive promoters. In an aspect, a disclosed inducible promoter can comprise a promoter that can be regulated by positive or negative control. Factors that can regulate an inducible promoter include, but are not limited to, chemical agents (e.g., the metallothionein promoter or a hormone inducible promoter), temperature, and light.

[0224] In an aspect, a disclosed AAV vector can be used to generate AAV particles. In an aspect, a disclosed AAV vector can be used to generate AAV particles comprising a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced under its control. In an aspect, a disclosed lentiviral vector can be used to generate lentiviral particles. In an aspect, a disclosed lentiviral vector can be used to generate lentiviral particles comprising a disclosed nucleic acid molecule and / or a disclosed nucleic acid sequence, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed non-coding viral RNA sequence, a disclosed transgene, and / or a disclosed sequence to be trans-spliced under its control.

[0225] In an aspect, a disclosed vector can be formulated for administration via one or more routes. Such methods are well known to those skilled in the art and include, but are not limited to, the following routes: oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, in utero administration, intrahepatic administration, intravaginal administration, ophthalmic administration, intraaural administration, otic administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-CSF administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can also include hepatic intra- arterial administration or administration through the hepatic portal vein (HPV). Administrationof a disclosed therapeutic agent, a disclosed pharmaceutical composition, or a combination thereof can comprise administration directly into the CNS (e.g., intraparenchymal, intracerebroventricular, intrathecal cisternal, intrathecal (lumbar), deep gray matter delivery, convection-enhanced delivery to deep gray matter) or the PNS. Administration can be continuous or intermittent. Administration can comprise administering a viral vector and / or generated optimized viral vector. Administration of a disclosed vector can be continuous or intermittent.

[0226] In an aspect, a disclosed AAV or a disclosed lentiviral particle or a disclosed AAV vector or a disclosed lentiviral vector can be particularly useful in a method of treating a subject having an autosomal dominant genetic disease or disorder (such as, for example, progeria, achondroplasia, antithrombin III deficiency, Ehlers-Danlos syndrome, Gilbert’s disease, hereditary hemorrhagic telangiectasia, hereditary elliptosis, hereditary spherocytosis, Huntington’s disease, idiopathic hypoparathyroidism, intestinal polyposis, marble bone disease, Marfan’s syndrome, neurofibromatosis, polycystic kidney disease (adult), protein C deficiency, osteogenesis imperfecta, Treacher Collins syndrome, tuberous sclerosis, Von Willebrand’s disease, etc.)

[0227] In an aspect, a disclosed vector can modulate RNA trans-splicing efficiency and / or can modulate expression and / or activity of one or more genes of interest. In an aspect, modulating can comprise increasing and / or decreasing RNA trans-splicing efficiency and / or increasing and / or decreasing expression and / or activity of one or more genes of interest (e.g., targeted genes). 7. Pharmaceutical Formulations

[0228] Disclosed herein is a pharmaceutical formulation comprising a disclosed nucleic acid molecule and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a disclosed vector and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a disclosed AAV particle and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a disclosed lentiviral particle and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a non-viral vector comprising one or more 5’ replacement constructs, one or more 3’ replacement constructs, or one or more 5’ replacement constructs and / or one or more 3’ replacement constructs, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a viral vector comprising one or more 5’ replacement constructs, one or more 3’ replacement constructs, or one or more 5’ replacement constructs and / or one or more 3’ replacement constructs, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a non-viral vector comprising oneor more disclosed expression cassettes, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising one or more disclosed expression cassettes, and one or more pharmaceutically acceptable carriers and / or excipients.

[0229] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, and one or more pharmaceutically acceptable carriers and / or excipients.

[0230] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre- mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, and one or more pharmaceutically acceptable carriers and / or excipients.

[0231] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non- coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, and one or more pharmaceutically acceptable carriers and / or excipients.

[0232] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans- spliced to a targeted endogenous pre-mRNA, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, and one or more pharmaceutically acceptable carriers and / or excipients.

[0233] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans- spliced to a targeted endogenous pre-mRNA, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, and one or more pharmaceutically acceptable carriers and / or excipients.

[0234] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising a non-coding viral RNA sequence comprising a structure set forth in Table 1, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed hereinis a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule comprising a non-coding viral RNA sequence comprising the structure of any one of Candidate 25 – Candidate 48, and one or more pharmaceutically acceptable carriers and / or excipients.

[0235] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients.

[0236] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients.

[0237] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients.

[0238] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre- mRNA and the 3’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients.

[0239] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceuticalformulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients.

[0240] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans- spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre- mRNA and the 5’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients.

[0241] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viralRNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein (i) the replacement construct enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA; or (ii) the replacement construct molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients.

[0242] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising an exogenous sequence to be trans- spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA, and one or more pharmaceutically acceptable carriers and / or excipients.

[0243] Disclosed herein is a pharmaceutical formulation comprising a vector comprising a nucleic acid molecule encoding a replacement construct comprising a non-coding viral RNA sequence comprising a structure set forth in Table 1, and one or more pharmaceutically acceptable carriers and / or excipients. Disclosed herein is a pharmaceutical formulation comprising a replacement construct comprising a nucleic acid molecule comprising a non-coding viral RNA sequence comprising the structure of any one of Candidate 25 – Candidate 48, and one or more pharmaceutically acceptable carriers and / or excipients. In an aspect, a disclosed pharmaceutical formulation can comprise (i) one or more active agents, (ii) biologically active agents, (iii) one or more pharmaceutically active agents, (iv) one or moreimmune-based therapeutic agents, (v) one or more clinically approved agents, or (vi) a combination thereof. In an aspect, a disclosed composition can comprise one or more immune modulators. In an aspect, a disclosed composition can comprise one or more proteasome inhibitors. In an aspect, a disclosed composition can comprise one or more immunosuppressives or immunosuppressive agents. In an aspect, an immunosuppressive agent can be anti-thymocyte globulin (ATG), cyclosporine (CSP), mycophenolate mofetil (MMF), or a combination thereof. In an aspect, a disclosed formulation can comprise an anaplerotic agent (such as, for example, C7 compounds like triheptanoin or MCT). In an aspect, immune modulator refers to an agent that is capable of adjusting a given immune response to a desired level (e.g., as in immunopotentiation, immunosuppression, or induction of immunologic tolerance). Examples of immune modulators include but are not limited to, a disclosed immune modulator can comprise aspirin, azathioprine, belimumab, betamethasone dipropionate, betamethasone valerate, bortezomib, bredinin, cyazathioprine, cyclophosphamide, cyclosporine, deoxyspergualin, didemnin B, fluocinolone acetonide, folinic acid, ibuprofen, IL6 inhibitors (such as sarilumab) indomethacin, inebilizumab, intravenous gamma globulin (IVIG), methotrexate, methylprednisolone, mycophenolate mofetil, naproxen, prednisolone, prednisone, prednisolone indomethacin, rapamycin, rituximab, sirolimus, sulindac, synthetic vaccine particles containing rapamycin (SVP-Rapamycin or ImmTOR), thalidomide, tocilizumab, tolmetin, triamcinolone acetonide, anti-CD3 antibodies, anti-CD4 antibodies, anti-CD19 antibodies, anti-CD20 antibodies, anti-CD22 antibodies, anti-CD40 antibodies, anti-FcRN antibodies, anti-IL6 antibodies, anti-IGF1R antibodies, an IL2 mutein, a BTK, or a combination thereof. In an aspect, a disclosed immune modulator can comprise one or more Treg (regulatory T cells) infusions (e.g., antigen specific Treg cells to AAV). In an aspect, a disclosed immune modulator can be bortezomib or SVP-Rapamycin.

[0244] In an aspect, a disclosed formulation can comprise an RNA therapeutic. In an aspect, a RNA therapeutics can refer to the use of oligonucleotides to target RNA. 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’-O-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 (lncRNA), 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 disclosedtherapeutic 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 that 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 known 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.

[0245] In an apect, an RNA therapeutic can comprise RNA-mediated interference (RNAi) and / or antisense oligonucleotides (ASO). In an aspect, a disclosed RNA therapeutic can be directed at any protein or enzyme that is overexpressed or is overactive due to a missing, deficient, and / or mutant protein or enzyme. In an aspect, a disclosed RNA therapeutic can comprise therapy delivered via LNPs. In an aspect, a disclosed formulation can comprise an enzyme or enzyme precursor for enzyme replacement therapy (ERT).

[0246] In an aspect, a disclosed formulation can comprise a disclosed small molecule. In an aspect, a disclosed small molecule can assist in restoring the functionality and / or structural integrity of a missing, deficient, and / or mutant protein or enzyme. In an aspect, small molecule can refer to any organic or inorganic material that is not a polymer. Small molecules exclude large macromolecules, such as large proteins (e.g., proteins with molecular weights over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000), large nucleic acids (e.g., nucleic acids with molecular weights of over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000), or large polysaccharides (e.g., polysaccharides with a molecular weight of over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000). In an aspect, a small molecule, for example, can be a drug that can enter cells easily because it has a low molecular weight. In an aspect, a small molecule can be used in conjunction with a disclosed composition in a disclosed method.

[0247] In an aspect, any disclosed pharmaceutical formulation can comprise one or more excipients and / or pharmaceutically acceptable carriers. Excipients and / or pharmaceutically acceptable carriers are known to the art and are discussed supra.

[0248] In an aspect, a therapeutically effective amount of a disclosed pharmaceutical formulation can comprise a range determined by a skilled person.

[0249] In an aspect, a disclosed pharmaceutical formulation can be used to restore and / or return expression of a disclosed protein coding gene (including those disclosed herein and includingthose large genes disclosed herein) to a wild-type, normal, or control expression level. In an aspect, a disclosed pharmaceutical formulation can restore one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation. In an aspect, a disclosed nucleic acid molecule can restore the functionality and / or structural integrity of a missing, deficient, and / or mutant protein or enzyme (such as those, for example, encoded by one of the genes provided supra). In an aspect, restoring one or more aspects of cellular homeostasis and / or cellular functionality can comprise one or more of the following: (i) correcting cell starvation in one or more cell types; (ii) normalizing aspects of the autophagy pathway (such as, for example, correcting, preventing, reducing, and / or ameliorating autophagy); (iii) improving, enhancing, restoring, and / or preserving mitochondrial functionality and / or structural 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 a genetic disease or disorder; (vii) reversing, inhibiting, preventing, stabilizing, and / or slowing the rate of progression of a genetic disease or disorder, or (viii) any combination thereof. In an aspect, restoring one or more aspects of cellular homeostasis can comprise improving, enhancing, restoring, and / or preserving one or more aspects of cellular structural and / or functional integrity.

[0250] In an aspect, restoring the activity and / or functionality of a missing, deficient, and / or mutant protein or enzyme can comprise a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any amount of restoration when compared to a pre-existing level such as, for example, a pre-treatment level. In an aspect, the amount of restoration can be 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% more than a pre-existing level such as, for example, a pre-treatment level. In an aspect, restoration can be measured against a control level or a reference level (e.g., determined, for example, using one or more subjects not having a missing, deficient, and / or mutant protein or enzyme). In an aspect, restoration can be a partial or incomplete restoration. In an aspect, restoration can be complete or near complete restoration such that the level of expression, activity, and / or functionality is similar to that of a wild-type or control level.

[0251] In an aspect, a disclosed pharmaceutical formulation can be particularly useful in a method of treating a subject having an autosomal dominant genetic disease or disorder (such as, for example, progeria, achondroplasia, antithrombin III deficiency, Ehlers-Danlos syndrome, Gilbert’s disease, hereditary hemorrhagic telangiectasia, hereditary elliptosis, hereditary spherocytosis, Huntington’s disease, idiopathic hypoparathyroidism, intestinal polyposis, marble bone disease, Marfan’s syndrome, neurofibromatosis, polycystic kidney disease (adult), protein C deficiency, osteogenesis imperfecta, Treacher Collins syndrome, tuberous sclerosis, VonWillebrand’s disease, etc.). In an aspect, a disclosed pharmaceutical formulation can modulate RNA trans-splicing efficiency and / or can modulate expression and / or activity of one or more genes of interest. In an aspect, modulating can comprise increasing and / or decreasing RNA trans- splicing efficiency and / or increasing and / or decreasing expression and / or activity of one or more genes of interest (e.g., targeted genes). 8. Plasmids

[0252] Disclosed herein is a plasmid comprising one or more disclosed nucleic acid molecules. Disclosed herein is a plasmid comprising one or more disclosed vectors. Disclosed here are plasmids used in methods of making a disclosed composition such as, for example, a disclosed nucleic acid molecule, a disclosed vector, or a disclosed pharmaceutical formulation. Plasmids and using plasmids are known to the art. 9. Cells

[0253] Disclosed herein are cells comprising a disclosed trans-splicing construct, a disclosed nucleic acid molecule, a disclosed vector, and / or a disclosed plasmid. Disclosed herein are cells transduced by one or more disclosed viral vectors. Disclosed herein are cells transfected with one or more disclosed nucleic acid molecules. Techniques to achieve transfection and transduction are known to the art and using transfected or transduced cells are known to the art. In an aspect, disclosed herein are human cells lines transduced by one or more disclosed viral vectors or transfected with one or more disclosed nucleic acids, one or more disclosed non-viral vectors, or one or more disclosed plasmids. In an aspect, disclosed herein are human cells lines having one or more genetic diseases or genetic disorders contacted with one or more disclosed trans-splicing constructs, one or more disclosed nucleic acid molecules, one or more disclosed vectors, and / or one or more disclosed pharmaceutical formulations. Disclosed herein are cells obtained for a subject treated with one or more disclosed trans-splicing constructs, one or more disclosed nucleic acid molecules, one or more disclosed vectors, one or more disclosed plasmids, and / or one or more disclosed pharmaceutical formulations. 10. Animals

[0254] Disclosed herein are animals treated with one or more disclosed trans-splicing constructs, one or more disclosed nucleic acid molecules, one or more disclosed vectors, one or more disclosed AAV particles, one or more disclosed pharmaceutical formulations, one or more disclosed plasmids, or any combination thereof. Transgenic animals are known to the art as are the techniques to generate transgenic animals. Disclosed herein are animals used to validate one or more disclosed trans-splicing constructs, one or more disclosed replacement constructs, one or more disclosed nucleic acid molecules, one or more disclosed AAV particles, one or more disclosed vectors, one or more disclosed pharmaceutical formulations.11. Libraries

[0255] Disclosed herein is a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the non-coding viral RNA sequence modulates RNA trans-splicing efficiency.

[0256] In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency comprises (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans- splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0257] Disclosed herein is a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the cDNA sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319.

[0258] Disclosed herein is a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the cDNA sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0259] Disclosed herein is a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705. Disclosed herein is a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the non-coding viral RNA sequence modulates RNA trans-splicing efficiency.

[0260] In an aspect, modulating RNA trans-splicing efficiency comprises (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency comprises (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans- splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0261] Disclosed herein is a library comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698. Disclosed herein is a library comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the non-coding viral RNA sequence modulates RNA trans-splicing efficiency. Disclosed herein is a library comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 can modulate RNA trans-splicing efficiency.

[0262] In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans- splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0263] In an aspect, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372,SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. In an aspect, a disclosed cDNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0264] Disclosed herein is a library comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a library comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the non-coding viral RNA sequence modulates RNA trans- splicing efficiency. In an aspect, a disclosed non-coding viral RNA sequence comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731 can modulate RNA trans-splicing efficiency.

[0265] In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) decreasing and / or diminishing the RNA trans-splicing efficiency of an exogenous pre-trans- splicing RNA and / or (ii) de-stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced.

[0266] In an aspect, a disclosed RNA sequence can comprise 50 or fewer nucleotides of the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705.

[0267] Disclosed herein is a library comprising one or more non-coding viral RNA sequences comprising a structure set forth in Table 1. Disclosed herein is a non-coding viral RNA sequence,comprising the structure of any one of Candidate 25 – Candidate 48. In an aspect, a disclosed non-coding viral RNA sequence can be obtained from and / or associated with Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, or Filo_Bundibugyo7_40. In an aspect, a disclosed non-coding viral RNA sequence can comprise Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, Filo_Bundibugyo7_40, or any combination thereof.

[0268] In an aspect, a disclosed library can comprise one or more nucleic acid barcode sequences. In an aspect, a disclosed nucleic acid barcode sequence can comprise the sequence set forth in any one of SEQ ID NO:3849 - SEQ ID NO:7696. 12. Kits

[0269] Disclosed herein is a kit comprising one or more disclosed trans-splicing constructs, one or more disclosed replacement constructs, one or more disclosed nucleic acid molecules, one or more disclosed AAV particles, one or more disclosed vectors, one or more disclosed pharmaceutical formulations. Disclosed herein is a kit comprising one or more disclosed trans- splicing constructs, one or more disclosed replacement constructs, one or more disclosed nucleic acid molecules, one or more disclosed AAV particles, one or more disclosed vectors, one or more disclosed pharmaceutical formulations, and a package insert with instructions for use. Disclosed herein is a kit one or more disclosed trans-splicing constructs, one or more disclosed replacement constructs, one or more disclosed nucleic acid molecules, one or more disclosed AAV particles, one or more disclosed vectors, one or more disclosed pharmaceutical formulations for use in a method disclosed herein.

[0270] In an aspect, a kit can comprise one or more disclosed trans-splicing constructs, one or more disclosed replacement constructs, one or more disclosed nucleic acid molecules, one or more disclosed AAV particles, one or more disclosed vectors, one or more disclosed pharmaceutical formulations, and one or more agents. “Agents” and “Therapeutic Agents” are known to the art and are described supra. In an aspect, the one or more agents can treat, prevent, inhibit, and / or ameliorate one or more comorbidities in a subject. In an aspect, one or more active agents cantreat, inhibit, prevent, and / or ameliorate cellular and / or metabolic complications related to a missing, deficient, and / or mutant protein or enzyme.

[0271] In an aspect, a disclosed kit can comprise at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose (such as, for example, treating a subject diagnosed with or suspected of having a genetic disease or genetic disorder). Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0272] In an aspect, a kit for use in a disclosed method can comprise one or more containers holding one or more disclosed trans-splicing constructs, one or more disclosed replacement constructs, one or more disclosed nucleic acid molecules, one or more disclosed AAV particles, one or more disclosed vectors, one or more disclosed pharmaceutical formulations, and a label or package insert with instructions for use. In an aspect, suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The containers can be formed from a variety of materials such as glass or plastic. The container can hold one or more disclosed trans-splicing constructs, one or more disclosed replacement constructs, one or more disclosed nucleic acid molecules, one or more disclosed AAV particles, one or more disclosed vectors, one or more disclosed pharmaceutical formulations, and can have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The label or package insert can indicate that one or more disclosed trans-splicing constructs, one or more disclosed replacement constructs, one or more disclosed nucleic acid molecules, one or more disclosed AAV particles, one or more disclosed vectors, one or more disclosed pharmaceutical formulations can be used for treating, preventing, inhibiting, and / or ameliorating a disease or disorder or complications and / or symptoms associated with a disease or disorder. A disclosed kit can comprise additional components necessary for administration such as, for example, other buffers, diluents, filters, needles, and syringes. In an aspect, a disclosed kit can be used in any disclosed method. In an aspect, a disclosed kit can be used to generate one or more disclosed trans-splicing constructs, one or more disclosed replacement constructs, one or more disclosed nucleic acid molecules, one or more disclosed AAV particles, one or more disclosed vectors, one or more disclosed pharmaceutical formulations. In an aspect, a disclosed kit can be used to treat a genetic disease or genetic disorder. In an aspect, a disclosed kit can be used to inhibit and / or minimize disease progression.

[0273] Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698.

[0274] Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the non-coding viral RNA sequence modulates RNA trans-splicing efficiency.

[0275] Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the cDNA sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:1763, SEQ ID NO:1372, SEQ ID NO:2525, SEQ ID NO:1956, SEQ ID NO:3406, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:1371, SEQ ID NO:1831, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:3740, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:3004, SEQ ID NO:1910, SEQ ID NO:520, SEQ ID NO:1225, SEQ ID NO:3543, SEQ ID NO:7697, SEQ ID NO:7698, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:1944, or SEQ ID NO:1319. Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences, wherein the non- coding viral RNA sequence comprises the cDNA sequence set forth in SEQ ID NO:2413, SEQ ID NO:656, SEQ ID NO:2525, SEQ ID NO:1456, SEQ ID NO:1375, SEQ ID NO:2891, SEQ ID NO:3755, SEQ ID NO:1467, SEQ ID NO:2371, SEQ ID NO:1815, SEQ ID NO:1627, SEQ ID NO:1694, SEQ ID NO:520, SEQ ID NO:3299, SEQ ID NO:55, SEQ ID NO:2951, SEQ ID NO:760, SEQ ID NO:2214, SEQ ID NO:3543, SEQ ID NO:1944, or SEQ ID NO:1319.

[0276] Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences, wherein the non-coding viral RNA sequence comprises the sequence set forth in SEQ ID NO:7706, SEQ ID NO:7707, SEQ ID NO:7710, SEQ ID NO:7713, SEQ ID NO:7714, SEQ ID NO:7717, SEQ ID NO:7718, SEQ ID NO:7719, SEQ ID NO:7721, SEQ ID NO:7722, SEQ ID NO:7723, SEQ ID NO:7724, SEQ ID NO:7727, SEQ ID NO:7699, SEQ ID NO:7700, SEQ ID NO:7701, SEQ ID NO:7702, SEQ ID NO:7703, SEQ ID NO:7704, SEQ ID NO:7729, or SEQ ID NO:7705. Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences, wherein the non- coding viral RNA sequence comprises the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the non-coding viral RNA sequence modulates RNA trans-splicing efficiency.

[0277] Disclosed herein is a kit comprising a library one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698.

[0278] Disclosed herein is a kit comprising a library one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the non-coding viral RNA sequence modulates RNA trans-splicing efficiency. Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698 can modulate RNA trans-splicing efficiency.

[0279] Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731. Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the non-coding viral RNA sequence modulates RNA trans-splicing efficiency.

[0280] Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences comprising a structure set forth in Table 1. Disclosed herein is a non-coding viral RNA sequence, comprising the structure of any one of Candidate 25 – Candidate 48. Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences obtained from and / or associated with Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, or Filo_Bundibugyo7_40.

[0281] Disclosed herein is a kit comprising a library comprising one or more non-coding viral RNA sequences obtained from and / or associated with Paramyxo_Measles_4_42, Corona_MERS_4_20, Paramyxo_RSV_3_4, Filo_Tai Forest_2_22, Filo_Bundibugyo_8_53, Picorna_EnterovirusD_1_28, Toga_Chik_3_29, Filo_Tai Forest_2_33, Paramyxo_Measles_3_6, Flavi_Dengue type 2_2_12, Filo_Tai_Forest_6_33, Filo_Tai Forest_7_8, Corona_HKU1_2_3, Retro_HIV1_2_31, Arena_LCMV_2_2, Picorna_HepA_1_17, Corona_NL63_2_3, Flavi_Zika_2_26, Flavi_MVV_2_36, Filo_Bundibugyo7_40, or any combination thereof.

[0282] Disclosed herein is a kit comprising a library of nucleic acid barcode sequences. Disclosed herein is a kit comprising a library of nucleic acid barcode sequences comprising the sequence set forth in any one of SEQ ID NO:3849 - SEQ ID NO:7696. C. Methods of Generating a Trans-Spliced RNA Molecule

[0283] Disclosed herein is a method of generating a trans-spliced RNA molecule in a cell, the method comprising contacting an endogenous pre-mRNA in a cell with a disclosed trans-splicing construct, wherein the resulting trans-spliced RNA transcript comprises the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a disclosed trans-splicing construct, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0284] Disclosed herein is a method of generating a trans-spliced RNA molecule in a cell, the method comprising contacting an endogenous pre-mRNA in a cell with a disclosed nucleic acid molecule, wherein the resulting trans-spliced RNA transcript comprises the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a disclosed nucleic acid molecule, wherein the resulting trans-spliced RNA transcript comprises the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0285] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a nucleic acid molecule, comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a nucleic acid molecule, comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0286] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule, comprising one or more non- coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans- spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0287] Disclosed herein is a method of generating a trans-spliced RNA molecule in a cell, the method comprising contacting an endogenous pre-mRNA in a cell with a disclosed a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the resulting trans-spliced RNA transcript comprises the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a disclosed a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the resulting trans-spliced RNA transcript comprises the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0288] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule comprising one or more non- coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targetedendogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0289] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the resulting trans-spliced RNA transcript can comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0290] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a nucleic acid molecule, comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre- mRNA and the 5’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a nucleic acid molecule, comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0291] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule, comprising one or more non- coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre- mRNA and the 3’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a nucleic acid molecule, comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the cDNA sequence set forth in any one of SEQ ID NO:01 - SEQ ID NO:3848, SEQ ID NO:7697, or SEQ ID NO:7698; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0292] Disclosed herein is a method of generating a trans-spliced RNA molecule in a cell, the method comprising contacting an endogenous pre-mRNA in a cell with a disclosed a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the resulting trans-spliced RNA transcript comprises the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells with a disclosed a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the resulting trans-spliced RNA transcript comprises the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0293] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule comprising one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731; an RNA targeting motif specific for a targeted endogenous pre- mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA, wherein the nucleic acid molecule enables the 3’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 5’ portion of the targeted endogenous pre-mRNA and the 3’ portion of the exogenous RNA.

[0294] Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the resulting trans-spliced RNA transcript can comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA. Disclosed herein is a method of generating a trans-spliced RNA molecule, the method comprising contacting one or more cells a nucleic acid molecule comprising an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences comprising 50 or fewer nucleotides of the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731, wherein the nucleic acid molecule enables the 5’ replacement of the targeted endogenous pre-mRNA, wherein the resulting trans-spliced RNA transcript can comprise the 3’ portion of the targeted endogenous pre-mRNA and the 5’ portion of the exogenous RNA.

[0295] In an aspect, the one or more cells can be in a subject. In an aspect, a subject can be diagnosed with or can be suspected of having a genetic disease or disorder. In an aspect, a disease or disorder can comprise any disease or disorder caused by a disclosed gene or a missing, deficient, and / or mutant gene. In an aspect, a subject can be a subject in need of treatment of a disclosed disease or disorder (e.g., a genetic disease or disorder). Genetic diseases and disorders are discussed extensively herein.

[0296] In an aspect, a disclosed method of generating a trans-spliced RNA molecule can further comprise identifying a subject in need of generating a trans-spliced RNA molecule. In an aspect of a disclosed method of generating a trans-spliced RNA molecule, a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed nucleic acid molecule, or a disclosed vector can be formulated for administration via one or more routes. Such methods are well known to those skilled in the art and include, but are not limited to, the following routes: oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, in utero administration, intrahepatic administration, intravaginal administration, ophthalmic administration, intraaural administration, otic administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-CSF administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can also include hepatic intra- arterial administration or administration through the hepatic portal vein (HPV). Administration of a disclosed therapeutic agent, a disclosed pharmaceutical composition, or a combination thereof can comprise administration directly into the CNS (e.g., intraparenchymal, intracerebroventricular, intrathecal cisternal, intrathecal (lumbar), deep gray matter delivery, convection-enhanced delivery to deep gray matter) or the PNS. Administration can be continuous or intermittent.

[0297] In an aspect, administration can be performed by one or more ex vivo methods such as, for example, an ex vivo perfusion protocol. In an aspect, an ex vivo perfusion protocol can be employed with one or more cells, tissues, and / or organs affected by a genetic disease or disorder obtained for a subject. In an aspect, one or more cells and / or one or more tissues and / or one or more organs can be obtained from the subject in need thereof, can be subjected to an ex vivo perfusion and / or treatment and / or contact protocol, and can be returned to the subject in need thereof, wherein the one or more cells generate a trans-spliced RNA transcript.

[0298] In an aspect, a disclosed method of generating a trans-spliced RNA molecule in cells can comprise validating the trans-splicing event and / or the generation of the trans-spliced RNA molecule. Validation of the trans-splicing event and / or generation of the trans-spliced RNA molecule can be accomplished using methods and techniques known to the art (e.g., flow cytometry, next generation sequencing (NGS), NGS with barcode analysis, northern blots, FISH, PCR, RNA-Seq, 3’ RACE, 5’ RACE, etc.). In an aspect, validation of the trans-splicing event can be validated by measuring and / or identifying and / or ascertaining one or more clinical improvements.

[0299] In an aspect, a disclosed method of generating a trans-spliced RNA molecule in cells can comprise validating the trans-splicing event and / or the generation of the trans-spliced RNA molecule using flow cytometry. In an aspect, flow cytometry can measure mean fluorescence intensity of the trans-spliced RNA molecule and / or the percent of cells expressing the trans- spliced RNA molecule. In an aspect, trans-splicing efficiency can be measured using a barcode analysis. In an aspect, a barcode analysis can comprise one or more nucleic acid barcode sequences. In an aspect, one or more disclosed nucleic acid barcode sequences can comprise the sequence set forth in any one of SEQ ID NO:3849 - SEQ ID NO:7696.

[0300] In an aspect, a disclosed method of generating a trans-spliced RNA molecule can comprise preparing a disclosed trans-splicing construct, a disclosed replacement construct, a disclosed nucleic acid molecule, a disclosed vector, a disclosed pharmaceutical formulation, or any combination thereof.

[0301] In an aspect, a disclosed method can modulate RNA trans-splicing efficiency and / or can modulate expression and / or activity of one or more genes of interest. In an aspect, modulating can comprise increasing and / or decreasing RNA trans-splicing efficiency and / or increasing and / or decreasing expression and / or activity of one or more genes of interest (e.g., targeted genes). In an aspect, modulating can comprise decreasing and / or diminishing RNA trans-splicing efficiency and / or decreasing and / or diminishing expression and / or activity of one or more genes of interest (e.g., targeted genes). In an aspect, a disclosed method can further comprise modulating trans- splicing efficiency. In an aspect, the trans-splicing efficiency can be measured using flow cytometry. In an aspect, flow cytometry can measure mean fluorescence intensity of the trans- spliced RNA molecule and / or the percent of cells expressing the trans-spliced RNA molecule. In an aspect, trans-splicing efficiency can be measured using a barcode analysis. In an aspect, a disclosed barcode analysis can comprise one or more nucleic acid barcode sequences. In an aspect, a disclosed nucleic acid barcode sequences can comprise the sequence set forth in any one of SEQ ID NO:3849 - SEQ ID NO:7696.

[0302] In an aspect, a trans-spliced RNA molecule generating by a disclosed method can improve and / or enhance trans-splicing efficiency in one or more cells. In an aspect, a trans-spliced RNA molecule generating by a disclosed method can improve and / or enhance trans-splicing efficiency in one or more cells.

[0303] In an aspect, a trans-spliced RNA molecule generating by a disclosed method can modulate trans-splicing efficiency in one or more cells. In an aspect, modulating RNA trans-splicing efficiency can comprise (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans-splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre-mRNA molecule and an exogenous RNA to be trans-spliced. In ...

Claims

VIII. CLAIMS What is claimed is:

1. A non-coding viral RNA sequence, comprising: the sequence set forth in any one of SEQ ID NO:7699 – SEQ ID NO:7731.

2. A nucleic acid molecule, comprising: one or more non-coding viral RNA sequences of Claim 1; an RNA targeting motif specific for a targeted endogenous pre-mRNA; a 3’ hemi intron; and an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA.

3. A nucleic acid molecule, comprising: an exogenous sequence to be trans-spliced to a targeted endogenous pre-mRNA; a 5’ hemi intron; an RNA targeting motif specific for a targeted endogenous pre-mRNA; and one or more non-coding viral RNA sequences of Claim 1.

4. The nucleic acid molecule of Claim 2 or Claim 3, wherein the targeted endogenous pre-mRNA comprises one or more mutations in one or more exons.

5. The nucleic acid molecule of Claim 4, wherein the one or more mutations are in the 3’ portion of the targeted endogenous pre-mRNA.

6. The nucleic acid molecule of Claim 4, wherein the one or more mutations are in the 5’ portion of the targeted endogenous pre-mRNA.

7. The nucleic acid molecule of Claim 2 or Claim 3, wherein the targeted endogenous pre-mRNA encodes a protein coding gene.

8. The nucleic acid molecule of Claim 4, wherein the one or more mutations in one or more exons contribute to pathogenesis in one or more cells.

9. The nucleic acid molecule of Claim 8, wherein the one or more cells are in a subject.

10. The nucleic acid molecule of Claim 2, wherein a 5’ portion of the targeted endogenous pre- mRNA is trans-spliced with the exogenous RNA.

11. The nucleic acid molecule of Claim 3, wherein a 3’ portion of the targeted endogenous pre- mRNA is trans-spliced with the exogenous RNA.

12. The nucleic acid molecule of Claim 2 or Claim 3, wherein the RNA targeting motif binds to the targeted endogenous pre-mRNA.

13. The nucleic acid molecule of Claim 12, wherein the RNA targeting motif comprises an antisense oligonucleotide.

14. The nucleic acid molecule of Claim 13, wherein the antisense oligonucleotide comprises about 15 nucleotides to about 50 nucleotides.

15. The nucleic acid molecule of Claim 2, wherein the RNA targeting motif is directed to the intron immediately 3’ to the exon of the targeted endogenous pre-mRNA with which it is to be spliced.

16. The nucleic acid molecule of Claim 3, wherein the RNA targeting motif is directed to the intron immediately 5’ to the exon of the targeted endogenous pre-mRNA with which it is to be spliced.

17. The nucleic acid molecule of Claim 2, 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.

18. The nucleic acid molecule of Claim 3, wherein the hemi intron comprises a 5’ splice site.

19. The nucleic acid molecule of any preceding claim, wherein the one or more non-coding viral RNA sequences bind to one or more RNA binding proteins.

20. The nucleic acid molecule of any preceding claim, wherein the one or more non-coding viral RNA sequences (i) improve and / or enhance trans-splicing efficiency; (ii) stabilize the resulting trans-spliced RNA transcript; (iii) localize the RNA to the nucleus; (iv) stabilize the interaction between the targeted endogenous pre-mRNA molecule and the exogenous RNA to be trans-spliced; or (v) any combination thereof.

21. A viral vector, comprising: the nucleic acid molecule of any one of Claims 1 - 20.

22. The viral vector of Claim 21, wherein the viral vector is a recombinant viral vector.

23. The viral vector of Claim 21, wherein the recombinant viral vector is an adeno-associated virus (AAV) viral vector.

24. A pharmaceutical formulation, comprising: the vector of Claim 21; and one or more pharmaceutically acceptable carriers.

25. A method of generating a trans-spliced 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 - 20 or the vector of Claim 21, wherein the resulting trans-spliced RNA molecule comprises a trans-spliced mRNA sequence.

26. The method of Claim 25, the one or more non-coding viral RNA sequences modulate RNA trans-splicing efficiency.

27. The method of Claim 26, wherein modulating RNA trans-splicing efficiency comprises (i) improving and / or enhancing the RNA trans-splicing efficiency of an exogenous pre-trans- splicing RNA and / or (ii) stabilizing the interaction between a targeted endogenous pre- mRNA molecule and an exogenous RNA to be trans-spliced.

28. The method of Claim 25, wherein the one or more cells are in a subject that has been diagnosed as having a genetic disease or a genetic disorder.

29. A method of treating a subject, the method comprising: generating a trans-spliced RNA molecule in one or more cells by administering to a subject having a genetic disease or a genetic disorder a therapeutically effective amount of the vector of Claim 21 or the pharmaceutical formulation of Claim 24; wherein the resulting trans-spliced RNA molecule comprises a trans-spliced nucleic acid sequence; and wherein the resulting trans-spliced RNA molecule restores one or more aspects of cellular homeostasis and / or cellular functionality and / or metabolic dysregulation associated with or caused by the genetic disease or genetic disorder.

30. The method of Claim 29, 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.

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