Regulatable gene expression via adaptamers

Abstract

Provided herein, inter alia, are compositions including nucleic acid sequences (e.g., RNA or DNA) or portions thereof and methods of using the same. The nucleic acid compositions provided herein are, inter alia, useful for expressing a gene of interest (e.g., a transgene) in a cell. The compositions and methods provided herein, inter alia, include nucleic acid sequences, expression vectors, cellular compositions and methods of using the same. In addition, provided herein are, inter alia, are compositions and methods comprising aptamers for use in regulating gene expression.

Description

REGULATABLE GENE EXPRESSION VIA ADAPT AMERSRELATED APPLICATION DATA

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Patent Application No. 63 / 570,483, filed on March 27, 2024, which is hereby incorporated by reference in its entirety and for all purposes.SEQUENCE LISTING

[0002] The material in the accompanying Sequence Listing is hereby incorporated by reference in its entirety. The accompanying file, named “048537-666001WO_SL_ST26.xml” was created on March 27, 2025, and is 265,410 bytes in size.GOVERNMENT SUPPORT CLAUSE

[0003] This invention was made with government support under HG012351 and OD032742 awarded by National Institutes of Health and under W81XWH-22-1-0401 awarded by the U.S. Department of Defense. The government has certain rights in the invention.BACKGROUND

[0004] While there are numerous prokaryotic gene control systems, the complexity of eukaryotic gene expression has made engineering control of mammalian gene expression difficult. Current systems, such as the Tet-ON system, predominantly rely on constitutive expression of foreign proteins, or RNA cleavage based mechanisms. The use of foreign proteins can trigger an immune response, limiting the effectiveness and therapeutic application of the system. Meanwhile, cleavage based switches have limited utility in RNA based systems such as lentiviral or synthetic mRNA delivery. We have engineered a novel, orthogonally controlled, highly specific genetic switch with control at the RNA level in human cells. Logistic and ethical concerns with gene and cell therapies drive the need for inducible expression capable of deployment in humans without unintentional effects or undesirable immune responses. Provided herein, inter alia, are compositions and methods of use thereof to address these and other problems in the art.BRIEF SUMMARY

[0005] In an aspect is provided a ribonucleic acid (RNA) sequence including from 5’ to 3' a first member of a double- stranded adenosine deaminase acting on RNA (ds AD AR) -binding region, a ligand-binding aptamer, a second member of the dsAD AR -binding region, and a transgene-encoding sequence, wherein upon binding a ligand to the ligand-binding aptamer,the first member of the dsAD AR -binding region and the second member of the ds ADAR- binding region are capable of hybridizing to form a ds ADAR-binding region, wherein the dsADAR-binding region includes at least 1 mismatched base pair, forming at least 1 doublestranded bulge, wherein the double-stranded bulge includes a mismatched base pair including an adenosine that forms part of an UAG stop codon.

[0006] In another aspect is provided a ribonucleic acid (RNA) sequence including from 5' to 3' a first member of a double- stranded nucleic acid sequence, a first member of a split ligand-binding aptamer, a first member of an adenosine deaminase acting on RNA (ds AD AR) -binding region, a second member of the dsADAR-binding region, a second member of the ligand-binding aptamer, a second member of the double-stranded nucleic acid sequence, and a transgene-encoding sequence, wherein the first member of a split ligandbinding aptamer is capable of hybridizing the second member of the split ligand-binding aptamer to form a ligand-binding aptamer capable of binding a ligand, wherein upon binding a ligand to the ligand-binding aptamer, the first member of the dsADAR-binding region and the second member of the dsADAR-binding region are capable of hybridizing to form a dsADAR-binding region, wherein the dsADAR-binding region includes at least 1 mismatched base pair, forming at least 1 double- stranded bulge, wherein the double-stranded bulge includes a mismatched base pair including an adenosine that forms part of an UAG stop codon.

[0007] In another aspect is provided a ribonucleic acid (RNA) sequence including from 5' to 3' a first member of an adenosine deaminase acting on RNA (dsADAR)-binding region, a first member of a first split ligand-binding aptamer, an RNA stem-loop sequence, a second member of the first split ligand-binding aptamer, a second member of the dsADAR-binding region, and a transgene-encoding sequence, wherein the first member of a split ligandbinding aptamer is capable of hybridizing the second member of the ligand-binding aptamer to form a ligand-binding aptamer capable of binding a ligand, wherein upon binding a ligand to the ligand-binding aptamer, the first member of the dsADAR-binding region and the second member of the dsADAR-binding region are capable of hybridizing to form a dsADAR-binding region, wherein the dsADAR-binding region includes at least 1 mismatched base pair, forming at least 1 double- stranded bulge, wherein the double-stranded bulge includes a mismatched base pair including an adenosine that forms part of an UAG stop codon.

[0008] In another aspect is provided a deoxyribonucleic acid (DNA) sequence encoding the RNA sequence provided herein including embodiments thereof.

[0009] In another aspect is provided an expression vector including the DNA sequence provided herein including embodiments thereof.

[0010] In another aspect is provided a virus including the expression vector provided herein including embodiments thereof.

[0011] In another aspect is provided a cell including the DNA sequence provided herein including embodiments thereof or the expression vector provided herein including embodiments thereof.

[0012] In another aspect is provided a method of expressing a transgene in a cell including contacting the cell provided herein including embodiments thereof with a ligand, thereby expressing the transgene in the cell.

[0013] In another aspect is provided a nucleic acid including an aptamer, an editable domain, and a target gene domain.

[0014] In another aspect is provided an expression vector including the nucleic acid provided herein including embodiments thereof.

[0015] In another aspect is provided a method for regulating gene expression, the method including: (a) contacting a cell with an expression vector including the nucleic acid provided herein including embodiments thereof; (b) transducing the cell with the expression vector; (c) allowing the cell to express the nucleic acid; (d) contacting the cell with a small molecule or a protein, thereby activating adenosine deaminases acting on RNA (ADAR) editing of the editable domain; and (e) allowing the cell to express the target gene domain, thereby regulating gene expression.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1 shows an exemplary structure of a cb32 aptamer, minimer version, provided herein.

[0017] FIGS. 2A-2B show an exemplary construct plasmid design (FIG. 2A) and comparison to construct version with 3x Flag replaced with alternative short peptide (FIG. 2B).

[0018] FIG. 3 shows 27 construct designs for preliminary testing. These constructs are broken into 3 major categories depending on if the aptamer is placed at the top (Constructs #1-10), middle (Constructs #24-27), or bottom (Constructs #11 -16) of the loop. Additionalvariables include loop length, aptamer placement, aptamer binding pocket to stop codon distance, and aptamer Pl and P2 lengths.

[0019] FIG. 4 shows A and G reporter controls. The A reporter should be double stranded and experiencing moderate ADAR editing even without drug stabilization. The G reporter and v28 have no stop codon and should therefore have no sensitivity to drug as they do not require editing. The last control is the plasmid with GFP and no loop structure, and should also always be expressed.

[0020] FIGS. 5A-5B show exemplary RNA sequences provided herein effectively express transgene (e.g. fluorescent reporter) in response to ligand binding. FIG. 5A shows a representative graph of mean fluorescence values from a single experiment. FIG. 5B shows mean fluorescence intensity fold changes from three completely independent experiments. Constructs with error bars that do not cross y=l have consistently displayed an MFI increase upon drug addition.

[0021] FIG. 6 shows representative fluorescent images 18 hours after the top sample has been drugged with 80 pM tetracycline. The A reporter control is not expected to change in response to drug.

[0022] FIG. 7 shows fluorescence activated cell sorting (FACS) plots from selected experiments showing shifting fluorescent peaks. The v7 -9 and v24 peaks are increasing in FfTC-A intensity with addition of drug while the vl9 peak remains constant.

[0023] FIGS. 8A-8C: FIG. 8A shows representative images demonstrating dose-dependent fluorescence. FIG. 8B shows mean fluorescence intensity of constructs 7 and 8 at different tetracycline concentrations. FIG. 8C shows mean fluorescence of drugged conditions divided by undrugged condition.

[0024] FIG. 9 shows 18-hour fluorescence imaging of the A reporter and V8 that are drugged the same day as the transfection. Background is limited in V8 compared to experiments where drugging occurs 24 hours after transfection. The V8 trials with drug are more fluorescent than the A reporter.

[0025] FIGS. 10A-10C: FIG. 10A shows representative images demonstrating fluorescence after NTC and ADAR shRNA. FIG. 10B shows mean fluorescence intensity of constructs in different conditions with and without shRNA-mediated ADAR knockdown. FIG. 10C shows expression in ADAR shRNA wells compared to NTC wells.

[0026] FIG. 11 shows a representative Western blot confirming GFP expression with 3X Flag antibody, which is upstream of the aptamer construct.

[0027] FIGS. 12A-12D: FIG. 12A shows an exemplary adaptamer additionally stabilized by binding to endogenous RNA transcript. FIG. 12B shows exemplary adaptamers in series folding independently. FIG. 12C show exemplary identical adaptamers in series forming one large hairpin in the absence of drug. FIG. 12D shows exemplary adaptamers with 2 stop codons and 1-2 aptamers.

[0028] FIGS. 13A-13E: FIG. 13A shows an exemplary adaptamer capped with two aptamers for increased stabilizing impact. FIGS. 13B-13C show exemplary HIV Tat protein- activated adaptamers potentially capable of expressing a gene upon HIV infection of a cell. FIG. 13D: ASP2905 activated adaptamer. FIG. 13E: Data from double adaptamer designs(v29-v35) demonstrating inducibility.

[0029] FIG. 14 shows exemplary aptamer design iterations to increase expression shift upon tetracycline exposure and reduce leaky expression.

[0030] FIG. 15 shows an exemplary schematic of the structure and mechanism of action of RNA sequences (e.g., adaptamers) provided herein.

[0031] FIGS. 16A-16C show a summary of maximum expression and inducibility, the two optimized variables for adaptamer loops of different stem and root lengths (in base pairs). FIG. 16A: Exemplary RNA sequence construct (e.g., adaptamer) provided herein. HEK293T cells (FIG. 16B) are a human cell line while N2a cells (FIG. 16C) are a mouse neuroblastoma line. As a neuronal line N2a cells express more ADAR and consistently edit at higher rates.

[0032] FIGS. 17A-17D show dose dependent fluorescence in both HEK293T cells (FIGS. 17A-17B) and N2a cells (FIGS. 17C-17D). Percent expression (FIGS. 17A and 17C)is calculated as a fraction of the mean fluorescence intensity (MFI) of the G reporter. Fold change (FIGS. 17B and 17D) is calculated as percent expression at a dose divided by the average of the percent expression of the 0 p M tetracycline condition.

[0033] FIGS. 18A-18D show inducible transgene expression using RNA sequences (e.g., adaptamers) provided herein. FIG. 18A: Responsiveness of switch to modulation of ADAR levels. FIG. 18B: Images of exemplary switch (v7i2) in response to ADAR and tetracycline modulation. FIG. 18C: Control constructs response to tetracycline and ADAR modulation. FIG. 18D: RNA editing data.

[0034] FIGS. 19A-19D show experimental data from exemplary RNA sequences (e.g., adaptamers) provided herein. FIG. 19A: Function of adaptamer with another tetracyclineresponsive riboswitch. FIGS. 19C-19D: Function of adaptamer in backbone with additional regulatory elements (e.g. chimeric intron and WRPE).

[0035] FIGS. 20A-20D show data from experiments using viral expression vector deliver of RNA sequences (e.g., adaptamers) provided herein. FIG. 20A: Function of adaptamer via AAV-DJ delivery in HEK293T cells and HeLa cells. FIG. 20B: Titer-dependent transgene expression. FIG. 20C: Comparable expression and inducibility on protein and RNA editing level. FIG. 20D: FACS plots showing increased expression in drugged condition over undrugged condition.

[0036] FIGS. 21A-21B show function of adaptamer via lentiviral delivery in HEK293T cells in ePIP backbone (FIG. 21A). FIG. 21B: Transduction-controlled construct optimized for screening.

[0037] FIGS. 22A-22B show inducible expression of Navl.7-targeting zinc finger in N2a cells with associated editing data (FIG. 22A). FIG. 22B: Editing of version without HA tag for improved activity.

[0038] FIG. 23 shows addition of 6 base pair AC spacers on either side of adaptamer moderately increases expression.

[0039] FIG. 24 shows data from double adaptamer designs (v29-v35), demonstrating inducibility.

[0040] FIGS. 25A-25E show simulated folding of exemplary RNA sequences provided herein, which helps describe categories and motifs relevant to adaptamer.

[0041] FIG 26 shows ADAR expression across human tissues. While virtually every tissue and cell type expresses ADAR due to its essential role in innate immunity and modifying dsRNA stability, it is most highly expressed throughout the nervous system, reproductive cells, and arteries. The cells where ADAR is the most active are ideal for this technology.

[0042] FIGS. 27A-27B show exemplary RNA sequences disclosed herein further including an ADAR-encoding sequence. FIG. 27A: ADAR feedback loop in which ADAR or an ADAR based derivative is produced as a transgene of the adaptamer creating a positive feedback loop and increasing maximum expression FIG. 27B: Version of the loop using an engineered split or intact ADAR linked to RNA binding proteins (e.g. MS2 coat protein) and a MS2 localized to target site to increase on target editing while decreasing off target effects

[0043] FIGS. 28A-28B show results from ADAR knockdown and overexpression experiments. FIG. 28A: Confirmation of ADAR knockdown and overexpression fromshRNA and ADAR pl 10 transfections. FIG. 28B: RNA editing data showing reduced editing after ADAR shRNA transfection.DETAILED DESCRIPTIONDEFINITIONS

[0044] While various embodiments and aspects of the present invention are shown and described herein, it will be obvious to those skilled in the art that such embodiments and aspects are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

[0045] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.

[0046] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0047] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. See, e.g., Singleton el al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed„ J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this invention. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0048] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In embodiments, “nucleic acid” does not include nucleosides. The terms “polynucleotide,” “oligonucleotide,” “oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term “nucleoside” refers, in the usual and customary sense, to a glycosylamine includinga nucleobase and a five-carbon sugar (ribose or deoxyribose). Non limiting examples, of nucleosides include cytidine, uridine, adenosine, guanosine, thymidine and inosine. The term “nucleotide” refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA. Examples of nucleic acid, e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term “duplex” in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.

[0049] Nucleic acids, including e.g., nucleic acids with a phosphothioate backbone, can include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions. By way of example, the nucleic acid can include an amino acid reactive moiety that reacts with an amino acid on a protein or polypeptide through a covalent, non-covalent or other interaction.

[0050] The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non- naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine.; and peptide nucleic acid backbones and linkages. Other analognucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Patent Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In embodiments, the intemucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

[0051] Nucleic acids can include nonspecific sequences. As used herein, the term "nonspecific sequence" refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence. By way of example, a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.

[0052] A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when the polynucleotide is RNA). Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and / or modified nucleotides.

[0053] The term “complement,” as used herein, refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanosine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a secondnucleic acid sequence. The nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. A further example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.

[0054] As described herein the complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other, may have a specified percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region).

[0055] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, y- carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0056] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0057] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may In embodiments be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.

[0058] An amino acid or nucleotide base "position" is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5’-end). Due to deletions, insertions, truncations, fusions, and the like that must be considered when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0059] The terms "numbered with reference to" or "corresponding to," when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. An amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural position within the protein as the given residue. One skilled in the art will immediately recognize the identity and location of residues corresponding to a specific position in a protein (e.g., ADAR) in other proteins with different numbering systems. For example, byperforming a simple sequence alignment with a protein (e.g., ADAR) the identity and location of residues corresponding to specific positions of the protein are identified in other protein sequences aligning to the protein. For example, a selected residue in a selected protein corresponds to glutamic acid at position 138 when the selected residue occupies the same essential spatial or other structural relationship as a glutamic acid at position 138. In some embodiments, where a selected protein is aligned for maximum homology with a protein, the position in the aligned selected protein aligning with glutamic acid 138 is the to correspond to glutamic acid 138. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the glutamic acid at position 138, and the overall structures compared. In this case, an amino acid that occupies the same essential position as glutamic acid 138 in the structural model is said to correspond to the glutamic acid 138 residue.

[0060] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, "conservatively modified variants" refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Because of the degeneracy of the genetic code, a number of nucleic acid sequences will encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence.

[0061] As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservativelymodified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the disclosure.

[0062] The following eight groups each contain amino acids that are conservative substitutions for one another:1) Alanine (A), Glycine (G);2) Aspartic acid (D), Glutamic acid (E);3) Asparagine (N), Glutamine (Q);4) Arginine (R), Lysine (K);5) Isoleucine (1), Leucine (L), Methionine (M), Valine (V);6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W);7) Serine (S), Threonine (T); and8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)).

[0063] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site www.ncbi.nlm.nih.gov / BLAST / or the like). Such sequences are then said to be "substantially identical." This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.

[0064] "Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining thenumber of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.

[0065] A "comparison window", as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of, e.g., a full length sequence or from 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman (1988) Proc. Nat’l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)).

[0066] An example of an algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402, and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate thecumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negativescoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11 , an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89: 10915) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[0067] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873- 5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[0068] An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequence.

[0069] The phrase "specifically (or selectively) binds" to an antibody or "specifically (or selectively) immunoreactive with," when referring to a protein or peptide, refers to a binding reaction that is determinative of the presence of the protein, often in a heterogeneous population of proteins and other biologies. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein at least two times the background andmore typically more than 10 to 100 times background. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only a subset of antibodies that are specifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity) .

[0070] A "ligand" refers to an agent, e.g., a polypeptide or other molecule, capable of binding to a receptor or antibody, antibody variant, antibody region or fragment thereof.

[0071] Techniques for conjugating therapeutic agents to antibodies are well known (see, e.g., Amon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery’in Controlled Drug Delivery (2ndEd.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review" in Monoclonal Antibodies ‘84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody- Toxin Conjugates", Immunol. Rev., 62: 119-58 (1982)). As used herein, the term “antibodydrug conjugate” or “ADC” refers to a therapeutic agent conjugated or otherwise covalently bound to to an antibody.

[0072] For specific proteins described herein, the named protein includes any of the protein’s naturally occurring forms, variants or homologs that maintain the protein transcription factor activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to the native protein). In some embodiments, variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring form. In other embodiments, the protein is the protein as identified by its NCBI sequence reference. In otherembodiments, the protein is the protein as identified by its NCB1 sequence reference, homolog or functional fragment thereof.

[0073] The term "gene" means the segment of DNA involved in producing a protein; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons). The leader, the trailer as well as the introns include regulatory elements that are necessary during the transcription and the translation of a gene. Further, a "protein gene product" is a protein expressed from a particular gene.

[0074] The term “aptamer” or “ligand-binding aptamer” is used herein according to its plain ordinary meaning and refers to a nucleic acid sequence that binds a specific target biomolecule (e.g., ligand) or family of target biomolecules. In embodiments, the ligandbinding aptamer includes complex secondary and / or tertiary structures that bind tightly and specifically to a ligand. In embodiments, the ligand is a small molecule, a metabolite, or a protein. In embodiments, the ligand-binding aptamer may be divided (e.g., split), thereby forming a first member of the split ligand-binding aptamer and a second member of the split ligand-binding aptamer. In embodiments, the ligand-binding aptamer can be split at any residue of the ligand-binding aptamer. In embodiments, the ligand-binding aptamer includes the nucleotide sequence of any one of SEQ ID NOs: 1-12. Aptamers are well known in the art. See, e.g., sites.utexas.edu / aptamerdatabase / and www.aptagen.com / apta-index / ; Liu et al., Analytical Methods, 2024; 16(19):3039-46, each of which is incorporated herein by reference in its entirety and for all purposes.

[0075] The term “mismatched base pair” is used herein according to its plain ordinary meaning and refers to a non-complementary pairing of nucleotides resulting in the base pairing not being bound together by hydrogen bonds (e.g. resulting in a double- stranded bulge). In embodiments, the mismatched base pair includes a first purine nucleotide paired with a second purine nucleotide; or a first pyrimidine nucleotide paired with a second pyrimidine nucleotide. In embodiments, the mismatched base pair includes a first cytosine paired with a second cytosine; a cytosine paired with a uracil; a first guanosine paired with a second guanosine; an adenosine paired with a guanosine; or a uracil paired with a guanosine.

[0076] The term “double- stranded bulge” is used herein according to its plain ordinary meaning and refers to secondary structure of a nucleic acid (e.g. RNA) formed by at least one mismatched base pair in the double-stranded nucleic acid.

[0077] The term “stop codon” is used herein according to its plain ordinary meaning and refers to a three-nucleotide sequence that signals termination of the translation process of the nucleic acid (e.g., messenger RNA). In embodiments, a UAG stop codon is a stop codon that includes a uracil (U), an adenosine (A), and a guanosine (G).

[0078] The term “editable domain” refers to a nucleic acid sequence that can be edited by proteins, peptides or enzymes. In embodiments, the editing can be activated by an exogenous or endogenous stimulus. In embodiments, the editing can be activated by a small molecule or a protein. In embodiments, the editable domain can be edited by adenosine deaminases acting on RNA (ADARs).

[0079] The term “adenosine deaminases acting on RNA” or “ADAR” is used herein according to its plain ordinary meaning and refers to an enzyme that deaminates an adenosine residue in a nucleic acid. In embodiments, the deamination of the adenosine residue converts it to an inosine residue. In embodiments, the nucleic acid is RNA. In embodiments, the nucleic acid is double-stranded RNA. In embodiments, the nucleic acid is duplex RNA. In embodiments, the ADAR is an endogenous ADAR or an exogenous ADAR. In embodiments, the ADAR is a naturally occurring ADAR, an engineered ADAR, or a recombinant ADAR. In embodiments, the ADAR is AD ARI, ADAR2, ADAR3, ADAR pl 10, ADAR pl 50, MS2 coat protein (MCP)-ADAR, a MCP-ADAR E488Q, a split-ADAR, or a split-ADAR E488Q. In embodiments, the ADAR includes the amino acid sequence of any one of SEQ ID NOs:299-304 or 307. In embodiments, the term “ADAR-encoding sequence” is used herein according to its plain ordinary meaning and refers to a nucleic acid sequence that encodes an ADAR enzyme. ADAR enzymes are known to be expressed in various species, including but not limited to: humans, mice, rabbits, rats, non-human primates, zebrafish, Drosophila, and C. elegans. Cells that express ADAR are well known in the art. See, e.g., www.gtexportal.org / home / multiGeneQueryPage / ADAR, AD ARB 1 ,ADARB2 which is incorporated herein by reference in its entirety and for all purposes (Note: AD ARB 1 = ADAR2, ADARB2 = ADAR3).

[0080] The term “double- stranded AD AR -binding region” or “dsADAR-binding region” refers to a double-stranded nucleic acid sequence which binds to (e.g. interacts with) an ADAR enzyme. In embodiments, an adenosine residue in the dsADAR-binding region is deaminated, thereby converting the adenosine residue to an inosine. In embodiments, the dsADAR-binding region recruits an ADAR enzyme. In embodiments, the ADAR enzyme is an endogenous ADAR enzyme or an exogenous ADAR enzyme.

[0081] The term “transgene-encoding sequence” is used herein according to its plain ordinary meaning and refers to a nucleic acid sequence that encodes an exogenous gene (e.g., transgene) that encodes a protein. In embodiments, the transgene-encoding sequence encodes an RNA-guided DNA endonuclease, a base editor protein, a prime editor protein, a zinc finger protein domain, or a chimeric antigen receptor (CAR) protein. In embodiments, the transgene-encoding sequence encodes an exogenous gene or an exogenous protein to replace a defective and / or mutant gene or protein in a cell. In embodiments, the transgene-encoding sequence encodes an insulin peptide hormone, a CFTR gene, a MECP2 gene, or a HEXA gene. In embodiments, the transgene-encoding sequence encodes an insulin peptide hormone. In embodiments, the transgene-encoding sequence encodes a CFTR gene. In embodiments, the transgene-encoding sequence encodes a MECP2 gene. In embodiments, the transgene- encoding sequence encodes or a HEXA gene. In embodiments, the transgene-encoding sequence encodes a differentiation factor (e.g. a Yamanaka factor) to induce pluripotency in a cell.

[0082] The term “deoxyribonucleic acid (DNA) endonuclease enzyme” and the like refer, in the usual and customary sense, to an enzyme that cleaves a phosphodiester bond within a DNA polynucleotide chain. In embodiments, the DNA endonuclease enzyme is a CRIS PR- associated protein.

[0083] The term “CRISPR-associated protein” or “CRISPR protein” refers to any CRISPR protein that functions as a DNA endonuclease enzyme or a nuclease-deficient DNA endonuclease enzyme, (i.e., a CRISPR protein in which catalytic sites for endonuclease activity are defective or lack activity). Exemplary nuclease -deficient CRISPR-associated proteins include dCas9, dCpfl, dCasl2, Cas-phi, a nuclease-deficient Cas9 variant, a nuclease-deficient Class II CRISPR endonuclease, and the like.

[0084] The term “Class II CRISPR endonuclease” refers to endonucleases that have similar endonuclease activity as Cas9 and participate in a Class II CRISPR system. An example Class II CRISPR system is the type II CRISPR locus from Streptococcus pyogenes SF370, which contains a cluster of four genes Cas9, Casl , Cas2, and Csnl, as well as two non-coding RNA elements, tracrRNA and a characteristic array of repetitive sequences (direct repeats) interspaced by short stretches of non-repetitive sequences (spacers, about 30 bp each). The Cpfl enzyme belongs to a putative type V CRISPR-Cas system. Both type II and type V systems are included in Class II of the CRISPR-Cas system.

[0085] A “CRISPR associated protein 9,” “Cas9,” “Csnl” or “Cas9 protein” as referred to herein includes any of the recombinant or naturally-occurring forms of the Cas9 endonuclease or variants or homologs thereof that maintain Cas9 endonuclease enzyme activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to Cas9). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring Cas9 protein. In embodiments, the Cas9 protein is substantially identical to the protein identified by the UniProt reference number Q99ZW2 or a variant or homolog having substantial identity thereto. In embodiments, the Cas9 protein has at least 75% sequence identity to the amino acid sequence of the protein identified by the UniProt reference number Q99ZW2. In embodiments, the Cas9 protein has at least 80% sequence identity to the amino acid sequence of the protein identified by the UniProt reference number Q99ZW2. In embodiments, the Cas9 protein has at least 85% sequence identity to the amino acid sequence of the protein identified by the UniProt reference number Q99ZW2. In embodiments, the Cas9 protein has at least 90% sequence identity to the amino acid sequence of the protein identified by the UniProt reference number Q99ZW2. In embodiments, the Cas9 protein has at least 95% sequence identity to the amino acid sequence of the protein identified by the UniProt reference number Q99ZW2.

[0086] The term “nuclease-deficient RNA-guided DNA endonuclease domain” and the like refer, in the usual and customary sense, to an RNA-guided DNA endonuclease (e.g. a mutated form of a naturally occurring RNA-guided DNA endonuclease) that targets a specific phosphodiester bond within a DNA polynucleotide, wherein the recognition of the phosphodiester bond is facilitated by a separate polynucleotide sequence (for example, a RNA sequence (e.g., single guide RNA (sgRNA)), but is incapable of cleaving the target phosphodiester bond to a significant degree (e.g. there is no measurable cleavage of the phosphodiester bond under physiological conditions or the amount of cleavage is reduced (e.g. by 50%, 60%, 60%, 90%, 90%, 95%, 96%, 97%, 98%, 99% or more) relative to the wild type sequence). A nuclease-deficient RNA-guided DNA endonuclease thus retains DNA- binding ability (e.g. specific binding to a target sequence) when complexed with a polynucleotide (e.g., sgRNA), but may lack significant endonuclease activity (e.g. any amount of detectable endonuclease activity). In embodiments, the nuclease-deficient RNA- guided DNA endonuclease domain is a CRISPR-associated protein. In embodiments, thenuclease-deficient RNA-guided DNA endonuclease domain is a dCas9, dCpfl, ddCpfl , Cas- phi, a nuclease-deficient Cas9 variant, a nuclease-deficient Class II CRISPR endonuclease, a zinc finger domain, a transcription activator-like effector (TALE), a leucine zipper domain, a winged helix domain, a helix-turn-helix motif, a helix-loop-helix domain, an HMB-box domain, a Wor3 domain, an OB-fold domain, an immunoglobulin domain, or a B3 domain. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is a zinc finger domain, a leucine zipper domain, a winged helix domain, a helix-turn-helix motif, a helix-loop-helix domain, an HMB-box domain, a Wor3 domain, an OB-fold domain, an immunoglobulin domain, or a B3 domain. In embodiments, the nuclease-deficient RNA- guided DNA endonuclease domain is a leucine zipper domain. In embodiments, the nuclease- deficient RNA-guided DNA endonuclease domain is a winged helix domain. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is a helix-tum- helix motif. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is a helix-loop-helix domain. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is an HMB-box domain. In embodiments, the nuclease-deficient RNA- guided DNA endonuclease domain is a Wor3 domain. In embodiments, the nuclease- deficient RNA-guided DNA endonuclease domain is an OB-fold domain. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is an immunoglobulin domain. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is a B3 domain. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is dCas9, ddCpfl, Cas-phi, a nuclease-deficient Cas9 variant, or a nuclease-deficient Class II CRISPR endonuclease. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is dCas9. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is dCas9 from .S', pyogenes. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is dCas9 from S. aureus. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is dCasl2a from Lachnospiracea (dLbCasl2a). In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is dCasl2a from Lachnospiracea bacterium. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is dCasl2a. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is dCasl2. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is ddCas!2a. In embodiments, the nuclease- deficient RNA-guided DNA endonuclease domain is Cas-phi.

[0087] The terms “dCas9” or “dCas9 protein” as referred to herein is a Cas9 protein in which both catalytic sites for endonuclease activity are defective or lack activity. In embodiments, the dCas9 protein has mutations at positions corresponding to D10A and H840A of S. pyogenes Cas9. In embodiments, the dCas9 protein lacks endonuclease activity due to point mutations at both endonuclease catalytic sites (RuvC and HNH) of wild type Cas9. The point mutations can be D10A and H840A. In embodiments, the dCas9 has substantially no detectable endonuclease (e.g., endodeoxyribonuclease) activity.

[0088] The terms “DNAse-dead Cpfl” or “ddCpfl” refer to mutated Acidaminococcus sp. Cpfl (AsCpfl) resulting in the inactivation of Cpfl DNAse activity. In embodiments, ddCpfl includes an E993A mutation in the RuvC domain of AsCpfl. In embodiments, the ddCpfl has substantially no detectable endonuclease (e.g., endodeoxyribonuclease) activity. In embodiments, the nuclease-deficient RNA-guided DNA endonuclease domain is dCasl2a from Lachnospiracea bacterium.

[0089] The term “dLbCpfl” refers to mutated Cpfl from Lachnospiraceae bacterium ND2006 (LbCpfl) that lacks DNAse activity. In embodiments, dLbCpfl includes a D832A mutation. In embodiments, the dLbCpfl has substantially no detectable endonuclease (e.g., endodeoxyribo-nuclease) activity.

[0090] The term “dFnCpfl” refers to mutated Cpfl from Francisella novicida U112 (FnCpfl) that lacks DNAse activity. In embodiments, dFnCpfl includes a D917A mutation. In embodiments, the dFnCpfl has substantially no detectable endonuclease e.g., endodeoxyribo-nuclease) activity.

[0091] A "Cpfl " or " Cpfl protein" as referred to herein includes any of the recombinant or naturally-occurring forms of the Cpfl (CRISPR from Prevotella and Francisella 1) endonuclease or variants or homologs thereof that maintain Cpfl endonuclease enzyme activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to Cpfl). In embodiments, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring Cpfl protein. In embodiments, the Cpfl protein is substantially identical to the protein identified by the UniProt reference number U2UMQ6 or a variant or homolog having substantial identity thereto. In embodiments, the Cpfl protein is identical to the protein identified by the UniProt reference number U2UMQ6. In embodiments, the Cpfl protein has at least 75% sequence identity to the amino acid sequence of the protein identifiedby the UniProt reference number U2UMQ6. Tn embodiments, the Cpfl protein has at least 80% sequence identity to the amino acid sequence of the protein identified by the UniProt reference number U2UMQ6. In embodiments, the Cpfl protein is identical to the protein identified by the UniProt reference number U2UMQ6. In embodiments, the Cpfl protein has at least 85% sequence identity to the amino acid sequence of the protein identified by the UniProt reference number U2UMQ6. In embodiments, the Cpfl protein is identical to the protein identified by the UniProt reference number U2UMQ6. In embodiments, the Cpfl protein has at least 90% sequence identity to the amino acid sequence of the protein identified by the UniProt reference number U2UMQ6. In embodiments, the Cpfl protein is identical to the protein identified by the UniProt reference number U2UMQ6. In embodiments, the Cpfl protein has at least 95% sequence identity to the amino acid sequence of the protein identified by the UniProt reference number U2UMQ6.

[0092] The term “nuclease-deficient Cas9 variant’- refers to a Cas9 protein having one or more mutations that increase its binding specificity to PAM compared to wild type Cas9 and further include mutations that render the protein incapable of or having severely impaired endonuclease activity. Without wishing to be bound by theory, it is believed that the target sequence should be associated with a PAM (protospacer adjacent motif); that is, a short sequence recognized by the CRISPR complex. The precise sequence and length requirements for the PAM differ depending on the CRISPR enzyme used, but PAMs are typically 2-5 base pair sequences adjacent the protospacer (that is, the target sequence). The binding specificity of nuclease-deficient Cas9 variants to PAM can be determined by any method known in the art. Descriptions and uses of known Cas9 variants may be found, for example, in Shmakov et al., Diversity and evolution of class 2 CRISPR-Cas systems. Nat. Rev. Microbiol. 15, 2017 and Cebrian-Serrano et al, CRISPR-Cas orthologues and variants: optimizing the repertoire, specificity and delivery of genome engineering tools. Mamm. Genome 7-8, 2017.

[0093] The term “TALE’- or “transcription activator-like effector’- refers to artificial restriction enzymes generated by fusing the TAL effector DNA binding domain to a DNA cleavage domain. TALEs enable efficient, programmable, and specific DNA cleavage and represent powerful tools for genome editing in situ. Transcription activator-like effectors (TALEs) can be quickly engineered to bind practically any DNA sequence. The term TALE, as used herein, is broad and includes a monomeric TALE that can cleave double stranded DNA without assistance from another TALE. The term TALE is also used to refer to one or both members of a pair of TALEs that are engineered to work together to cleave DNA at thesame site. TALEs that work together may be referred to as a left-TALE and a right-TALE, which references the handedness of DNA. TALE are proteins secreted by Xanthomonas bacteria. The DNA binding domain contains a highly conserved 33-34 amino acid sequence with the exception of the 12th and 13th amino acids. These two locations are highly variable (repeat variable diresidue (RVD)) and show a strong correlation with specific nucleotide recognition. This simple relationship between amino acid sequence and DNA recognition has allowed for the engineering of specific DNA binding domains by selecting a combination of repeat segments containing the appropriate RVDs.

[0094] The term “base editor protein” is used herein according to its plain ordinary meaning and refers to a non-double strand break-dependent gene editor protein which modifies at least one nucleobase in a gene. In embodiments, the base editor protein modification of the nucleobases is directed by a nucleic acid guide sequence. In embodiments, the nuclei acid guide sequence is a guide RNA. In embodiments, the base editor protein includes a catalytically impaired Cas nuclease. In embodiments, the base editor protein includes a base- modification enzyme. In embodiments, the base-modification enzyme modifies single- stranded DNA. In embodiments, the base-modification enzyme does not modify double- stranded DNA. In embodiments, the base-modification enzyme includes a nucleobase deaminase enzyme. In embodiments, the base editor protein includes a cytidine base editor protein (CBE). In embodiments, the base editor protein includes an adenine base editor protein (ABE). In embodiments, the base editor protein includes a dual base editor protein.

[0095] The term “cytidine base editor protein” or “CBE” is used herein according to its plain ordinary meaning and refers to a base editor protein which mediates a cytosine to thymine modification in a gene. The terms cytidine base editor protein and cytosine base editor protein are used interchangeably herein. In embodiments, the CBE deaminates the exocyclic amine of the target cytosine to generate uracil. In embodiments, the CBE includes a BE1 protein, a BE2 protein, a BE3 protein, an HF2-BE2 protein, an HF-BE3 protein, an SaBE4 protein, an SaBE4-Gam protein, a BE4 protein, a BE4-Gam protein, a BE4max protein, an AncBE4max protein, a CBE6 protein, an eBE-Sl protein, an eBE-S3 protein, a YE1-BE3 protein, a YE2-BE3 protein, an EE-BE3 protein, a YEE-BE3 protein, a VQR-BE3 protein, a VRER-BE3 protein, an SaBE3 protein, an SaKKH-BE3 protein, a dCpfl-BE protein, a dCpfl-BE-YE protein, a dCpfl -eBE protein, a dCpfl -eBE-YE protein, an xBE3, a BE-PLUS protein, an hA3A-BE3 protein, an hA3A-BE3-Y13OF protein, an hA3A-BE3-Y132D protein, an hA3A-eBE-Y130F protein, an hA3A-eBE-Yl 32D protein, an eA3A-BE3 protein, an eA3A-HFl-BE3-2xUGI protein, an eA3A-Hypa-BE3-2xUGI protein, a DBE- A3A protein, a Target- AID protein, a Target- AID-NG protein, a TAM protein, a CRISPR-X protein, or a DBE-AIDmono protein.

[0096] The term “adenine base editor protein” or “ABE” is used herein according to its plain ordinary meaning and refers to a base editor protein which mediates an adenosine to guanosine modification in a gene. In embodiments, the ABE deaminates the exocyclic amine of the target adenosine to generate inosine. In embodiments, the inosine is read as guanosine by a polymerase. In embodiments, the inosine exhibits the base-pairing preference of guanosine in the context of a polymerase active site. In embodiments, the ABE includes an ABE7.9 protein, an ABE7.10 protein, an AB Emax protein, an xABE protein, a VQR-ABE protein, a VRER-ABE protein, an SaKKH-ABE protein, an ABEsa protein, or an ABE8e protein.

[0097] The term “dual base editor protein” is used herein according to its plain ordinary meaning and refers to a base editor protein which mediates either a cytosine to thymine modification and / or an adenosine to guanosine modification in a gene. In embodiments, the dual base editor protein deaminates the exocyclic amine of the target cytosine to generate uracil. In embodiments, the dual base editor protein deaminates the exocyclic amine of the target adenosine to generate inosine. In embodiments, the inosine is read as guanosine by a polymerase. In embodiments, the inosine exhibits the base-pairing preference of guanosine in the context of a polymerase active site. In embodiments, the dual base editor protein includes an A&C-BEmax protein, an SpCas9 TadDE protein, an SaCas9 TadDE protein, or a CABE protein.

[0098] The term “prime editor protein” or “PE” is used herein according to its plain ordinary meaning and refers to a non-double strand break-dependent gene editor protein which modifies at least one nucleobase in a gene. In embodiments, the PE is capable all 12 possible base-to base conversions. In embodiments, the PE is capable of converting a cytosine to a thymine, an adenosine, or a guanosine. In embodiments, the PE is capable of converting an adenosine to a thymine, a cytosine, or a guanosine. In embodiments, the PE is capable of converting a thymine to an adenosine, a cytosine, or a guanosine. In embodiments, the PE is capable of converting a guanosine to a thymine, an adenosine, or a cytosine. In embodiments, the PE is capable of inserting a nucleotide into a gene. In embodiments, the PE is capable of deleting a nucleotide form a gene. In embodiments, the PE includes a nickase.In further embodiments, the nickase includes a Cas 9 H840A nickase. In embodiments, the PE includes a reverse transcriptase. In further embodiments, the PE includes a Moloney Murine Leukemia Virus (M-MLV) reverse transcriptase. In embodiments, the PE includes a PEI protein, a PE2 protein, a PE3 protein, a PE4 protein, a PE5 protein, a PE6 protein, a PE7 protein, a PE2max protein, a PE3max protein, a PE4max protein, or a PE5max protein.

[0099] The term “zinc finger (ZF) protein” or “zinc finger binding domain” or “zinc finger DNA binding domain” are used interchangeably herein and refer to a protein, or a domain within a larger protein, that binds DNA. In embodiments, the zinc finger protein binds DNA in a sequence-specific manner. In embodiments, the zinc finger protein binds DNA through one or more zinc finger motifs. In embodiments, the zinc finger motifs are regions of amino acid sequence within the binding domain whose structure is stabilized through coordination of a zinc ion. In embodiments, the zinc finger domain is non-naturally occurring in that it is engineered to bind to a target site of choice. In embodiments, the zinc finger binding domain refers to a protein, a domain within a larger protein, or a nuclease-deficient RNA-guided DNA endonuclease enzyme that is capable of binding to any zinc finger motif known in the art, such as the C2H2 type of zinc finger motifs. In embodiments, a poly dactyl zinc finger protein includes at least two zinc finger motifs, at least three zinc finger motifs, at least four zinc finger motifs, or at least six zinc finger motifs. In embodiments, the polydactyl zinc finger protein includes six zinc finger motifs. In embodiments, a polydactyl zinc finger protein includes at least two alpha helix domains, at least three alpha helix domains, at least four alpha helix domains, or at least six alpha helix domains. In embodiments, the polydactyl zinc finger protein includes six alpha helix domains. Polydactyl zinc finger proteins are well known in the art. See, e.g., Liu et al., “Design of polydactyl zinc-finger proteins for unique addressing within complex genomes,” PNAS, 1997, 94(11):5525-30; Beerli & Barbas, “Engineering polydactyl zinc-finger transcription factors,” Nat Biotechnol, 2002, 20(2): 135- 41; and Segal et al., “Structure of Aart, a Designed Six-finger Zinc Finger Peptide, Bound to DNA,” J Mol Biol, 2006, 363(2):405-21, each of which is incorporated herein in their entirety by reference and for all purposes.

[0100] The term “chimeric antigen receptor protein” or “CAR protein” is used herein according to its plain ordinary meaning and refers to a recombinant protein that includes both antigen binding and T cell activating functions. In embodiments, the CAR protein includes a heavy chain variable domain and a light chain variable domain which binds antigens. In embodiments, the binding of a CAR to an antigen activates a T cell.

[0101] A “nuclear localization sequence” or “nuclear localization signal” or “NLS” is a peptide that directs proteins to the nucleus. In embodiments, the NLS includes five basic, positively charged amino acids. The NLS may be located anywhere on the peptide chain. In embodiments, the NLS is an NLS derived from SV40.

[0102] The term “RNA stem-loop sequence” is used herein according to its plain ordinary meaning and refers to two regions of the same RNA strand, usually complementary in nucleotide sequence, that base-pair to form a double helix that ends in a loop of unpaired nucleotides. Ine embodiments, the two regions of the same RNA strand are complementary in nucleotide sequence and base-pair to form a double helix that ends in a loop of unpaired nucleotides. The term “RNA loop sequence” refers to the loop of unpaired nucleotides in an RNA stem-loop sequence.

[0103] The term “spacer domain” is used herein according to its plain ordinary meaning and refers to a nucleic acid sequence that separates two nucleic acid sequences.

[0104] The terms "plasmid", "vector" or "expression vector" refer to a nucleic acid molecule that encodes for genes and / or regulatory elements necessary for the expression of genes. Expression of a gene from a plasmid can occur in cis or in trans. If a gene is expressed in cis, the gene and the regulatory elements are encoded by the same plasmid. Expression in trans refers to the instance where the gene and the regulatory elements are encoded by separate plasmids In embodiments, the expression vector further includes a transposase or a recombinase.

[0105] The term “transposase” is used herein according to its plain ordinary meaning and refers to an enzyme capable of binding to a nucleic acid sequence (e.g., DNA) and catalyzing its movement to another part of a genome. In embodiments, the nucleic acid sequence bound by a transposase is referred to as a transposon. In embodiments, the transposase binds the transposon and catalyzes its movement to another part of a genome via a cut-and-paste mechanism or a replicative mechanism. In embodiments, the movement of a transposon to another part of the genome is referred to as transposition. In embodiments, the transposase is a Piggybac (PB) transposase.

[0106] The term “transposon” or “transposable element” is used herein according to its plain ordinary meaning and refers to a nucleic acid sequence (e.g., DNA) that can chance its position within a genome. In embodiments, the transposon is a Piggybac (PB) transposon.

[0107] The term “recombinase” is used herein according to its plain ordinary meaning and refers to a genetic recombination enzyme capable of directionally catalyzing nucleic acid(e.g., DNA) reactions between target site sequences (e.g., 30-40 nucleotides) that are specific to the enzyme. In embodiments, the nucleic acid exchange reaction is an excision reaction, an insertion reaction, an inversion reaction, a translocation reaction, or a cassette exchange reaction. In embodiments, the recombinase is a Cre recombinase, a Hin recombinase, a Tre recombinase, or a FLP recombinase.

[0108] The terms "transfection", "transduction", "transfecting" or "transducing" can be used interchangeably and are defined as a process of introducing a nucleic acid molecule or a protein to a cell. Nucleic acids are introduced to a cell using non-viral or viral-based methods. The nucleic acid molecules may be gene sequences encoding complete proteins or functional portions thereof. Non-viral methods of transfection include any appropriate transfection method that does not use viral DNA or viral particles as a delivery system to introduce the nucleic acid molecule into the cell. Exemplary non-viral transfection methods include calcium phosphate transfection, liposomal transfection, nucleofection, sonoporation, transfection through heat shock, magnetifection and electroporation. In some embodiments, the nucleic acid molecules are introduced into a cell using electroporation following standard procedures well known in the art. For viral-based methods of transfection any useful viral vector may be used in the methods described herein. Examples for viral vectors include, but are not limited to retroviral, adenoviral, lentiviral and adeno-associated viral vectors. In some embodiments, the nucleic acid molecules are introduced into a cell using a retroviral vector following standard procedures well known in the art. The terms "transfection" or "transduction" also refer to introducing proteins into a cell from the external environment. Typically, transduction or transfection of a protein relies on attachment of a peptide or protein capable of crossing the cell membrane to the protein of interest. See, e.g., Ford et al. (2001) Gene Therapy 8:1-4 and Prochiantz (2007) Nat. Methods 4:119-20.

[0109] A "label" or a "detectable moiety" is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include 32P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. Any appropriate method known in the art for conjugating an antibody to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego.

[0110] When the label or detectable moiety is a radioactive metal or paramagnetic ion, the agent may be reacted with another long-tailed reagent having a long tail with one or more chelating groups attached to the long tail for binding to these ions. The long tail may be a polymer such as a polylysine, polysaccharide, or other derivatized or derivatizable chain having pendant groups to which the metals or ions may be added for binding. Examples of chelating groups that may be used according to the disclosure include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTP A), DOTA, NOTA, NETA, TETA, porphyrins, polyamines, crown ethers, bis- thiosemicarbazones, polyoximes, and like groups. The chelate is normally linked to the PSMA antibody or functional antibody fragment by a group, which enables the formation of a bond to the molecule with minimal loss of immunoreactivity and minimal aggregation and / or internal cross-linking. The same chelates, when complexed with non-radioactive metals, such as manganese, iron and gadolinium are useful for MRI, when used along with the antibodies and carriers described herein. Macrocyclic chelates such as NOTA, DOTA, and TETA are of use with a variety of metals and radiometals including, but not limited to, radionuclides of gallium, yttrium and copper, respectively. Other ring-type chelates such as macrocyclic polyethers, which are of interest for stably binding nuclides, such as223Ra for RAIT may be used. In certain embodiments, chelating moieties may be used to attach a PET imaging agent, such as an A1-18F complex, to a targeting molecule for use in PET analysis.

[0111] "Contacting" is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. antibodies and antigens) to become sufficiently proximal to react, interact, or physically touch. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0112] The term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be, for example, a pharmaceutical composition as provided herein and a cell. In embodiments contacting includes, for example, allowing a pharmaceutical composition as described herein to interact with a cell.

[0113] A "cell" as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine witha second gamete to produce a viable offspring. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells.

[0114] The term "recombinant" when used with reference, e.g., to a cell, nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all. Transgenic cells and plants are those that express a heterologous gene or coding sequence, typically as a result of recombinant methods.

[0115] The term "isolated", when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0116] The term "heterologous" when used with reference to portions of a nucleic acid indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature. For instance, the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).

[0117] The term "exogenous" refers to a molecule or substance (e.g., a compound, nucleic acid or protein) that originates from outside a given cell or organism. For example, an "exogenous promoter" as referred to herein is a promoter that does not originate from the cell or organism it is expressed by. Conversely, the term "endogenous" or "endogenous promoter" refers to a molecule or substance that is native to, or originates within, a given cell or organism.

[0118] As defined herein, the term "inhibition", "inhibit", "inhibiting" and the like in reference to cell proliferation (e.g., cancer cell proliferation) means negatively affecting (e.g., decreasing proliferation) or killing the cell. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease (e.g., cancer, cancer cell proliferation). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein (e.g. a cancer-associated protein). Similarly an "inhibitor" is a compound or protein that inhibits a receptor or another protein, e.g.,, by binding, partially or totally blocking, decreasing, preventing, delaying, inactivating, desensitizing, or down-regulating activity (e.g., a receptor activity or a protein activity).

[0119] The term "expression" includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0120] “Biological sample” or “sample” refer to materials obtained from or derived from a subject or patient. A biological sample includes sections of tissues such as biopsy and autopsy samples, and frozen sections taken for histological purposes. Such samples include bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells) stool, urine, synovial fluid, joint tissue, synovial tissue, synoviocytes, fibroblast-like synoviocytes, macrophage-like synoviocytes, immune cells, hematopoietic cells, fibroblasts, macrophages, T cells, etc. A biological sample is typically obtained from a eukaryotic organism, such as a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish.

[0121] A “control” or “standard control” refers to a sample, measurement, or value that serves as a reference, usually a known reference, for comparison to a test sample, measurement, or value. For example, a test sample can be taken from a patient suspected of having a given disease (e.g. cancer) and compared to a known normal (non-diseased) individual (e.g. a standard control subject). A standard control can also represent an average measurement or value gathered from a population of similar individuals (e.g. standard control subjects) that do not have a given disease (i.e. standard control population), e.g., healthyindividuals with a similar medical background, same age, weight, etc. A standard control value can also be obtained from the same individual, e.g. from an earlier-obtained sample from the patient prior to disease onset. For example, a control can be devised to compare therapeutic benefit based on pharmacological data (e.g., half-life) or therapeutic measures (e.g., comparison of side effects). Controls are also valuable for determining the significance of data. For example, if values for a given parameter are widely variant in controls, variation in test samples will not be considered as significant. One of skill will recognize that standard controls can be designed for assessment of any number of parameters (e.g. RNA levels, protein levels, specific cell types, specific bodily fluids, specific tissues, etc).

[0122] One of skill in the art will understand which standard controls are most appropriate in a given situation and be able to analyze data based on comparisons to standard control values. Standard controls are also valuable for determining the significance (e.g. statistical significance) of data. For example, if values for a given parameter are widely variant in standard controls, variation in test samples will not be considered as significant.

[0123] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.NUCLEIC ACID COMPOSITIONS

[0124] The compositions provided herein include nucleic acid sequences or portions thereof provided herein including embodiments thereof. The nucleic acid sequences (e.g., RNA sequence, DNA sequence) provided herein are useful for expressing a gene of interest (e.g., a transgene) in a cell. The nucleic acids provided herein including embodiments thereof are described in detail throughout the application (including the description above and in the examples section). The inventors surprisingly found that the nucleic acid sequences (e.g. RNA or DNA) provided herein including embodiments thereof (e.g., adaptamers) are capable of efficiently recruiting endogenous ADAR enzymes, once the nucleic acid sequences are stabilized by binding of a ligand to the ligand-binding aptamer. Once recruited, the endogenous ADAR efficiently deaminate an adenosine in a UAG stop codon, thereby allowing translation of the downstream transgene. Thus, in an aspect is provided a ribonucleic acid (RNA) sequence including from 5' to 3' a first member of a double- strandedadenosine deaminase acting on RNA (dsADAR)-binding region, a ligand-binding aptamer, a second member of the dsADAR-binding region, and a transgene-encoding sequence, wherein upon binding a ligand to the ligand-binding aptamer, the first member of the dsADAR- binding region and the second member of the dsADAR-binding region are capable of hybridizing to form a dsADAR-binding region, wherein the dsADAR-binding region includes at least 1 mismatched base pair, forming at least 1 double-stranded bulge, wherein the double-stranded bulge includes a mismatched base pair including an adenosine that forms part of an UAG stop codon.

[0125] In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of any one of SEQ ID NOs:13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 172, 174, 175, 178, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, or 222. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 15. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 17. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 19. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:21. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:23. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:27. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:31. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 188. In embodiments, the first member of the dsADAR- binding region includes the nucleotide sequence of SEQ ID NO: 190. In embodiments, thefirst member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR- binding region includes the nucleotide sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 198. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:200. In embodiments, the first member of the dsADAR- binding region includes the nucleotide sequence of SEQ ID NO:202. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR- binding region includes the nucleotide sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NQ:210. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR- binding region includes the nucleotide sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:216. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR- binding region includes the nucleotide sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:222.

[0126] In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of any one of SEQ ID NOs: 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 172, 174, 175, 178, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, or 222. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 15. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:17. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 19. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:21 . In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:23. In embodiments, the first member ofthe ds ADAR-binding region has the nucleotide sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:27. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:31 . In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:172. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR- binding region has the nucleotide sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 188. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR- binding region has the nucleotide sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 198. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:200. In embodiments, the first member of the dsADAR- binding region has the nucleotide sequence of SEQ ID NO:202. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR- binding region has the nucleotide sequence of SEQ ID NO:210. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:216. In embodiments, the first member of the dsADAR- binding region has the nucleotide sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:222.

[0127] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 13. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO:13.

[0128] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 contiguous nucleotides of the sequence of SEQ ID NO: 15. In embodiments, the first member of the dsADAR-bindingregion includes a nucleotide sequence having 70% sequence identity to 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 contiguous nucleotides of the sequence of SEQ ID NO: 15. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 15. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 15. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO:15. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 15. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO:15. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 15. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO:15. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 15. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO:15. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 15.

[0129] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 17. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO:17. In embodiments,the first member of the dsAD AR -binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 17. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO:17. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 17. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO:17. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 17. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO:17. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 17. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO:17. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 17. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO:17.

[0130] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO: 19. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO: 19. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:19. Inembodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO: 19. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:19. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO: 19. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO: 19. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:19. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO: 19. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO: 19. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO: 19. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO: 19.

[0131] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO: 21. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:21. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO: 21. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:21. In embodiments,the first member of the dsAD AR -binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:21. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:21. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:21. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:21. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:21. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:21. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:21. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:21.

[0132] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO: 23. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:23. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:23. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:23. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQID NO:23. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:23. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:23. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:23. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:23. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:23. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:23. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:23.

[0133] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO: 25. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguousnucleotides of the sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:25. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:25.

[0134] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:27. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:27. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 27. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:27. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 27. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:27. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95%sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:27. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:27. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:27. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:27. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:27. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:27.

[0135] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, 30, 31 , 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes anucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, 30, 31 , 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:29.

[0136] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO: 31. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:31. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:31. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:31. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:31. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:31. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:31. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:31. In embodiments, the first member of thedsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:31. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:31. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:31. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:31.

[0137] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes a nucleotidesequence having 98% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 172.

[0138] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 174. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, or 30contiguous nucleotides of the sequence of SEQ ID NO: 174. Tn embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 174.

[0139] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100%sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 176.

[0140] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 178. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:178.

[0141] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 188. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:188. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 188. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:188. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 188. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 188. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 188. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 188. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 188. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 188. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 188. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:188.

[0142] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 190.

[0143] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR-binding region includesa nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:192. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 192. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 192.

[0144] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4,5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 194.

[0145] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguousnucleotides of the sequence of SEQ ID NO: 196. Tn embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 196. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 196.

[0146] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 198. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 198. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 198. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:198. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ IDNO: 198. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 198. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 198. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 198. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 198. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 198. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 198. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 198.

[0147] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:200. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:200. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NQ:200. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:200. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:200. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19contiguous nucleotides of the sequence of SEQ ID NO:200. Tn embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:200. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:200. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:200. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:200. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NQ:200. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:200.

[0148] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:202. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:202. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:202. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NQ:202. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:202. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:202. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides ofthe sequence of SEQ TD NO:202. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:202. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NQ:202. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:202. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:202. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:202.

[0149] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204. In embodiments, the firstmember of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:204.

[0150] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206. In embodiments, the first member of thedsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:206.

[0151] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208. In embodiments, the firstmember of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:208.

[0152] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:210. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:210. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:210. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:210. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:210. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:210. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:210. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:210. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NQ:210. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:210. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:210. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100%sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:210.

[0153] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:212.

[0154] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:214.

[0155] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of thesequence of SEQ ID NO:216. In embodiments, the first member of the ds ADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:216. In embodiments, the first member of the ds ADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:216. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:216. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:216. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:216. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:216. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:216. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:216. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:216. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:216. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:216.

[0156] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguousnucleotides of the sequence of SEQ ID NO:218. Tn embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:218. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:218.

[0157] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ IDNO:220. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:220. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:220.

[0158] In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%; sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222. In embodiments, the first member of thedsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222. In embodiments, the first member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222. In embodiments, the first member of the dsADAR- binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:222.

[0159] In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of any one of SEQ ID NOs:14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 173, 175, 177, 179, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, or 223. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 14. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 16. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 18. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:27. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:28.In embodiments, the second member of the dsAD AR-binding region includes the nucleotide sequence of SEQ ID NO:30. In embodiments, the second member of the dsAD AR-binding region includes the nucleotide sequence of SEQ ID NO:32. In embodiments, the second member of the dsAD AR-binding region includes the nucleotide sequence of SEQ ID NO: 173. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 178. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 179. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 191. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 194. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:201. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:203. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:205. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:207. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:211. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO :219. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ IDNO:221. In embodiments, the second member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:223.

[0160] In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of any one of SEQ ID NOs: 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 173, 175, 177, 179, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, or 223. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 14. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 16. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 18. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:30. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:32. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:173. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 178. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:179. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 191. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 194. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ IDNO:201. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:203. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:205. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NQ:207. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:211. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:219. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:221. In embodiments, the second member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:223.

[0161] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 14. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 14. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO:14. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 14. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 14. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO:14. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 14. In embodiments, the second member of the dsADAR-bindingregion includes a nucleotide sequence having 96% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 14. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 14. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 14. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 14. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 6, 7, 8, 9, or 10 contiguous nucleotides of the sequence of SEQ ID NO: 14.

[0162] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 16. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 16. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 16. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 16. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO:16. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 16. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO:16. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 contiguous nucleotides of the sequence of SEQ ID NO: 16. In embodiments, the second member of thedsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO:16. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 16. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO:16. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, or 12 contiguous nucleotides of the sequence of SEQ ID NO: 16.

[0163] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 18. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 18. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 18. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 18. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 18. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 18. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO:18. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 18. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 18. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO: 18. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO:18. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous nucleotides of the sequence of SEQ ID NO:18.

[0164] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NQ:20. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4,5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:20. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 16, 17, or 18 contiguous nucleotides of the sequence of SEQ ID NO:20.

[0165] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having99% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides of the sequence of SEQ ID NO:22.

[0166] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 21 , 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 21, 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 21 , 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24. In embodiments, the second member of the dsADAR-binding region includes anucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 21 , 22, 23, or 24 contiguous nucleotides of the sequence of SEQ ID NO:24.

[0167] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, 26, or 27 contiguous nucleotides of the sequence of SEQ ID NO:26.

[0168] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, 26, 27, 28, 29, or 30 contiguous nucleotides of the sequence of SEQ ID NO:28.

[0169] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or100% sequence identity to 4, 5, 10, 20, 25, 30, 31 , 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:30. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:30. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:30. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:30. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:30. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NQ:30. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:30. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:30. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:30. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:30. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NQ:30. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, 30, 31, 32, or 33 contiguous nucleotides of the sequence of SEQ ID NO:30.

[0170] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:32. In embodiments, the second member of the dsADAR-bindingregion includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:32. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:32. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:32. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO: 32. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:32. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:32. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:32. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:32. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:32. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:32. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, 30, 35 or 36 contiguous nucleotides of the sequence of SEQ ID NO:32.

[0171] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173. In embodiments, the secondmember of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 173.

[0172] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR-binding region includes a nucleotidesequence having 80% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 175.

[0173] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20,25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177. Tn embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 177.

[0174] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 179. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 179. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 179. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 179. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 179. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotidesof the sequence of SEQ TD NO: 179. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 179. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 179. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 179. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 179. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 179. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 179.

[0175] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ IDNO: 189. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 189. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 189.

[0176] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 191. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:191. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 191. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 191. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 191. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 191. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 191. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19contiguous nucleotides of the sequence of SEQ ID NO:191. Tn embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 191. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 191. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 191. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO: 191.

[0177] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 193. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 193. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 193. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 193. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 193. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 193. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 193. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 193. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides ofthe sequence of SEQ TD NO: 193. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 193. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 193. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 193.

[0178] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195. In embodiments, thesecond member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 195.

[0179] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197. In embodiments, the second member of thedsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO: 197.

[0180] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO: 199.

[0181] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:201. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:201. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:201. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:201. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NQ:201. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:201. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:201. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:201. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:201. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:201. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:201. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of SEQ ID NO:201.

[0182] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:203. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:203. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:203. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:203. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:203. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NQ:203. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:203. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:203. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 203. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:203. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:203. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:203.

[0183] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:205. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25contiguous nucleotides of the sequence of SEQ ID NO:205. Tn embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:205. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 205. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:205. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:205. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:205. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:205. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO: 205. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:205. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:205. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:205.

[0184] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:207. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:207. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ IDNO:207. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:207. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:207. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:207. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:207. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:207. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:207. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:207. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:207. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:207.

[0185] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209. In embodiments, the secondmember of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:209.

[0186] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:211. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:211. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:211. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO :211. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:211. In embodiments, thesecond member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:211. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:211. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:211. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:211. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:211. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:211. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:211.

[0187] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO :213. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR-binding region includes anucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:213. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:213.

[0188] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215. Tn embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having96% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:215.

[0189] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97 % sequenceidentity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, 30, or 35 contiguous nucleotides of the sequence of SEQ ID NO:217.

[0190] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15,20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219. Tn embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, or 25 contiguous nucleotides of the sequence of SEQ ID NO:219.

[0191] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:221. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:221. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:221. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:221. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:221. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:221. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:221. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:221. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:221. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:221. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguousnucleotides of the sequence of SEQ ID NO:221 . Tn embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, or 30 contiguous nucleotides of the sequence of SEQ ID NO:221.

[0192] In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 70% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 75% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 80% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 85% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 90% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223. In embodiments, the second member of the dsADAR- binding region includes a nucleotide sequence having 95% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 96% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 97% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 98% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 99% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223. In embodiments, the second member of the dsADAR-binding region includes a nucleotide sequence having 100% sequence identity to 4, 5, 10, 15, 20, 25, or 35 contiguous nucleotides of the sequence of SEQ ID NO:223.

[0193] In embodiments, the RNA sequence further includes an additional RNA domain 3' of the second member of the dsADAR-binding region and 5' of the transgene-encoding sequence, wherein the additional RNA domain includes from 5’ to 3' a third member of a dsADAR-binding region, a second ligand-binding aptamer, and a fourth member of the dsADAR-binding region 5' of the transgene-encoding sequence, wherein upon binding a second ligand to the second ligand-binding aptamer, the third member of the dsADAR- binding region and the fourth member of the dsADAR-binding region are capable of hybridizing to form a second dsADAR-binding region, wherein the second dsADAR-binding region includes at least 1 additional mismatched base pair, forming at least 1 additional double-stranded bulge, wherein the additional double- stranded bulge includes an additional mismatched base pair including an adenosine that forms part of an UAG stop codon.

[0194] In embodiments, the first member of the dsADAR-binding region and the third member of the dsADAR-binding region are the same; and the second member of the dsADAR-binding region and the fourth member of the dsADAR-binding regions are the same. In embodiments, the first member of the dsADAR-binding region and the third member of the dsADAR-binding region are the same. In embodiments, the second member of the dsADAR-binding region and the fourth member of the dsADAR-binding regions are the same.

[0195] In embodiments, the first member of the dsADAR-binding region and the third member of the dsADAR-binding region are different sequences; and the second member of the dsADAR-binding region and the fourth member of the dsADAR-binding regions are different sequences. In embodiments, the first member of the dsADAR-binding region and the third member of the dsADAR-binding region are different sequences. In embodiments, the second member of the dsADAR-binding region and the fourth member of the dsADAR- binding regions are different sequences.

[0196] In embodiments, the ligand-binding aptamer and the second ligand binding aptamer are the same aptamer. In embodiments, the ligand-binding aptamer and the second ligand binding aptamer are different aptamers.

[0197] In embodiments, the RNA sequence includes the nucleotide sequence of any one of SEQ ID NOs:33-42, 180-183, or 224-275. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:33. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:34. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:35. In embodiments, the RNA sequence includes thenucleotide sequence of SEQ ID NO:36. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:37. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:38. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:39. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NQ:40. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:41. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:42. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO: 180. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO: 181. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO: 182. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO: 183.

[0198] In embodiments, the RNA sequence includes the nucleotide sequence of SEQ IDNO:224. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:225. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:226. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:227. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:228. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:229. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:230. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:231. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:232. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:233. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:234. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:235. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:236. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:237. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:238. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:239. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:240. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ IDNO:241.

[0199] In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:242. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:243. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ IDNO:244. In embodiments, the RNA sequence includes the nucleotide sequence ot SEQ ID NO:245. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:246. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:247. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:248. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:249. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:250. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:251. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:252. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:253. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:254. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:255. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:256. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:257. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:258. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:259. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:260. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:261. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:262. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:263. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:264. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:265. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:266. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:267. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:268. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:269. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NQ:270. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:271. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:272. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:273. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:274. In embodiments, the RNA sequence includes the nucleotide sequence of SEQ ID NO:275.

[0200] In embodiments, the RNA sequence has the nucleotide sequence of any one of SEQ ID NOs:33-42, 180-183, or 224-275. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:33. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:34. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:35. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:36. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:37. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:38. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:39. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:40. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:41. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:42. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO: 180. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO: 181. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO: 182. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO: 183.

[0201] In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:224. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:225. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:226. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:227. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:228. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:229. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:230. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:231. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:232. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:233. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:234. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:235. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:236. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:237. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:238. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:239. In embodiments, the RNA sequence has the nucleotide sequence of SEQ IDNO:240. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:241.

[0202] In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:242. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:243. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:244. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:245. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:246. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:247. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:248. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:249. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:250. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:251. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:252. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:253. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:254. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:255. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:256. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:257. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:258. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:259. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:260. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:261. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:262. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:263. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:264. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:265. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:266. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:267. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:268. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:269. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:270. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:271. In embodiments, the RNA sequence has the nucleotide sequence of SEQ IDNO:272. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:273. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:274. In embodiments, the RNA sequence has the nucleotide sequence of SEQ ID NO:275.

[0203] In another aspect is provided a ribonucleic acid (RNA) sequence including from 5' to 3' a first member of a double-stranded nucleic acid sequence, a first member of a split ligand-binding aptamer, a first member of an adenosine deaminase acting on RNA (ds AD AR) -binding region, a second member of the dsADAR-binding region, a second member of the ligand-binding aptamer, a second member of the double- stranded nucleic acid sequence, and a transgene-encoding sequence, wherein the first member of a split ligandbinding aptamer is capable of hybridizing the second member of the split ligand-binding aptamer to form a ligand-binding aptamer capable of binding a ligand, wherein upon binding a ligand to the ligand-binding aptamer, the first member of the dsADAR-binding region and the second member of the dsADAR-binding region are capable of hybridizing to form a dsADAR-binding region, wherein the dsADAR-binding region includes at least 1 mismatched base pair, forming at least 1 double- stranded bulge, wherein the double- stranded bulge includes a mismatched base pair including an adenosine that forms part of an UAG stop codon.

[0204] In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 50 nucleotides in length. In embodiments, the first member of the doublestranded nucleic acid sequence and the second member of the double- stranded nucleic acid sequence are from 5 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the doublestranded nucleic acid sequence are from 6 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 7 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 8 nucleotides to 50 nucleotides in length. In embodiments, the first member of the doublestranded nucleic acid sequence and the second member of the double- stranded nucleic acidsequence are from 9 nucleotides to 50 nucleotides in length. Tn embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the doublestranded nucleic acid sequence are from 10 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 15 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 20 nucleotides to 50 nucleotides in length. In embodiments, the first member of the doublestranded nucleic acid sequence and the second member of the double- stranded nucleic acid sequence are from 25 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the doublestranded nucleic acid sequence are from 30 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 35 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 40 nucleotides to 50 nucleotides in length. In embodiments, the first member of the doublestranded nucleic acid sequence and the second member of the double- stranded nucleic acid sequence are from 45 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the doublestranded nucleic acid sequence are from 46 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 47 nucleotides to 50 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 48 nucleotides to 50 nucleotides in length. In embodiments, the first member of the doublestranded nucleic acid sequence and the second member of the double- stranded nucleic acid sequence are from 49 nucleotides to 50 nucleotides in length.

[0205] In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 49 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 48 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 47 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the doublestranded nucleic acid sequence are from 4 nucleotides to 46 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 45 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 40 nucleotides in length. In embodiments, the first member of the doublestranded nucleic acid sequence and the second member of the double- stranded nucleic acid sequence are from 4 nucleotides to 35 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the doublestranded nucleic acid sequence are from 4 nucleotides to 30 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 25 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 20 nucleotides in length. In embodiments, the first member of the doublestranded nucleic acid sequence and the second member of the double- stranded nucleic acid sequence are from 4 nucleotides to 15 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the doublestranded nucleic acid sequence are from 4 nucleotides to 10 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 9 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 8 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 7 nucleotides in length. In embodiments, the first member of the doublestranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 6 nucleotides in length. In embodiments, the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 5 nucleotides in length.

[0206] In embodiments, the first member of a double-stranded nucleic acid sequence includes the nucleotide sequence of any one of SEQ ID NOs:43, 51, 59, 67, 75, 83, 91, 99, 107, 115, 123, 131, or 139. In embodiments, the first member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:43. In embodiments, the first member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:51. In embodiments, the first member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:59. In embodiments, the first member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 67. In embodiments, the first member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:75. In embodiments, the first member of a doublestranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 83. In embodiments, the first member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:91. In embodiments, the first member of a doublestranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:99. In embodiments, the first member of a double- stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 107. In embodiments, the first member of a doublestranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 115. In embodiments, the first member of a double- stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 123. In embodiments, the first member of a doublestranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 131. In embodiments, the first member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 139.

[0207] In embodiments, the first member of a double- stranded nucleic acid sequence has the nucleotide sequence of any one of SEQ ID NOs:43, 51, 59, 67, 75, 83, 91, 99, 107, 115, 123, 131, or 139. In embodiments, the first member of a double- stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:43. In embodiments, the first member of a double-stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:51. In embodiments, the first member of a double- stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:59. In embodiments, the first member of a double- stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:67. In embodiments, the first member of a double-stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:75. In embodiments, the first member of a double-stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:83. In embodiments, the first member of a double-stranded nucleic acid sequence has the nucleotide sequence of SEQ TD NO:91 . In embodiments, the first member of a double- stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:99. In embodiments, the first member of a double- stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 107. In embodiments, the first member of a double-stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 115. In embodiments, the first member of a double-stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 123. In embodiments, the first member of a doublestranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 131. In embodiments, the first member of a double- stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 139.

[0208] In embodiments, the second member of a double-stranded nucleic acid sequence includes the nucleotide sequence of any one of SEQ ID NOs:49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, or 145. In embodiments, the second member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:49. In embodiments, the second member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:57. In embodiments, the second member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:65. In embodiments, the second member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:73. In embodiments, the second member of a double- stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:81. In embodiments, the second member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:89. In embodiments, the second member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO:97. In embodiments, the second member of a doublestranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 105. In embodiments, the second member of a double- stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 113. In embodiments, the second member of a double- stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 121. In embodiments, the second member of a double-stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 129. In embodiments, the second member of a doublestranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 137. In embodiments, the second member of a double- stranded nucleic acid sequence includes the nucleotide sequence of SEQ ID NO: 145.

[0209] In embodiments, the second member of a double-stranded nucleic acid sequence has the nucleotide sequence of any one of SEQ ID NOs:49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, or 145. In embodiments, the second member of a double- stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:49. In embodiments, the second member of a double-stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:57. In embodiments, the second member of a double-stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:65. In embodiments, the second member of a doublestranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:73. In embodiments, the second member of a double-stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:81. In embodiments, the second member of a doublestranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 89. In embodiments, the second member of a double- stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO:97. In embodiments, the second member of a double- stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 105. In embodiments, the second member of a double- stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 113. In embodiments, the second member of a doublestranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 121. In embodiments, the second member of a double-stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 129. In embodiments, the second member of a doublestranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 137. In embodiments, the second member of a double-stranded nucleic acid sequence has the nucleotide sequence of SEQ ID NO: 145.

[0210] In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of any one of SEQ ID NOs:45, 53, 61, 69, 77, 85, 93, 101, 109, 117, 125, 133, or 141. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:45. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:53. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:61. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:69. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:77. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:85. In embodiments, the first member of the dsADAR-bindingregion includes the nucleotide sequence of SEQ TD NO:93. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO:101. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 109. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 117. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 125. In embodiments, the first member of the dsADAR-binding region includes the nucleotide sequence of SEQ ID NO: 133. In embodiments, the first member of the dsADAR- binding region includes the nucleotide sequence of SEQ ID NO: 141.

[0211] In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of any one of SEQ ID NOs:45, 53, 61, 69, 77, 85, 93, 101, 109, 117, 125, 133, or 141. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 45. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:53. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:61. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 69. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 77. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 85. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO:93. In embodiments, the first member of the dsADAR-binding region has the nucleotide sequence of SEQ ID NO: 101. In embodiments, the first member of the dsAD...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A ribonucleic acid (RNA) sequence comprising from 5' to 3’ a first member of a double-stranded adenosine deaminase acting on RNA (dsADAR)-binding region, a ligand-binding aptamer, a second member of the dsADAR-binding region, and a transgene-encoding sequence, wherein upon binding a ligand to the ligand-binding aptamer, the first member of the dsADAR-binding region and the second member of the dsADAR-binding region are capable of hybridizing to form a dsADAR-binding region, wherein the dsADAR-binding region comprises at least 1 mismatched base pair, forming at least 1 double- stranded bulge, wherein the double-stranded bulge comprises a mismatched base pair comprising an adenosine that forms part of an UAG stop codon.

2. The RNA sequence of claim 1 , wherein the first member of the dsADAR binding region and the second member of the dsADAR-binding region are from 4 nucleotides to 50 nucleotides in length.

3. The RNA sequence of claim 1, wherein the dsADAR-binding region comprises from 1 to 10 additional double-stranded bulges.

4. The RNA sequence of claim 1, wherein the double- stranded bulge and / or the additional double-stranded bulges each independently comprise between 1 to 3 mismatched base pairs.

5. The RNA sequence of claim 1, further comprising an adenosine deaminase acting on RNA (ADAR) -encoding sequence 3' of the transgene-encoding sequence.

6. The RNA sequence of claim 1, wherein the RNA sequence comprises a nucleotide sequence from 20 nucleotides to 200 nucleotides in length excluding the transgene-encoding sequence.

7. The RNA sequence of claim 1, wherein the first member of the dsADAR-binding region comprises the nucleotide sequence of any one of SEQ ID NOs: 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 172, 174, 175, 178, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, or 222.

8. The RNA sequence of claim 1 , wherein the second member of the dsADAR-binding region comprises the nucleotide sequence of any one of SEQ ID NOs: 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 173, 175, 177, 179, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, or 223.

9. The RNA sequence of claim 1, further comprising an additional RNA domain 3' of the second member of the dsADAR-binding region and 5' of the transgeneencoding sequence, wherein the additional RNA domain comprises from 5’ to 3' a third member of a dsADAR-binding region, a second ligand-binding aptamer, and a fourth member of the dsADAR-binding region 5’ of the transgene-encoding sequence, wherein upon binding a second ligand to the second ligand-binding aptamer, the third member of the dsADAR-binding region and the fourth member of the dsADAR- binding region are capable of hybridizing to form a second dsADAR-binding region, wherein the second dsADAR-binding region comprises at least 1 additional mismatched base pair, forming at least 1 additional double- stranded bulge, wherein the additional double-stranded bulge comprises an additional mismatched base pair comprising an adenosine that forms part of an UAG stop codon.

10. The RNA sequence of claim 9, wherein the first member of the dsADAR-binding region and the third member of the dsADAR-binding region are the same; and the second member of the dsADAR-binding region and the fourth member of the dsADAR-binding regions are the same.

11. The RNA sequence of claim 9, wherein the ligand-binding aptamer and the second ligand binding aptamer are the same aptamer.

12. The RNA sequence of claim 1, wherein the ligand is a small molecule, a metabolite, or a protein.

13. The RNA sequence of claim 1, wherein the ligand is tetracycline, theophylline, ASP2905, xanthine, adenosine triphosphate (ATP), dopamine, interleukin-8 (IL-8), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) p502, or a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid.

14. The RNA sequence of claim 1, wherein the ligand-binding aptamer is a cb32 minimer aptamer, an mTCT8-4 aptamer, an AC 17-4 aptamer, an XAB aptamer, an ATP-40-1 aptamer, a modified ATP-40-1 aptamer, a dopa2 / c.4 aptamer, an 8A-35 aptamer, or an a-p50 aptamer.

15. The RNA sequence of claim 1 , wherein the ligand binding aptamer comprises the nucleotide sequence of any one of SEQ ID NOs: l-12.

16. The RNA sequence of claim 1 , wherein the RNA sequence comprises the nucleotide sequence of any one of SEQ ID NOs:33-42, 180-183, or 224-275.

17. The RNA sequence of claim 1, wherein the transgene-encoding sequence encodes a DNA endonuclease, a base editor protein, a prime editor protein, a zinc finger protein, or a chimeric antigen receptor (CAR) protein.

18. A ribonucleic acid (RNA) sequence comprising from 5' to 3’ a first member of a double-stranded nucleic acid sequence, a first member of a split ligand-binding aptamer, a first member of an adenosine deaminase acting on RNA (dsADAR)-binding region, a second member of the dsADAR-binding region, a second member of the ligandbinding aptamer, a second member of the double-stranded nucleic acid sequence, and a transgene-encoding sequence, wherein the first member of a split ligand-binding aptamer is capable of hybridizing the second member of the split ligand-binding aptamer to form a ligand-binding aptamer capable of binding a ligand, wherein upon binding a ligand to the ligand-binding aptamer, the first member of the dsADAR-binding region and the second member of the dsADAR-binding region are capable of hybridizing to form a dsADAR-binding region, wherein the dsADAR-binding region comprises at least 1 mismatched base pair, forming at least 1 double- stranded bulge, wherein the double-stranded bulge comprises a mismatched base pair comprising an adenosine that forms part of an UAG stop codon.

19. The RNA sequence of claim 18, wherein the first member of the dsADAR binding region and the second member of the dsADAR-binding region are from 4 nucleotides to 50 nucleotides in length.

20. The RNA sequence of claim 18, wherein the dsADAR-binding region comprises from 1 to 10 additional double-stranded bulges.

21. The RNA sequence of claim 18, wherein the double-stranded bulge and / or the additional double-stranded bulges each independently comprise between 1 to 3 mismatched base pairs.

22. The RNA sequence of claim 18, wherein the first member of the double-stranded nucleic acid sequence and the second member of the double-stranded nucleic acid sequence are from 4 nucleotides to 50 nucleotides in length.

23. The RNA sequence of claim 18, wherein the first member of the double-stranded nucleic acid sequence comprises the nucleotide sequence of any one of SEQ ID NOs:43, 51, 59, 67, 75, 83, 91, 99, 107, 115, 123, 131, or 139.

24. The RNA sequence of claim 18, wherein the second member of the double-stranded nucleic acid sequence comprises the nucleotide sequence of any one of SEQ lD NOs:49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, or 145.

25. The RNA sequence of claim 18, further comprising an adenosine deaminase acting on RNA (ADAR) -encoding sequence 3' of the transgene-encoding sequence.

26. The RNA sequence of claim 18, wherein the RNA sequence comprises a nucleotide sequence from 20 nucleotides to 200 nucleotides in length excluding the transgene-encoding sequence.

27. The RNA sequence of claim 18, wherein the first member of the dsADAR-binding region comprises the nucleotide sequence of any one of SEQ ID NOs:45,53, 61, 69, 77, 85, 93, 101, 109, 117, 125, 133, or 141.

28. The RNA sequence of claim 18, wherein the second member of the dsADAR-binding region comprises the nucleotide sequence of any one of SEQ ID NOs:46,54, 62, 70, 78, 86, 94, 102, 110, 118, 126, 134, or 142.

29. The RNA sequence of claim 18, wherein the first member of the split ligand-binding aptamer comprises the nucleotide sequence of any one of SEQ ID NOs:44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, 132, or 140.

30. The RNA sequence of claim 18, wherein the second member of the split ligand-binding aptamer comprises the nucleotide sequence of any one of SEQ ID NOs:48, 56, 64, 72, 80, 88, 96, 104, 112, 120, 128, 136, or 144.

31. The RNA sequence of claim 18-30, wherein the ligand is a small molecule, a metabolite, or a protein.

32. The RNA sequence of claim 18, wherein the ligand is tetracycline, theophylline, ASP2905, xanthine, adenosine triphosphate (ATP), dopamine, interleukin-8 (IL-8), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) p502, or a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid.

33. The RNA sequence of claim 18, wherein the ligand-binding aptamer is a cb32 minimer aptamer, an mTCT8-4 aptamer , an AC17-4 aptamer, an XAB aptamer, an ATP-40-1 aptamer, a modified ATP-40-1 aptamer, a dopa2 / c.4 aptamer, an 8A-35 aptamer, or an a-p50 aptamer.

34. The RNA sequence of claim 18, wherein the ligand binding aptamer comprises the nucleotide sequence of any one of SEQ ID NOs: l-12.

35. The RNA sequence of claim 18, wherein the RNA sequence comprises the nucleotide sequence of any one of SEQ ID NOs:50, 58, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, or 146.

36. The RNA sequence of claim 18, wherein the transgene-encoding sequence encodes a DNA endonuclease, a base editor protein, a prime editor protein, a zinc finger protein, or a chimeric antigen receptor (CAR) protein.

37. A ribonucleic acid (RNA) sequence comprising from 5' to 3’ a first member of an adenosine deaminase acting on RNA (dsADAR)-binding region, a first member of a first split ligand-binding aptamer, an RNA stem-loop sequence, a second member of the first split ligand-binding aptamer, a second member of the dsADAR-binding region, and a transgene-encoding sequence, wherein the first member of a split ligand-binding aptamer is capable of hybridizing the second member of the ligand-binding aptamer to form a ligand-binding aptamer capable of binding a ligand, wherein upon binding a ligand to the ligand-binding aptamer, the first member of the dsADAR-binding region and the second member of the dsADAR-binding region are capable of hybridizing to form a dsADAR-binding region, wherein the dsADAR-binding region comprises at least 1 mismatched base pair, forming at least 1 double- stranded bulge, wherein the double-stranded bulge comprises a mismatched base pair comprising an adenosine that forms part of an UAG stop codon.

38. The RNA sequence of claim 37, wherein the RNA stem-loop sequence comprises a second ligand-binding aptamer; or a first member of a second split ligandbinding aptamer and a second member of a second split ligand binding aptamer.

39. The RNA sequence of claim 37, wherein the first member of the ds AD AR binding region and the second member of the dsADAR-binding region are from 4 nucleotides to 50 nucleotides in length.

40. The RNA sequence of claim 37, wherein the dsADAR-binding region comprises from 1 to 10 additional double-stranded bulges.

41. The RNA sequence of claim 37, wherein the double-stranded bulge and / or the additional double-stranded bulges each independently comprise between 1 to 3 mismatched base pairs.

42. The RNA sequence of claim 37, wherein the RNA stem-loop sequence is from 4 nucleotides to 100 nucleotides in length.

43. The RNA sequence of claim 37, further comprising an adenosine deaminase acting on RNA (ADAR) -encoding sequence 3’ of the transgene-encoding sequence.

44. The RNA sequence of claim 37, wherein the RNA sequence comprises a nucleotide sequence from 20 nucleotides to 200 nucleotides in length excluding the transgene-encoding sequence.

45. The RNA sequence of claim 37, wherein the RNA stem-loop sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 149, 155, 161, or 167.

46. The RNA sequence of claim 37, wherein the first member of the dsADAR-binding region comprises the nucleotide sequence of any one of SEQ ID NOs: 147, 153, 159, or 165.

47. The RNA sequence of claim 37, wherein the second member of the dsADAR-binding region comprises the nucleotide sequence of any one of SEQ ID NOs: 151, 157, 163, or 169.

48. The RNA sequence of claim 37, wherein the ligand is a small molecule, a metabolite, or a protein.

49. The RNA sequence of claim 37, wherein the ligand is tetracycline, theophylline, ASP2905, xanthine, adenosine triphosphate (ATP), dopamine, interleukin-8 (IL-8), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB) p502, or a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid.

50. The RNA sequence of claim 37, wherein the ligand-binding aptamer is a cb32 minimer aptamer, an mTCT8-4 aptamer , an AC 17-4 aptamer, an XAB aptamer, an ATP-40-1 aptamer, a modified ATP-40-1 aptamer, a dopa2 / c.4 aptamer, an 8A-35 aptamer, or an a-p50 aptamer.51 . The RNA sequence of claim 37, wherein the ligand binding aptamer comprises the nucleotide sequence of any one of SEQ ID NOs:l-12.

52. The RNA sequence of claim 37, wherein the RNA sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 152, 158, 164, or 170.

53. The RNA sequence of claim 37, wherein the trans gene-encoding sequence encodes a DNA endonuclease, a base editor protein, a prime editor protein, a zinc finger protein, or a chimeric antigen receptor (CAR) protein.

54. A deoxyribonucleic acid (DNA) sequence encoding the RNA sequence of any one of claims 1, 18, or 37.

55. An expression vector comprising the DNA sequence of claim 54.

56. The expression vector of claim 55, wherein the expression vector further comprises a DNA sequence encoding a transposase and / or a recombinase.

57. The expression vector of claim 56, wherein the transposase is a PiggyBac (PB) transposon; and / or wherein the recombinase is a Bxbl recombinase or a Cre recombinase.

58. A virus comprising the expression vector of claim 55.

59. The virus of claim 58, wherein the virus is a Lentivirus, an Adenovirus, or an Adeno-associated virus (AAV).

60. A cell comprising the DNA sequence of claim 54 or the expression vector of claim 55.

61. The cell of claim 60, wherein the cell is a neuron, a glial cell, a thyroid cell, a lung cell, a skeletal muscle cell, a cardiomyocyte, a hepatocyte, an erythrocyte, a platelet, a vascular endothelial cell, an endothelial cell, an epithelial cell, an adipocyte, a secretory cell, a hormone-secreting cell, an exocrine secretory epithelial cell, an immune cell, a lymphocyte, a chimeric antigen receptor (CAR) T cell, a dorsal root ganglion cell, a retinal pigmented epithelium (RPE) cell, a photoreceptor cell, a skin keratinocyte, a mesenchymal stem cell (MSC), a hematopoietic stem cell (HSC), an induced pluripotent stem cell (iPSC), a human embryonic stem cell (hESC), a HEK293T cell, a HeLa cell, a Neuro2a cell, an A375 cell, an HPAEC-BMI1 cell, an hTERT immortalized cell, or a cancer cell.

62. The cell of claim 60, wherein the cell is a human cell.

63. A method of expressing a transgene in a cell comprising contacting the cell of claim 60 with a ligand, thereby expressing the transgene in the cell.

64. The method of claim 63, wherein the cell is transfected with the expression vector of claim 55; or the virus of claim 58 prior to contacting the cell with the ligand.

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