Compositions and methods for correction of TREX1 mutations

Abstract

Compositions and methods for correction of RVCL-causing mutations in a TREX1 gene are provided.

Description

COMPOSITIONS AND METHODS FOR CORRECTION OF TREX1 MUTATIONSINCORPORA TION-BY-REFERENCE OF MATERIAL SUBMITTED IN ELECTRONICFORMApplicant hereby incorporates by reference the Sequence Listing material filed in electronic form herewith. The file is labelled “UPN-23-10210PCT.xml”, was created May 28, 2025, and is 8,866,900 bytes.BACKGROUND OF THE INVENTIONRetinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL or RVCL-S) is a dominantly inherited age-related small vessel disease (SVD) that affects multiple organs, including the liver, kidney, retina, and brain. Patients with RVCL develop symptoms affecting these organs betw een the ages of 35 and 55. All patients with RVCL exhibit brain lesions and atrophy, and the large brain lesions often resemble tumors on 95 magnetic resonance imaging (MRI). One half of family members are affected by the diseasecausing mutations, leading to disability and premature death in 100% of affected individuals, often within 5 to 10 years of symptom onset.RVCL is caused by heterozygous, dominant mutations in the three-prime repair exonuclease (TREX1) gene, which encodes the most abundant mammalian 3" -5' exonuclease in mammals. In patients with RVCL, a C-terminally truncated TREX1 exonuclease completely lacks the transmembrane domain (TMD), which anchors TREX1 to the endoplasmic reticulum (ER). Anchoring of TREX1 at the ER can prevent TREX1 from interacting with genomic DNA, and ER localization also allows TREX1 to degrade aberrant cytosolic DNA, thus negatively regulating cGAS-STING-type I interferon (IFN) signaling. Indeed, TREX1 loss-of-function or dominant negative variants cause interferonopathy in humans and mice, including in patients w ith Aicardi-Goutieres syndrome (AGS). Whereas some have proposed that RVCL mutant TREX1 may also cause interferonopathy, larger studies do not suggest systemic inflammation in RVCL. Nevertheless, MRI imaging frequently reveals contrast enhancement of brain lesions, suggesting that local inflammation might contribute to disease. Thus, the role of local inflammation in RVCL pathogenesis remains to be fully defined. There is currently no approved treatment for RVCL.What is needed is an effective and lasting treatment of RVCL that reduces or eliminates RVCL symptoms.SUMMARY OF THE INVENTIONThe present disclosure provides compositions and methods for effecting a durable cure of a patients with RVCL or RVCL-S via the correction of causative mutations in a TREX1 gene.In one aspect, provided herein is a prime editing guide RNA (pegRNA) comprising, from 5' to 3': a) a spacer that is complementary to a target sequence on a first strand of a TREX1 gene; b) a scaffold sequence capable of binding to a Cas9 protein: and c) an extension sequence comprising: i) an editing template that comprises a region of complementarity to an editing target sequence on a second strand of the TREX 1 gene, and ii) a primer binding site, wherein the first strand and the second strand are complementary to each other, and wherein the editing target sequence on the second strand comprises or is complementary to a portion of the TREX1 gene comprising a mutation. In certain embodiments, the editing target sequence of the second strand comprises or is complementary to a sequence in a region of the TREX1 gene that encodes amino acids 231-236, amino acids 251-256, amino acids 249-255, amino acids 263-269, amino acids 270-275, amino acids 273-278, amino acids 223-249, amino acids 242-251, amino acids 257-275, amino acids 264-280, amino acids 267-288, amino acids 276-283, or amino acids 277-298 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209. In certain embodiments, the editing target sequence of tire second strand comprises or is complementary to a sequence in a region of the TREX1 gene comprising a mutation in amino acid 235, 236, 249, 249, 250, 253, 262, 266, 267, 267, 267, 268, 270, 271, 272, 272. 275, 277, 278, 284, 285, 287, 290, or 310 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209. In certain embodiments, the mutation is V235Gfs. T236Nfs, T249Nfs, T249Sfs. T250Nfs. H253Qfs, P262Gfs, E266X, S267Efs, S267Rfs, S267Qfs, S268Gfs, T270Nfs, K271Qfs, D272Lfs, D272Ifs, P275Qfs, K277X, D278Efs, R284Kfs, E285X, L287Afs, P290_A310del and / or A3 lOEfs. In certain embodiments, the spacer sequence and / or the extension sequence comprise RNA sequences, or variants thereof, of a pegRNA set forth in Table 1.In another aspect, provided herein is an sgRNA having a sequence that targets a prime editor to nick a non-edited strand of a TREX1 gene, wherein tire sgRNA comprises a spacer sequence, or variant thereof, corresponding to an sgRNA set forth in Table 1, optionally wherein the sgRNA includes nucleoside modifications.In another aspect, provided herein is an mRNA encoding a prime editor, wherein tire prime editor is a PEI, PE2, PE3, PE3b, or PEmax fusion enzyme, optionally wherein the mRNA includes nucleoside modifications. In certain embodiments, the PEmax fusion enzyme is encodedby the modified RNA sequence set forth SEQ ID NO: 9214, or a sequence at least 95% identical thereto.In yet another aspect, provided herein are nucleic acids comprising sequences encoding pegRNA, sgRNA, and or mRNA disclosed herein for targeting a TREX1 gene. In certain embodiments, the nucleic acids are plasmids.In further aspect, provided herein is a composition comprising a lipid nanoparticle (LNP), the LNP encapsulating a pegRNA o, an sgRNA, an mRNA, and / or a nucleic acid disclosed herein for targeting a TREX1 gene. In certain embodiments, the LNP comprises targeting moieties, optionally antibodies or fragments thereof that bind PECAM or ICAM.In another aspect, provided herein is a composition for editing one or more RVCL- causing mutations in a TREX1 polynucleotide comprising one or more recombinant viral vectors for delivery of a) a nucleic acid sequence encoding a Cas nickase-reverse transcriptase prime editor and b) a nucleic acid sequence encoding a prime editing guide RNA (pegRNA) disclosed herein. In certain embodiments, the composition further comprises a sequence encoding an sgRNA disclosed herein.In another aspect, provided herein is a method of treating RVCL in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition for editing one or more RVCL-causing mutations in a TREX1 polynucleotide comprising one or more recombinant viral vectors for delivery of a) a nucleic acid sequence encoding a Cas nickase-reverse transcriptase prime editor and b) a nucleic acid sequence encoding a prime editing guide RNA (pegRNA) disclosed herein. In certain embodiments, the subject has a mutation in a TREX1 allele in a region of the TREX1 gene that encodes amino acids 231-236, amino acids 251-256, amino acids 249-255, amino acids 263-269, amino acids 270-275, amino acids 273-278, amino acids 223-249, amino acids 242-251, amino acids 257-275, amino acids 264-280, amino acids 267-288, amino acids 276-283, or amino acids 277-298 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209. In certain embodiments, the subject has a mutation in a TREX1 allele that is a mutation in amino acid 235. 236, 249. 249, 250, 253, 262, 266, 267, 267, 267, 268, 270, 271. 272, 272. 275, 277. 278, 284. 285, 287, 290, or 310 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209. In certain embodiments, the mutation is V235Gfs, T236Nfs, T249Nfs, T249Sfs, T250Nfs, H253Qfs, P262Gfs, E266X, S267Efs, S267Rfs, S267Qfs, S268Gfs, T270Nfs, K271Qfs, D272Lfs, D272Ifs, P275Qfs, K277X, D278Efs, R284Kfs, E285X, L287Afs, P290_A31 Odel and / or A31 OEfs.In yet another aspect, provided herein is a method for editing a TREX1 gene comprising one or more RVCL-causing mutations, the method comprising contacting the TREX1 gene with a prime editing system comprising a Cas nickase and a prime editing guide RNA (pegRNA) of any one of claims 1 to 8, wherein pegRNA targets the prime editor to effect a correction of the one or more RVCL-causing mutations in the TREX1 gene. In certain embodiments, the TREX1 gene has a mutation in a region that encodes amino acids 231-236, amino acids 251-256, amino acids 249-255, amino acids 263-269, amino acids 270-275, amino acids 273-278, amino acids 223-249, amino acids 242-251, amino acids 257-275, amino acids 264-280, amino acids 267-288, amino acids 276-283, or amino acids 277-298 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209. In certain embodiments, the TREX1 gene has a mutation in amino acid 235, 236, 249, 249, 250, 253, 262, 266. 267, 267, 267, 268, 270, 271, 272, 272, 275, 277, 278, 284, 285, 287, 290, or 310 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209. In certain embodiments, the mutation is V235Gfs, T236Nfs, T249Nfs, T249Sfs, T250Nfs, H253Qfs, P262Gfs, E266X, S267Efs, S267Rfs, S267Qfs, S268Gfs, T270Nfs, K271Qfs, D272Lfs, D272Ifs, P275Qfs, K277X, D278Efs, R284Kfs, E285X, L287Afs, P290_A31 Odel and / or A31 OEfs.Other aspects and advantages of tire invention will be readily apparent from the following detailed description of the invention.BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1A - FIG. IF show disease-causing, C -terminally truncated TREX1 exacerbates the rough eye phenotype in Drosophila. (FIG. 1A) Representative images of compound eyes from Drosophila over-expressing WT human TREX1 (WT), the TREX1 C-terminal frameshift mutant (RVCL), the TREX1 C-terminal frameshift mutant lacking exonuclease activity (AExo RVCL), and control (Normal). (FIG. IB) Quantification of rough eye phenotypic scores from (FIG. 1 A). (P < 0.0001 for Control vs. WT, WT vs. AExo RVCL, and RVCL vs. AExo RVCL, P = 0.0033 for WT vs. RVCL) (FIG. 1C) Representative fluorescence microscopy in Drosophila Kenyon cells over-expressing WT TREX1, RVCL TREX1 (V235Gfs), or AExo RVCL with immunostaining for Myc (TREX1), DAPI (nucleus), and CD8-GFP (structural integrity). Scale bar = 4 pm. (FIG. ID) Quantification of the ratio of nucleic to cytoplasmic TREX1 signal from (FIG. 1C). (P = 0.0004 for WT vs. RVCL, P = 0.0005 for WT vs. AExo RVCL) (FIG. ID) Representative image of compound eye of Drosophila overexpressing RVCL TREX1 w ith either control RNAi or the rough eye-modifying rad50 RNAi. (FIG. IE) Over-represented GO termsenriched by genes with reduced toxicity of RVCL mutant TREX1 with respect to biological process classification. The plots are size-scaled by the number of effective genes enriched for each GO temi and color-scaled by the gene ratio (ratio of the number of effective genes to the number of genes associated with the GO term). Data in (FIG. 1 A). (FIG. 1C) and (FIG. IE) are representative of independent experiments. Data in (FIG. IB) represent n = 25 control, n = 36 WT, n = 29 RVCL. and n = 34 AExo RVCL. Data in (FIG. ID) represent n = 10 for all groups. Boxes in (FIG. IB) represent the 25thand 75thpercentiles, with a solid line within the box showing the median value. Whiskers show the largest and smallest observed value. Data in (FIG. ID) represent tire mean ± SD. Data in (b) and (d) were analyzed one-way ANOVA with a two- sided Bonferroni post hoc test. Source data are provided as a Source Data file. ** P < 0.01; *** P < 0.001; 0.0001.FIG. 2A - FIG. 2H show aberrant nuclear activity of C-terminally truncated TREX1 triggers DNA damage and senescence in mammalian cells. (FIG. 2A) Schematic depicting the distinction between locations of interferonopathy-associated TREX1 variants and RVCL-causing TREX1 variants. The exonuclease (EXO) and transmembrane (TMD) domains are indicated. (FIG. 2B) Representative confocal immunofluorescence images of Flp-in 293T cells stably expressing WT TREX1 or disease-causing TREX1 mutants associated with RVCL, SLE, AGS, or FCL or RVCL TREX1 (V235Gfs) w ith a nuclear export signal (NES RVCL) or lacking enzymatic activity (AExo RVCL) with immunostaining for 53BP1 and yH2AX. Scale bar = 15 pm. (FIG. 2C) Quantitation of cells with >5 yH2AX / 53BPl foci in cells from (b). (P = 0.008) (FIG. 2D) Representative images of pATM foci in IMR-90 cells wdth doxycycline-inducible WT TREX1, RVCL TREX1, AExo RVCL, or NES RVCL. Scale bar = 10 pm. (FIG. 2E) Quantitation of frequency of cells with >5 pATM foci in cells from (FIG. 2F). (P = 0.01 for WT vs. RVCL, P = 0.0007 for RVCL vs. AExo RVCL, P = 0.045 RVCL vs. NES RVCL) (FIG. 2F) Line graph of the change in proliferation rate over time of IMR-90 cells expressing WT TREX1, RVCL TREX1, NES RVCL or AExo RVCL. The graph show s the data as 100% of the average value on day 0. (P = 0.0001) (FIG. 2G) Gene set enrichment analysis (GSEA) profile of SASP gene sets from RNA-seq performed in IMR-90 cells stably expressing RVCL mutant TREX1 (TREX1 V235Gfs) by doxycycline for 2 weeks and in cells without doxycycline. Analysis was performed w ith n = 4 replicates. (FIG. 2H) Representative fluorescence microscopy images of IMR-90 cells with immunostaining for NM23-Hl, DAPI (nucleus), and myc (TREX1). Data in (FIG. 2H) are representative of 3 independent experiments. Scale bar = 15 pm. Data in (FIG. 2B, FIG. 2B, and FIG. 2F) are representative of at least 2 independent experiments performed with n = 5 replicatesper cell line. Data in (FIG. 2D - FIG. 2E) are representative of at least 2 independent experiments performed with n = 6 replicates per cell line. Data in (FIG. 2C, FIG. 2E, and FIG. 2F) represent the mean ± SD. Data in (FIG. 2C and FIG. 2E) were analyzed by one-way ANOVA with a two- sided Bonferroni post hoc comparison. Data in (FIG. 2F) were analyzed by two-way ANOVA. Source data are provided as a Source Data file. * P < 0.05: ** P < 0.01; P < 0.001; **** P < 0.0001.FIG. 3 A - FIG. 3K show high expression of C-terminally truncated TREX1 causes vulnerability to DNA-damaging agents. (FIG. 3A) Representative flow cytometric plots of live (NIR ) and dead (NIR+) WT and RVCL MEF cell populations following 72h treatment with vehicle control (DMSO) or 10 pM olaparib. MEFs used in (a-c) express TREX1 out of the endogenous locus under control of the endogenous promoter. (FIG. 3B) Quantitation of percent dead (NIR+) cells from (a). (P = 0.0002) (FIG. 3C) Representative histogram of yH2AX immunostaining in WT and RVCL (TREX1 T235Gfs) MEFs following 72 hours of treatment with vehicle (DMSO) or olaparib (10 pM). (FIG. 3D) Representative flow cytometric analysis of TREX110and TREXlhlprimary BMDM populations from these animals (upper panel) and a schematic of Cre-mediated recombination at the ROSA locus of Floxed-STOP WT TREX1 and V235Gfs TREX1 mice (lower panel). (FIG. 3E) Representative histograms ofyH2AX expression of gated TREXl'” and TREXl111WT and RVCL BMDMs treated with vehicle (DMSO) or olaparib (10 pM) for 72 hours. (FIG. 3F) Quantitation of median fluorescence intensity (MFI) of yH2AX immunostaining of TREXlhlWT and RVCL BMDM populations from (FIG. 2E). (P = 0.0003 for vehicle, P < 0.0001 for olaparib) (FIG. 3G) Representative histograms of yH2AX in TREXlhlWT and RVCL BMDMs treated with olaparib (10 pM) and TREXl inhibitor (10 pM). (FIG. 3H) Quantitation of MFI of yH2AX from (FIG. 3G). (P < 0.0001) (FIG. 31) Representative images of DNA DSB STRIDE analysis of WT or RVCL BMDMs treated with olaparib (10 pM) for 72 hours. Scale bar = 10 pm. (FIG. 3 J) Quantitation of nuclear DSB STRIDE foci in WT and RVCL BMDMs treated with 10 pM olaparib. (P < 0.0001) (FIG. 3K) Representative histological images of liver tissue sections stained with hematoxylin and eosin from WT litter mate control and heterozygous RVCL TREXl (T235Gfs) mice treated with olaparib (40 mg / kg) for 14 days. Scale bar = 40 pm. Data in (FIG. 3 A - FIG. 3C and FIG. 3K) are from mice expressing TREXl from the endogenous locus under control of the endogenous promoter. Data in (FIG. 3D - FIG. 3J) arc from mice expressing TREXl under control of tire CAG promoter. Data in (FIG. 3A, FIG. 3C, FIG. 3D, FIG. 3E, FIG. 3G. and FIG. 3K) are representative of at least 3 independent experiments. Data in (FIG. 3B, FIG. 3F. and FIG. 3H) represent the mean ± SEM of n = 8samples per genotype from 2 independent experiments. Data in (FIG. 31) are representative of 2 biologically independent experiments, each with multiple technical replicates. Data in (FIG. 3 J) represent die mean ± SEM of WT n = 451, RVCL n = 494. Results in (FIG. 3B, FIG. 3F, FIG. 3H. FIG. 3J) were analyzed using two-sided Mann-Whitney test. Source data are provided as a Source Data fde. ***P < 0.001; ****P <0.0001.FIG. 4A - FIG. 4K show ionizing radiation and cytokines up-regulate TREX1 and cause excessive DNA damage in RVCL cells. (FIG. 4A) Schematic of the TREX1 gene showing the location of consensus sequences for NFkB binding sites, STAT binding sites, and Interferon- stimulated response elements (ISREs). (FIG. 4B) Representative Western blot of BMDMs from WT or heterozygous mice expressing RVCL mutant TREX1 under control of the endogenous promoter after 6 hours of incubation with vehicle or LPS (1 pg / mL) with immunoblotting for TREX1 and GAPDH. (FIG. 4C) Western blots of BMDMS from WT or RVCL mice after 3 days of incubation with vehicle, IFN-P (100 lU / mL), or IFN-y (10 ng / mL), follow ed by immunoblotting for TREX1 and GAPDH. (FIG. 4D) Western blot of liver from WT or heterozygous RVCL mice after intraperitoneal injection of vehicle or LPS (5 mg / kg), followed by immunoblotting for TREX1 and GAPDH. (FIG. 4E - FIG. 4F) Representative Western blot of liver (FIG. 4E) and brain (FIG. 4F) from WT or heterozygous RVCL mice at ages 1 month (Young) or 15 months (Old), followed by immunoblotting for TREX1 and GAPDH. (FIG. 4G) Quantitation of relative expression of the indicated ISGs by RT-qPCR in MEFs from WT or heterozygous RVCL mice 24 hours after X-ray irradiation. (P = 0.0001 for RVCL 0 Gy vs. RVCL 10 Gy IfitR P = 0.007 for RVCL 0 Gy vs. RVCL 10 Gy Isgl5. P = 0.0031 for RVCL 0 Gy vs. RVCL 10 Gy Rsad2. P < 0.0001 for WT 10 Gy vs. RVCL 10 Gy) (FIG. 4H) Representative histograms of yH2AX expression of BMDMs from WT or heterozygous RVCL mice treated with vehicle or IFN- (100 lU / mL) for 72 hours. (FIG. 41) Quantitation of mean fluorescence intensity (MFI) of yH2AX immunostaining from (h). (P < 0.0001) (FIG. 4J) Quantitation of MFI of yH2AX immunostaining of BMDMs fonn WT or heterozygous RVCL mice treated with vehicle or IFN-y (10 ng / mL) for 72 hours. (P = 0.02 for WT IFN-y vs. RVCL IFN-y, P = 0.0002 for WT vehicle vs. WT IFN-y, P < 0.0001 for RVCL vehicle vs. RVCL IFN- y) (FIG. 4K) Model of a malignant cycle of DNA damage and inflammation in cells expressing RVCL mutant TREX1. Data in (FIG. 4B - FIG. 4J) are from mice expressing TREX1 from the endogenous locus under control of the endogenous promoter. Data in (FIG. 4B - FIG. 4G, FIG. 4H) are representative of 2-3 independent experiments. Data in (FIG. 4G, FIG. 41, and FIG. 4 J) represent the mean ± SEM of n = 9 samples per genotype from 3 independent experiments. Datain (FIG. 4G, FIG. 41, and FIG. 4J) were analyzed by one-way ANOVA with two-sided Sidak’s multiple comparisons test. * P < 0.05; *' P < 0.01; *'* P < 0.001; **** P < 0.0001.FIG. 5A - FIG. 51 show CD1 lc+myeloid cells and monocytes have high TREX1 expression in mice. (FIG. 5 A) Model of TREXl-dsRed reporter mice that express TREX1 and dsRed, separated by an IRES, at the endogenous TREX1 locus under control of the endogenous TREX1 promoter. (FIG. 5B - FIG. 51) Representative flow cytometric histogram of dsRed expression (left) with quantitation of mean fluorescence intensity (MFI) of dsRed (right) in the indicated cell types. Histograms are representative of n = 3 independent experiments. Error bars denote the SEM.FIG. 6A - FIG. 6G show IFN-a up-regulates TREX1 and causes loss of CD1 lc+cells and macrophages in heterozygous RVCL mutant TREX1 mice. (FIG. 6A) Model of experimental layout. (FIG. 6B) Quantitation of relative expression of the indicated ISGs in tire liver of WT or IFNAR1 KO mice 1 week after injection with AAV-LacZ or AAV-IFN-a2. (P = 0.0043) (FIG. 6C) Representative Western blot of TREX1 and GAPDH from the livers of WT and heterozygous RVCL mice one month after injection with AAV-LacZ or AAV-IFN-a2. (FIG. 6D - FIG. 6G) Quantitation of cell number by flow cytometry from the spleen of WT or heterozygous RVCL mice one week after injection with AAV-LacZ or AAF-IFN-a2. (P = 0.0351 for FIG. 6D, P = 0.0048 for FIG. 6E) Data in (FIG. 6B - FIG. 6) are from mice expressing TREX1 from the endogenous locus under control of the endogenous promoter. Data in (FIG. 6B) represent tire mean ± SEM of n = 7 WT LacZ, n = 5 IFNAR1 KO LacZ, n = 6 WT IFN-a2, and n = 5 IFNAR1 KO !FN-a2 mice pooled from 2 independent experiments and were analyzed by Mann Whitney U-test. Data in (FIG. 6C) are representative of 3 independent experiments. Data in (FIG. 6D - FIG. 6G) represent the mean ± SEM of n = 7 WT LacZ, n = 8 RVCL LacZ, n = 6 WT IFN-a2, and n = 14 RVCL IFN-a2 mice pooled from 2 independent experiments and were analyzed by two-sided unpaired t-test. * P < 0.05; ** P < 0.01.FIG. 7A - FIG. 7J show catalytically active, nuclear TREX1 disrupts HDR and enhances NHEJ. (FIG. 7A) Schematic overview of the ddPCR-based HDR repair assay utilized in (FIG. 7B - FIG. 7C). (FIG. 7B) Quantitation of HDR mediated repair via ddPCR assay of doxycycline- treated Flp-in 293T cells expressing WT or RVCL TREX1. Data are expressed as percentage change in frequencies of HDR in doxycycline-treated cells relative to untreated cells. (P = 0.0017 for WT vs. RVCL, P < 0.0001 for WT vs 293T cells) (FIG. 7C) Quantitation of HDR mediated repair via ddPCR assay of Flp-in 293T cells expressing RVCL mutant TREX1, RVCL mutant TREX1 lacking enzymatic activity’ (AExo RVCL), or RVCL mutant TREX1 containing a nuclearexport signal (NES REVCL) with data expressed as percentage change in frequencies of HDR in doxycycline -treated cells relative to untreated cells. (P = 0.0154 for RVCL vs. NES RVCL, P = 0.0004 for RVCL vs. AExo RVCL) (FIG. 7D) A representative ScreenTape electrophoretic gel image of PCR amplicons digested with mismatch cleavage nuclease from non-edited Flp-in 293 T and CRISPR-Cas9-edited Flp-in WT TREXL and TREX1 V235Gfs (RVCL) 293T cells. (FIG. 7E) Quantification of NHEJ repair efficiency based on the mismatch cleavage band ratio in (FIG. 7D) with data expressed as percentage change in doxycycline treated cells relative to untreated cells. (P = 0.008) (FIG. 7F) Quantification of NHEJ repair efficiency based on the mismatch cleavage band ratio of PCR amplicons digested with mismatch cleavage nuclease from RVCL. AExo RVCL, and NES RVCL Flp-in 293 T cells. Data are expressed as percentage change in doxycycline-treated cells relative to untreated cells. (P = 0.0058 for RVCL vs AExo RVCL, P = 0.0003 for RVCL vs NES RVCL) (FIG. 7G) Representative read alignments from long-read deep sequencing around the cut site from (FIG. 7A) in WT and RVCL Flp-in 293T cells before and after doxycycline induction. (FIG. 7H - FIG. 71) Quantitation of the frequency of large (FIG. 7H) and small (FIG. 71) deletions from (FIG. 7G). (P = 0.0145 for WT Dox+ vs. RVCL Dox+ large deletions, P < 0.0001 for Dox- vs. Dox+ large deletions, P <0.0001 for WT Dox+ vs. RVCL Dox+ and RVCL Dox- vs. RVCL Dox+ small deletions) (FIG. 7J) RVCL mutant TREX1 disrupts DNA damage repair by degrading 3 ’ overhangs, leading to accumulation of deletions, cell death, and senescence. Data in (FIG. 7B - FIG. 7F, FIG. 7H, and FIG. 71) represent the mean ± SD and are representative of independent biological replicates; n = 5 (FIG. 7B and FIG. 7E). n = 6 (FIG. 7C), n = 10 (FIG. 7F), or n = 3 (FIG. 7H and FIG. 71). Data in (FIG. 7B. FIG. 7C, FIG. 7E, and FIG. 7F) were analyzed by AN OVA with Bonferroni post hoc comparison. Data in (FIG. 7H) and (FIG. 71) were analyzed by ANOVA with two-sided Sidak’s multiple comparisons test. * P < 0.05; **P < 0.01; *** P < 0.001; **** P < 0.0001.FIG. 8A - FIG. 8C show RVCL mutant TREX1 interacts with chromatin and nuclear proteins involved in the DNA damage response. (FIG. 8A) Representative Western blot after subcellular fractionation and SDS-PAGE of lysates from WT and heterozygous RVCL BMDMs followed by immunoblotting of TREX1, H3K27ac, and H3K27me3 from the indicated subcellular fractions. (FIG. 8B) A silver-stain of co-immunoprecipitated proteins using 3x- FLAG-tagged TREX1 V235Gfs as bait (left) and quantitation of unique co-precipitated peptides in the band that identified PARP1 and some of the other interacting partners (right). (FIG. 8C) Summary diagram of WT TREXl- and TREX1 V235Gfs-interacting proteins with at least 20 unique peptides detected by immunoprecipitation-mass spectrometry. TREXl -interactingproteins are organized by their subcellular localization and cellular functions. Data in (FIG. 8A) are representative of 3 independent experiments. Data in (FIG. 8B and FIG. 8C) are from one mass spectrometry screen.FIG. 9A - FIG. 9E show aneuploidy and reduced meiotic crossovers in embryos of a female RVCL patient and breast cancer in female patients with RVCL. (FIG. 9A) Diagram representing the observed chromosomal aneuploidy in embryos of a 27-year-old RVCL patient undergoing in vitro fertilization with pre-implantation genetic testing. Stars indicate location of deletion. (FIG. 9B) Heatmap showing the number of crossover events normalized to chromosome length (cM) per chromosome in healthy control and RVCL patient embryos. (FIG. 9C) A scatter plot show ing the distribution of total crossover events in healthy control and RVCL patient embryos. ( = 0.0004) (FIG. 9D) Interval plot depicting the odds ratio (OR) of breast cancer in females with RVCL-causing TREX1 variants compared with publicly available ORs of breast cancer in women with variants in BRCA1 or BRCA2. (FIG. 9E) Model of RVCL disease pathogenesis. Data in (FIG. 9A - FIG. 9C) represent independent embryos analyzed as part of routine clinical care: healthy control embryo n = 67, RVCL embryo n = 4. Error bars in (FIG. 9D) represent 95% confidence intervals from n = 19 female patients with RVCL. Data in (FIG. 9C) analyzed by two-sided Mann- Whitney U test. *** P < 0.001.FIG. 10A - FIG. 10C show disease-associated TREX1 mutants are stably expressed, but only RVCL mutants are mislocalized. (FIG. 10A) A representative Western blot showing expression of myc-tagged TREX1 in the eye of transgenic Drosophila with immunoblotting of for myc and a-Tubulin. (FIG. 10B) A representative Western blot of doxycycline-treated Flp-in 293T cells with inducible expression of myc-tagged TREX1 mutants associated with RVCL, AGS, SLE, or FCL or myc-tagged AExo RVCL (TREX1 R62A / V235fs) or NES RVCL (TREX1 V235Gfs with a nuclear export signal) mutant TREX1 with immunoblotting for myc and -actin. (FIG. 10C) Representative fluorescence microscopy images of Flp-in 293T cells expressing myc- tagged disease-associated TREX1 variants with immunostaining for myc (TREX1), protein disulfide isomerase (PDI; ER), and DAPI (nucleus). Scale bar = 15 pm. Data are representative of 3 independent experiments.FIG. HA - FIG. 11C show DDR signaling is up-regulated by TREX1 mutants associated with RVCL, but not by other TREX1 mutants associated with other diseases. (FIG. 11A) Representative Western blot of Flp-in293 cells before and after doxycycline-induced expression of WT TREX1, the indicated TREX1 mutants associated with RVCL, SLE, AGS, or FCL, or RVCL TREX1 (V235Gfs) with a nuclear export signal (NES RVCL) or lacking enzymaticactivity (AExo RVCL), followed by immunoblotting for p-ATM, ATM, p-Chk2, and Chk2. Vertical lines in tire image indicate that the images are from different blots. (FIG. 1 IB - FIG. 11C) Quantitation of the ratio of p-ATM to ATM (FIG. 1 IB) and p-Chk2 to Chk2 (FIG. 11C) from (FIG. 11A). Data in (FIG. 11 A) are representative of 3 independent experiments. Data in (FIG. 1 IB - FIG. 11C) represent the mean ± the SD of n = 3 independent biological repeats. Data were analyzed by AN OVA with Bonferroni post hoc comparison. *** P < 0.001.FIG. 12A - FIG. 12H show RVCL mutant TREX1 causes DNA damage via its exonuclease activity and nuclear localization. (FIG. 12A) Representative fluorescence microscopy images of IMR-90 cells expressing myc-tagged TREX1 with immuno staining for myc (TREX1), PDI (ER), and DAPI (nucleus). Scale bar = 15 pm. (FIG. 12B) Representative fluorescence microscopy images of IMR-90 cells with immunostaining for 53BP1, yH2AX, and DAPI at 48 hours after addition of doxycycline. Scale bar = 10 pm. (FIG. 12C) Quantitation of percent of cells with more than 3 53BP1 / / H2AX (DSB) foci from (FIG. 12B). (FIG. 12D) Representative Western blot of IMR-90 cells before and after doxycycline-induced expression of WT TREX1, RVCL TREX1, or RVCL TREX1 with a nuclear export signal (NES RVCL) or lacking enzymatic activity (AExo RVCL), followed by immunoblotting for p-Chk2 and Chk2. Vertical lines in tire image indicate that the images arc from different blots. (FIG. 12E) Quantitation of the ratio of p-Chk2 to Chk2 from (FIG. 12D). (FIG. 12F - FIG. 12H) Representative image of comet assay (FIG. 12F) with quantitation of tail length (FIG. 12G) and tail moment (FIG. 12H). Data in (FIG. 12A, FIG. 12B, FIG. 12D. FIG. 12FI) are representative of 3-4 independent experiments. Data in (FIG. 12C, FIG. 12E, FIG. 12G, and FIG. 12H) show mean ± SD, and were analyzed by ANOVA with Bonferroni post hoc comparison. *** P < 0.001;0.0001.FIG. 13A - FIG. 13B show heterozygous RVCL mutant mice express both full-length and C -terminally truncated TREX1. (FIG. 13 A) A schematic of the amino acid sequence of the RVCL-causing TREX1 C-terminal frameshift mutation at position 235, which results in a truncated form of the protein with a missing transmembrane domain (T235Gfs in mouse TREX1, and V235Gfs in human TREX1). (FIG. 13B) A representative Western blot of mouse TREX1 protein expression from bone marrow-derived macrophages (BMDMs) of WT littermate control and heterozygous TREX1 T235Gfs mice (RVCL), that express RVCL mutant TREX1 from the endogenous locus, under control of the endogenous promoter. Data in (FIG. 13B) are representative of 3 independent experiments.FIG. 14A - FIG. 14C show heterogeneity of TREX1 expression and sensitivity of RVCL cells to PARP1 inhibition or deletion. (FIG. 14A) Dose response curves of WT and non-clonal heterozygous RVCL MEFs treated with indicated dilutions of PARP inhibitors. Data expressed as viability relative to vehicle (DMSO) treated controls. (FIG. 14B) A representative Western blot of monoclonal heterozygous RVCL MEFs immunoblotted for TREXL PARP1, and vinculin. (FIG. 14C) A representative Western blot of WT and heterozygous RVCL MEFs transduced with a lentivirus encoding Cas9 and an sgRNA against PARP1 or a scrambled control sgRNA with immunoblotting for PARPL TREX1, and GAPDH. Data in (FIG. 14A) are from a screen with 3 biologically independent samples. Data in (FIG. 14B - FIG. 14C) are representative of 3 independent experiments.FIG. 15A - FIG. 15B show aberrant nuclear localization of TREX1 in primary bone marrow-derived macrophages from RVCL mice. (FIG. 15A) Representative confocal images of TREX1 localization and DAPI in WT or TREX1 V235Gfs (RVCL) bone marrow-derived macrophages from mice expressing human TREX 1 under control of the CAG promoter. (FIG. 15B) Representative fluorescent signal intensity of DAPI (nucleus) and TREX1 signal quantitation measured along the transverse plane of the cell (dotted yellow line) from (FIG. 15A). Data in (FIG. 15 A - FIG. 15B) are representative of many hundreds of cells observed in at least 3 independent experiments.FIG. 16A - FIG. 16C show sensitivity of RVCL cells and a patient with RVCL to aclarubicin. (FIG. 16A) Dose response curves of WT and RVCL MEFs treated with the indicated concentrations of aclarubicin. Data expressed as viability relative to the lowest dose of aclarubicin. (FIG. 16B) Line graph showing the total number of new' brain lesions over time after a patient was treated with the indicated doses of aclarubicin. (FIG. 16C) Axial FLAIR MRI images on the patient from (FIG. 16B) before and after receiving aclarubicin treatment for 12 months. Brain lesions indicated with arrow7. Data in (FIG. 16A) arc from mice expressing TREX1 out of the endogenous locus under control of tire endogenous promoter. Data in (FIG. 16A) represent the mean ± SEM of n = 9 samples from 3 independent repeats and were analyzed by F test of tire sum-of-squares. **** P < 0.0001.FIG. 17 shows interferon-stimulated gene expression in peripheral blood cells from patients with RVCL. Relative gene expression of the ISGs IFIT1, ISG15 and RSAD2 in peripheral blood mononuclear cells (PBMCs) of RVCL patients relative to those of healthy controls (HC). Data represent n = 4 independent biological replicates from experiments performed in triplicate.FIG. 18A - FIG. 18F show changes in TREX1 and ISG expression in human tissues with age. (FIG. 18A) Heatmap showing the relative gene expression of TREX1 in the indicated tissues in humans at the specified ages. (FIG. 18B - FIG. 18F) Heatmap showing the relative gene expression of select ISGs in the indicated tissues in humans of different ages. Data are from the publicly accessible voyAGEr database with transcriptome data from the tissues of over 700 individuals. Data are represented as the log2 counts per million normalized to average gene expression for all ages in that tissue. Missing data is indicated in grey.FIG. 19A - FIG. 19C show IFN ARI -dependent up-regulation of TREX1 in response to DNA-damaging agents. (FIG. 19A) Representative histograms of yH2AX expression of LysM- Crc-positivc LSL TREX1 BMDMs treated with vehicle or CPT (1.25 pM) for 72 hours. (FIG. 19B) Quantitation of mean fluorescence intensity (MFI) of yH2AX immunostaining from (FIG. 19A). (FIG. 19C) Representative Western blot of BMDMs from WT or heterozygous RVCL mice after 3 days of incubation with vehicle or CPT (125 ng / mL) plus isotype or anti-IFNARl blocking antibody (1 mg / mL), followed by immunoblotting for TREX1 and Vinculin. RVCL mice used in (FIG. 19C) express RVCL mutant TREX1 from the endogenous locus, under control of the endogenous promoter. Data in (FIG. 19A) and (FIG. 19C) are representative of 3 independent experiments. Data in (FIG. 19B) represent the mean ± SEM of n = 9 samples from 3 independent repeats. Data in (FIG. 19B) were analyzed by ANOVA with Sidak's correction for multiple comparisons. ** P < 0.01; **** P < 0.0001.FIG. 20A - FIG. 20D show optimization of prime editing in TREX1 V235Gfs-expressing 293T cells. (FIG. 20A) A schematic of TREX1 annotated with disease-causing mutations. (FIG. 20B) A diagram of the prime editing screen. TREX1 V235Gfs-expressing 293T cells were transfected with empty or RVCL prime editor and deep sequenced to determine editing efficiency of the TREX1 V235Gfs-expressing frameshift mutation. (FIG. 20C) Percent editing efficiency of epegRNA screen as outlined in (FIG. 20B), showing percent of reads with tire corrected nucleotide sequence. (FIG. 20D) Percent editing efficiency and indel frequency of a preliminary nicking sgRNA screen.FIG. 21A - FIG. 21D show the TREX1 V235Gfs mutant is efficiently converted to full- length WT TREX1 using different delivery systems. (FIG. 21A - FIG. 21D) TREX1 V235Gfs- expressing 293T cells were subjected to various prime editor therapies followed by SDS-PAGE and Western blotting using antibodies against the N- or C-terminus of full-length TREX1. (FIG. 21A) Conversion of TREX1 V235Gfs to WT TREX1 by prime editor plasmid DNA. (FIG. 21B) Conversion of TREX1 V235Gfs to WT TREX1 by AAV plasmid DNA. (FIG. 21C) Conversionof TREX1 V235Gfs to WT TREX1 by prime editor mRNA lipid nanoparticles (mRNA-LNP). (FIG. 21D) Schematic of TREX1 indicating binding regions of anti-HA (N-terminus) and anti- TREX1 (C-terminus) antibodies. Data in FIG. 21A are representative of three independent experiments.FIG. 22A - FIG. 22G show organ-limited RVCL due to parental TREX1 mosaicism with classic multi-organ RVCL in her progeny. (FIG. 22A) Pedigree of the family with inheritance of a mosaic disease-causing TREX1 mutation. Shaded boxes represent patients with germline TREX1 E266X mutations and the patterned shading indicates mosaicism in the mother. (FIG. 22B) MRI of patient II.2 from FIG. 20A with inherited RVCL. (FIG. 22C) Key clinical features in the affected family. (FIG. 22D) Schematic of the TREX1 protein with known disease-causing mutations. (FIG. 22E) Representative Western blot of TREX1 E266X expression in 293T cells. Data in FIG. 20E are representative of n = 3 independent experiments. (FIG. 22F) Frequency of TREX1 protein variants found in our cohort of 120 patients with RVCL. (FIG. 22G) Representative confocal immunofluorescence images of 293T cells expressing HA -tagged WT TREX1 or TREX1 E266X with immunostaining for TREX1 (HA). Scale bar = 15 pm. Data are representative of all cells observed in 2 independent experimentsFIG. 23 A - FIG. 23D show prime-editing gene therapy converts tire RVCL-causing TREX1 mutant protein to wild-type TREX1 in cultured cells and in mice. (FIG. 23 A) Schematic of prime-editing gene therapy for TREX1 V235Gfs. (FIG. 23B) Western blot of TREX1 in 293T cells expressing TREX1 V235Gfs and transfected with the RVCL gene editor. After SDS-PAGE, membranes were probed with antibodies against the N-terminal HA tag (left), or an antibody against the C-terminus of TREX1 (middle), or GAPDH (right). On the right, we include diagram indicating the regions of TREX1 detected by antibodies to the N- and C -termini. Data are representative of three independent experiments. (FIG. 23C) Prime editing efficiency in 293T cells (left) and livers of mice treated intravenously with AAV encoding the RVCL prime editor (right). For statistical analysis, the data represent the mean ± SEM of n = 3 samples pooled from three independent experiments and were analyzed by Student's t test (**P < 0.01; ***P < 0.001). (FIG. 23D) Representative epifluorescence images of liver sections from unedited and AAV prime-edited LSL CAG-Cre TREX1 mice expressing HA -tagged TREX1 V235Gfs and WT TREX1 (control), expression was induced with daily tamoxifen injection for three or four days. Scale bar = 20 pm. Data in FIG. 23D are representative of two independent experiments.FIG. 24A - FIG. 24C shows plasmid maps for prime editing performed using AAV vector delivery. The sequence for the plasmid depicted in FIG. 24A is provided in SEQ ID NO:9211. The sequence for the plasmid depicted in FIG. 24B is provided in SEQ ID NO: 9212. The sequence for the plasmid depicted in FIG. 24C is provided in SEQ ID NO: 9213.FIG. 25 shows frequencies of TREX1 variants in a clinical cohort of 120 RVCL patients at the University of Pennsylvania Perelman School of Medicine.FIG. 26 shows a diagram of a TREX1 protein and disease-causing mutations. TREX1 is the major 3 ’-5’ DNA exonuclease in mammalian cells. Mutations that inactivate the exonuclease activity are associated with Aicardi-Goutieres syndrome and lupus-like autoimmunity. Meanwhile, mutations that affect the transmembrane domain lead to TREX1 mislocalization and are associated with RVCL.FIG. 27 shows prime editor correction of RVCL-causing mutations. Editing efficiency of the TREX1 prime editors in 293T cells. Cell lines encoding the indicated RVCL-causing TREX1 mutations were transfected with 750 ng PEmax and 250 ng epegRNA. After three days, DNA was harvested and amplicons were generated for NGS sequencing analysis. Data represents the mean ± SEM of n = 3 samples, pooled from three independent experiments.FIG. 28 shows prime editors do not affect wild-type TREX1. Percentage of reads with unmodified, wild-type TREX1 and TREX1 containing indels. Cell lines encoding wild-type TREX1 were transfected with either a scramble epegRNA or the RVCL prime editor epegRNA prior to analysis by NGS sequencing. Data represent the mean ± SEM of n = 3 samples, pooled from three independent experiments.DETAILED DESCRIPTION OF THE INVENTIONProvided herein are compositions and methods for correction of mutations in a TREX1 gene. The compositions and methods are useful for treatment of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL).RVCL (also known as RVCL-S, ccrcbrorctinal vasculopathy (CRV), hereditary endotlieliopathy, retinopathy, nephropathy and stroke (HERNS), hereditary vascular retinopathy (HVR). hereditary systemic angiopathy (HSA), or TREX1 vasculopathy) is caused by autosomal- dominant C-terminal frameshift mutations in the gene TREX1. One hundred percent of patients with RVCL have similar, autosomal-dominant mutations in the carboxy (C)-terminal region of TREX1, and all of these patients develop multi-organ damage beginning around the age of 40 years. Furthermore, all patients with RVCL die prematurely from the disease, often within 5-10 years of the onset of symptoms. RVCL is clinically distinct from an autosomal-recessive autoinflammatory disease known as Aicardi-Goutieres syndrome (AGS), although both RVCLand AGS are characterized by mutations in TREX1. Whereas AGS can also be caused by mutations in other genes, RVCL is only caused by mutations in TREX1. Unlike RVCL, which is caused by a single truncation in one TREX1 allele, AGS can result from tire complete loss of TREX1 function.TREX1 encodes a DNA exonuclease and loss of TREX1 function in AGS leads to accrual of dsDNA in the cytosol and unabated activation of the cGAS-STING pathway, as TREX1 negatively regulates the expression of type I interferon and interferon-stimulated genes. The amino terminal domain of tire TREX1 enzyme contains all of the structural elements for full exonuclease activity, whereas the C-tenninal region controls localization of TREX1 at tire perinuclear space. The precise immunological and molecular mechanism by which TREX1 frameshift mutations cause RVCL is less well understood, although it might be related to mislocalization of a functional TREX1 enzyme or, alternatively, dysregulation of cGAS-STING signaling.There is currently no effective treatment available for RVCL. Patients with RVCL develop liver, kidney, and retinal disease, which are thought to be a consequence of endotheliopathy, making the endothelial cells a primary target for therapeutic intervention. Gene therapy for RVCL is especially challenging for three reasons: (1) the full-length TREX1 protein prevents systemic autoimmunity, so the wild-type allele must remain untouched. (2) traditional CRISPR / Cas9 strategies would disrupt tire mutant allele by introducing a different C-tenninal truncation, which would cause tire pathology, and (3) an effective therapeutic strategy would require targeting to the systemic vasculature (multiple organs).As used herein, '‘disease”, “disorder”, and “condition” are used interchangeably, to indicate an abnormal state in a subject.The term “expression” is used herein in its broadest meaning and comprises the production of RNA, of protein, or of both RNA and protein. With respect to RNA, the term “expression” or “translation” relates in particular to the production of peptides or proteins. Expression may be transient or may be stable.“Patient” or “subject”, as used herein interchangeably, means a male or female mammalian animal, including a human, a veterinary or farm animal, a domestic animal or pet, and animals normally used for clinical research such as canines, non-human primates, and mice. In certain embodiments, the subject has been identified as harboring a RVCL-causing mutation in a TREX1 allele. In certain embodiments, the subject is pre-symptomatic. In other embodiment, the subject exhibits one more symptoms of RVCL.Amino acids are referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by tire IUPAC-IUB Biochemical Nomenclature Commission. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation.As used herein, the term 'mutation.'’ refers to a substitution of a residue within a sequence, e.g., a nucleic acid or amino acid sequence, with another residue, or a deletion or insertion of one or more residues within a sequence. Mutations are typically described herein by identifying the original residue followed by the position of the residue within the sequence and by the identity of tire newly substituted residue.As used herein, the term “wild-type’’ is a term of the art understood by skilled persons and means the typical form of an organism, strain, gene or characteristic as it occurs in nature as distinguished from mutant or variant forms. As used herein the tenn “variant” should be taken to mean the exhibition of qualities that have a pattern that deviates from the wild-ty pe or a comprises non naturally occurring components.Terms such as “target site” and “target sequence”, unless indicated otherwise, are used herein to refer to a sequence that is recognized by one or more elements of a gene-editing system. For example, a pegRNA or sgRNA includes a sequence that binds (i.e., is complementary to) a target site or target sequence in the TREX1 gene.The terms “protein,” “peptide.” and “polypeptide” are used interchangeably herein, and refer to a polymer of amino acid residues linked together by peptide (amide) bonds. The terms refer to a protein, peptide, or polypeptide of any size, structure, or function. Typically, a protein, peptide, or polypeptide will be at least three amino acids long. A protein, peptide, or polypeptide may refer to an individual protein or a collection of proteins. One or more of the amino acids in a protein, peptide, or polypeptide may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a famesyl group, an isofamesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modification, etc. A protein, peptide, or polypeptide may also be a single molecule or may be a multi -molecular complex. A protein, peptide, or polypeptide may be just a fragment of a naturally occurring protein or peptide. A protein, peptide, or polypeptide may be naturally occurring, recombinant, or synthetic, or any combination thereof. The term “fusion protein” as used herein refers to a hybrid polypeptide which comprises protein domains from at least two different proteins. One protein may be located at the amino-terminal (N -terminal) portion of the fusion protein or at the carboxy-terminal (C-terminal) protein thus forming an “amino-terminal fusionprotein” or a “carboxy-terminal fusion protein,” respectively. A protein may comprise different domains, for example, a nucleic acid binding domain (e.g., the sgRNA binding domain of a Cas enzy me that directs tire binding of the protein to a target site) and a nucleic acid cleavage domain or a catalytic domain of a nucleic-acid editing protein. In some embodiments, a protein comprises a proteinaceous part, e.g., an amino acid sequence constituting a nucleic acid binding domain, and an organic compound, e.g., a compound that can act as a nucleic acid cleavage agent. In some embodiments, a protein is in a complex with, or is in association with, a nucleic acid, e.g., RNA. Any of the proteins provided herein may be produced by any method known in the art. For example, the proteins provided herein may be produced via recombinant protein expression and purification, which is especially suited for fusion proteins comprising a peptide linker. Methods for recombinant protein expression and purification are well known, and include those described by Green and Sambrook, Molecular Cloning: A Laboratory Manual (4.sup.th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)), tire entire contents of which are incorporated herein by reference.It is to be noted that the term “a” or "‘an” refers to one or more. As such, the terms "‘a” (or “an”), “one or more,” and “at least one” are used interchangeably herein.While various embodiments in the specification are presented using “comprising” language, under other circumstances, a related embodiment is also intended to be interpreted and described using “consisting of’ or “consisting essentially of’ language. The words “comprise”, “comprises”, and “comprising” are to be interpreted inclusively rather than exclusively. The words “consist”, “consisting”, and its variants, are to be interpreted exclusively, rather than inclusively.As used herein, the term “about” refers to a variant of ±10% from the reference integer and values therebetween. For example, “about” 40 base pairs, includes ±4 (i.e., 36 - 44, which includes the integers 36, 37, 38, 39, 40, 41, 42, 43, 44). For other values, particularly when reference is to a percentage (e.g., 90% identity, about 10% variance, or about 36% mismatches), the term “about” is inclusive of all values within the range including both the integer and fractions.Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of tire unit of the lower limit of the range, unless the context clearly dictates otherwise.Prime Editing“Prime editing” directly introduces new genetic information into a targeted DNA site. Typically editing is effected by a fusion protein (referred to herein as “prime editing enzyme” or “prime editing fusion enz me”) having a catalytically impaired Cas endonuclease and an engineered reverse transcriptase enzyme, and a prime editing guide RNA (pegRNA), capable of identifying the target site and providing the new genetic information to replace or insert target DNA nucleotides. By relying on DNA mismatch repair instead of non-homologous end joining (NHEJ) or homology-directed repair (HDR) to fix DNA breaks, prime editing avoids the generation of DSBsPrime editing typically involves three major components: (1) a prime editing guide RNA (pegRNA) that can identify of a target nucleotide sequence to be edited and that encodes the genetic information to incorporate at the targeted sequence. pegRNA comprises an extended single guide RNA (sgRNA) containing a primer binding site (PBS) and a reverse transcriptase (RT) template sequence (or extension sequence); (2) a fusion protein comprising a Cas protein (e.g., an H840A nickase) fused to a reverse transcriptase (e.g., Moloney Murine Leukemia Virus (M-MLV) reverse transcriptase); and (3) an optional single guide RNA (sgRNA) that directs tire Cas protein portion of tire fusion protein to nick the non-edited DNA strand.A fusion protein nicks the target DNA sequence to initiate (prime) the reverse transcription of the RT template portion of the pegRNA. The reannealed double stranded DNA contains nucleotide mismatches at the location where the RT template differs from the genomic sequence. To correct the mismatches, the cells exploit the intrinsic mismatch repair mechanism, with two possible outcomes: (i) the information in the edited strand is copied into the complementary strand, permanently installing the edit; or (ii) the original nucleotides are reincorporated into the edited strand, excluding the edit.The present disclosure provides for nucleic acid molecules encoding and / or expressing the pegRNAs, as well as expression vectors and constructs for expressing tire pegRNAs described herein, host cells comprising the nucleic acid molecules and expression vectors, and compositions for delivering and / or administering the pegRNAs in conjunction with a prime editing system described herein. In addition, the disclosure provides for isolated pegRNAs, as well as compositions comprising the pegRNAs as described herein. Still further, tire present disclosure provides for methods of making tire pegRNAs disclosed herein, as well as methods of using the pegRNAs in methods of prime editing for introducing one or more changes into a target nucleic acid molecule, e.g., a genome. The specification also provides methods for efficiently editing atarget nucleic acid molecule, e.g., a single nucleobase of a genome, with a prime editing system described herein (e.g., in the form of a prime editor as described herein or a vector or construct encoding same and an pegRNA described herein) or any prime editing system described previously. Still further, the specification provides therapeutic methods for treating a genetic disease and / or for altering or changing a genetic trait or condition by contacting a target nucleic acid molecule, e.g.. a genome, with a prime editing system described herein.As used herein, '‘prime editing guide RNA,” “pegRNA,’’ engineered pegRNA,” and “epegRNA” interchangeably refer to refer to a single RNA species that is capable of identifying a target nucleotide sequence to be edited and encodes the genetic information to be incorporated at the targeted sequence. pegRNA sequences can be transcribed from double-stranded DNA sequences inside a cell. A pegRNA recognizes a target DNA region of interest and directs an RNA-guided DNA endonuclease there for editing. A pegRNA has at least three regions. First, a spacer sequence (or protospacer), which is a nucleotide sequence complementary to the target nucleic acid, second a structure (referred to as a '‘scaffold” or “scaffold sequence”) allowing the hybridization of the pegRNA and Cas9, and which serves as a binding scaffold for the RNA- guided DNA endonuclease, and third a sequence that primes tire reverse transcriptase and provides the template for introducing targeted modifications (i.e., primer binding site (PBS) and RT template). The spacer RNA, scaffold, and the PBS / RT template can exist as one molecule or as two separate molecules. pegRNA refer to a single molecule comprising at least a spacer RNA region, a scaffold, and an RT template region or two separate molecules wherein the first comprises the spacer RNA region and the second comprises rest of the pegRNA. The spacer RNA region of the pegRNA is a customizable component that enables specificity in every prime editing reaction. The PBS / RT template is also customizable. pegRNA used in the systems and methods described herein can be short, single-stranded polynucleotide molecules from about 20 nucleotides to about 300 nucleotides in length. The spacer sequence (targeting sequence) that hybridizes to a complementary region of the target DNA of interest can be about 14, 15, 16, 17, 18, 19, 20, 25, 30, 35 or more nucleotides in length. A PBS / RT template capable of directing RNA-guided DNA endonuclease mediated substitution of, insertion at, or deletion of target sequence can be about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50 or more nucleotides in length. A PBS / RT template capable of directing RNA-guided DNA endonuclease mediated substitution of, insertion at, or deletion of target sequence can be about 50, 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11 or less nucleotides in length. pegRNAs can be synthetically generated or by making the pegRNA in vivo or in vitro, starting from a DNA template.In certain embodiments, provided herein is a prime editing guide RNA (pegRNA) comprising, from 5' to 3': a) a spacer that is complementary to a target sequence on a first strand of a TREX1 gene; b) a scaffold sequence capable of binding to a Cas9 protein; c) an extension sequence comprising: i) an editing template that comprises a region of complementarity to an editing target sequence on a second strand of the TREX1 gene, and ii) a primer binding site, wherein tire first strand and the second strand are complementary to each other, and wherein the editing target sequence on the second strand comprises or is complementary to a portion of the TREX1 gene comprising a mutation.In certain embodiments, a sequence of tire second strand comprises or is complementary to a sequence in a region of the TREX1 gene that encodes amino acids 231-236, amino acids 251- 256, amino acids 249-255, amino acids 263-269, amino acids 270-275, amino acids 273-278, amino acids 223-249, amino acids 242-251, amino acids 257-275, amino acids 264-280, amino acids 267-288, amino acids 276-283, or amino acids 277-298 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209. In certain embodiments, a sequence, a sequence of the second strand comprises or is complementary to a sequence in a region of the TREX1 gene comprising a mutation in amino acid 235, 236, 249, 249, 250, 253, 262, 266, 267, 267, 267, 268, 270, 271, 272, 272, 275, 277, 278, 284, 285, 287, 290, or 310 corresponding to a TREX1 protein lacking die mutation, optionally SEQ ID NO: 9209. In certain embodiment, the mutation is V235Gfs, T236Nfs, T249Nfs, T249Sfs, T250Nfs, H253Qfs, P262Gfs, E266X, S267Efs, S267Rfs, S267Qfs, S268Gfs, T270Nfs, K271Qfs, D272Lfs, D272Ifs, P275Qfs, K277X, D278Efs. R284Kfs. E285X, L287Afs, P290_A310del and / or A3 lOEfs.Table 1 identifies sequences corresponding to pegRNAs and sgRNAs for targeting TREX1. In certain embodiments, the spacer sequence and the extension sequence comprise RNA sequences corresponding to the sequences identified for any of pegRNA or sgRNA as set forth in Table 1.The term ‘‘primer binding site” or “the PBS” refers to tire portion of nucleotide sequence located on a pegRNA as component of the extension arm (typically for example, at the 3' end of the extension arm). The term “primer binding site” refers to a single-stranded portion of the pegRNA as a component of the extension arm that comprises a region of complementarity to a sequence on the non-target strand. In certain embodiments, the primer binding site is complementary to a region upstream of a nick site in a non-target strand. In certain embodiments, the primer binding site is complementary to a region immediately upstream of a nick site in the non-target strand. In some embodiments, the primer binding site is capable of binding to dieprimer sequence that is formed after nicking of the target sequence by the prime editor. When the prime editor nicks one strand of the target DNA sequence (e.g., by a Cas nickase component of the prime editor), a 3 '-ended ssDNA flap is formed, which sen es a primer sequence that anneals to the primer binding site on the pegRNA to prime reverse transcription. In some embodiments, the PBS is complementary to or substantially complementary to, and can anneal to a free 3' end on the non-target strand of the double stranded target DNA at the nick site. In certain embodiments, the PBS annealed to the free 3' end on the non-target strand can initiate target- primed DNA synthesis.As used herein, the term “protospacer” or “spacer” refers to the sequence (~20 bp) in DNA adjacent to the PAM (protospacer adjacent motif) sequence. The protospacer shares the same sequence as the spacer sequence of the guide RNA. The guide RNA anneals to the complement of the protospacer sequence on the target DNA (specifically, one strand thereof, i.e., the “target strand” versus the “non-target strand” of the target DNA sequence). In some embodiments, in order for a Cas nickase component of the prime editor to function, it also requires a specific protospacer adjacent motif (PAM), which varies depending on the Cas protein component itself, e.g., the type of Cas protein and the bacterial species from which it is derived. For example, the most commonly used Cas9 nuclease, derived from S. pyogenes, recognizes a PAM sequence of NGG that is directly downstream of the target sequence in the genomic DNA, on the non-target strand. The skilled person will appreciate that the literature in the state of the art sometimes refers to the “protospacer” as the ~20-nt target-specific guide sequence on the guide RNA itself, rather than referring to it as a “spacer.” Thus, in some cases, the term “protospacer” as used herein may be used interchangeably with the term “spacer.” The context of the description surrounding the appearance of either “protospacer” or “spacer” will help inform the reader as to whether the term is in reference to the gRNA or the DNA target.As used herein, the term “protospaccr adjacent sequence” or “PAM” refers to an approximately 2-6 base pair DNA sequence that is an important targeting component of a Cas9 nuclease. Typically, the PAM sequence is on either strand, and is downstream in the 5' to 3' direction of the Cas9 cut site. The canonical PAM sequence (i.e., the PAM sequence that is associated with the Cas9 nuclease of Streptococcus pyogenes or SpCas9) is 5'-NGG-3' wherein “N” is any nucleobase followed by two guanine (“G”) nucleobases. Different PAM sequences can be associated with different Cas9 nucleases or equivalent proteins from different organisms. In addition, any given Cas9 nuclease, e.g., SpCas9, may be modified to alter the PAM specificity of the nuclease such that the nuclease recognizes alternative PAM sequence.A pegRNA can be used alone (PE2), or in combination with an sgRNA (PE3 or PE3b) or a modified pegRNA developed to improve editing of some targets. These modifications can be, for example, mutations in the loop, addition of additional loops or incorporation of aptamers to recruit additional reverse transcriptase subunits, or any other enzyme that could improve editing outcomes, to the target site. Advances that improve PE efficiency include engineered pegRNAs, which include a structured RNA motif to stabilize and protect pegRNA 3' ends, and the PEmax architecture, which improves editor expression and nuclear localization. In certain embodiments, the pegRNA sequences disclosed herein are useful in a prime editing system utilizing PEmax and PEmax ARNase H. In other embodiments, pegRNA sequences disclosed herein are useful in a prime editing system utilizing other enzymes, for example, PE2, PEmax, PE6 variants, and split prime editors. In certain embodiments, tire prime editing system includes MLHldn or La proteins (referred to as PE5 and PE7 systems in literature).The provided pegRNA molecules can comprise one or more loops, one or more base modifications, or a combination of one or more loops and one or more base modifications to enhance prime editing activity. Any additional modifications such as to the linker between the gRNA loop and tire PBS / RT sequence can be incorporated to improve the efficacy of the pegRNA. See, e.g., Doman JL et al. Designing and executing prime editing experiments in mammalian cells. Nat Protoc. 2022 Nov;17(l l):2431-2468 and Anzalone AV, et al. Search-and- replace genome editing without double-strand breaks or donor DNA. Nature. 2019 Dec;576(7785):149-157, and which are incorporated herein by reference).In certain embodiments, the pegRNA includes a nucleic acid moiety linked thereto that is a toe-loop, hairpin, stem-loop, pseudoknot, aptamer, G-quadraplex, tRNA, riboswitch, or ribozyme. In certain embodiments, the nucleic acid moiety is a tevopreQl motif. In certain embodiments, the nucleic acid moiety is 3' to the end of the extension sequence. In certain embodiments, the nucleic acid moiety is 5' to the end of the extension sequence. See also, US20230357766A1, which is incorporated herein by reference.A pegRNA scaffold (also referred as a gRNA core, gRNA scaffold, or gRNA backbone sequence) of a pegRNA may contain a polynucleotide sequence that binds to a DNA binding domain (e.g., Cas9) of a prime editor. The scaffold sequence may interact with a prime editor as described herein, for example, by association with a DNA binding domain, such as a DNA nickase of the prime editor. One of skill in the art will recognize that different prime editors having different DNA binding domains from different DNA binding proteins may require different scaffold sequences specific to the DNA binding protein. In certain embodiments, thescaffold sequence is capable of binding to a Cas9-based prime editor. In certain embodiments, the scaffold sequences is capable of binding to a Cpfl -based prime editor. In certain embodiments, the scaffold sequences is capable of binding to a Casl2b-based prime editor. In certain embodiments, the scaffold sequence comprises: GUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUA UCAACUUGAAAAAGUGGCACCGAGUCGGUGC (SEQ ID NO: 22). In certain embodiments, the pegRNA is circular pegRNAs or a spli t / tcthcred pegRNAs (see, for example, Feng Yet al. Enhancing prime editing efficiency and flexibility with tethered and split pegRNAs. Protein Cell. 2023 Apr 21;14(4):304-308, which is incorporated herein by reference).In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids P231-T236 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 1-16, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 1-16 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 1-16. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 24-39, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 24-39 having at least 1, 2, 3, 4. 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 24-39 having at least 1, 2, 3. 4, 5, 6, 7. 8. 9, 10, 11. 12. 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 24-39. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 24-39, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, tire spacer sequence is the sequence set forth in SEQ ID NO: 21, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA 1 - epegRNA 16 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 21 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises tire sequence set forth in SEQ ID NO: 21 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in SEQ ID NO: 21. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the primeediting system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2. 3, 4, 5, 6. 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids P231-T236 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 17-20, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 17-20 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 17-20. In certain embodiments, the sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 151-195, or a variant thereof, in combination with scaffold sequence. In certain embodiments, the spacer sequence comprises tire sequence set forth in any one of SEQ ID NOs: 151-195 having at least 1, 2. 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, tire spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 151- 195 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 151-195. In certain embodiments, tire sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA 1 - sgRNA4 set forth in Tabic 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of tire prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids T251-T256 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 44-73. or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 44-73 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 44-73. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 121-150, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 121-150 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 121-150 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 121- 150. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 121 - 150, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, tire spacer sequence is the sequence set forth in any of SEQ ID NOs: 44-73, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA17 - epegRNA46 in Table1. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 119 or 120 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 119 or 120 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in SEQ ID NO: 119 or 120. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1,2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, tire epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids T251-T256 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 74-118, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 74-118 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 74-118. In certain embodiments, the sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 74- 118, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 151-195 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 151-195 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs : 151 - 195. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA5 - sgRNA49 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, 12. 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids T249-A255 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 196-267, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 196-267 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 343-414. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 343-414, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 343-414 having at least 1, 2. 3, 4, 5, 6. 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 343-414 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 343-414. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 343-414, or a variant thereof, that has been modified to include synonymous mutations that encode for tire same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 340-342, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA47 - epegRNA 118 in Table 1 . In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NO: 340-342 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises tire sequence set forth in any of SEQ ID NO: 340-342 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NO: 340-342. Suitable scaffold sequences can be identified by those skilled in the art depending on. for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, 12. 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX 1 gene or a sequence complementary thereto that encodes amino acids T249-A255 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth inany of SEQ ID NOs: 268-339, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 268-339 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 268-339. In certain embodiments, the sgRNA comprises tire spacer sequence set forth in any one of SEQ ID NOs: 415-486, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 415-486 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 415-486 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 415-486. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA50 - sgRNA121 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9. or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, 12. 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids S263-G269 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 497-687, or a variant thereof In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 497-687 having at least 1, 2, 3, 4, 5, 6, 7. 8, 9, 10, 11, 12. 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 497-687. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 844-1044, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 844-1044 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 844-1044 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 844-1044. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 844-1044, or a variant thereof, that has been modified to include synonymous mutations that encode for tire same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 838-843, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA 119 - epegRNA319 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 838-843 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth i in any of SEQ ID NOs: 838-843 having at least 1, 2. 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 838-843. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, 12. 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX 1 gene or a sequence complementary thereto that encodes amino acids S263-G269 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 688-837, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 688-837 having at least 1, 2. 3, 4, 5, 6. 7. 8, 9, 10, 11, 12. 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 74-118. In certain embodiments, the sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 1045-1194, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 1045-1194 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3'terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 1045-1194 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 1045- 1194. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA5 - sgRNA49 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on. for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9. or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, 12. 13. 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids T270-P275 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 1195-1404, or a variant thereof. In certain embodiments, tire epegRNA comprises the sequence of any of SEQ ID NOs: 1195-1404 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9. 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 1195-1404. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 1580-1789, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 1580-1789 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5’ terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 1580-1789 having at least 1, 2. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 1580-1789. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 1580-1789, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 1573-1579, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified asany one of epegRNA320 - epegRNA529 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 1573-1579 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 1573-1579 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in SEQ ID NO: 573-1579. Suitable scaffold sequences can be identified by those skilled in the art depending on. for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2. 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, 12. 13. 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids T270-P275 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 1405-1572, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 1405-1572 having at least 1. 2. 3, 4, 5. 6. 7, 8, 9. 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 1405- 1572. In certain embodiments, the sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 1790-1957, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 1790-1957 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, tire spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 1790-1957 having at least 1, 2, 3. 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 1790-1957. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA272 - sgRNA439 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises analternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9. or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2. 3. 4, 5, 6. 7. 8, 9, 10, 11, 12. 13. 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids L273-D278 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 1958-2191, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 1958-2191 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 1958-2191. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 2401-2634, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 2401-2634 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5’ terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 2401-2634 having at least 1, 2. 3, 4, 5, 6. 7, 8, 9, 10, 11, 12, 13. 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 2401-2634. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 2401-2634, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 2394-2400, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA530 - epegRNA763 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in in any of SEQ ID NOs: 2394-2400 having at least 1, 2. 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 2394-2400 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 2394-2400. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of tire prime editing system and / or Cas enzyme. Thus, in certain embodiments,the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4. 5, 6, 7. 8. 9, 10. 11. 12. 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids L273-D278 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 2192-2393, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 2192-2393 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 2192-2393. In certain embodiments, tire sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 2635-2836, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 2635-2836 having at least 1, 2. 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 2635-2836 having at least 1, 2. 3. 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 2635-2836. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA5 - sgRNA49 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids A223-T249 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, tire epegRNA comprises the sequence set forth in any of SEQ ID NOs: 2837-3533, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 2837-3533 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 2837-3533. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 3608-4304 or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 3608-4304 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 3608-4304 having at least 1, 2. 3, 4, 5, 6. 7, 8, 9, 10, 11, 12, 13. 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 3608-4304. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 3608-4304, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 3598-3607, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA764 - epegRNA 1460 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 3598-3607 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 3598-3607 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 3598-3607. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, tire epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certainembodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids A223-T249 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 3534-3597, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 3534-3597 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 3534-3597. In certain embodiments, tire sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 4305-4368, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, tire spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 4305-4368 having at least 1, 2. 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 4305-4368 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4305-4368. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA642 - sgRNA705 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in tire art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises tire scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids K242-H251 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 4369-4457, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 4369-4457 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to tire sequence set forth in any of SEQ ID NOs: 4369-4457. In certain embodiments, tire epegRNA comprises the extension sequence setforth in any one of SEQ ID NOs: 4497-4585, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 4497-4585 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 4497-4585 having at least 1, 2. 3, 4, 5, 6. 7, 8, 9, 10, 11, 12. 13. 14. or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4497-4585. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 4497-4585, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 4493-4496, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA1461 - epegRNA1549 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 4493-4496 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 4493-4496 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4493-4496. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, tire epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, tire structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids K242-H251 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 4458-4492, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 4458-4492 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9.10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4458-4492. In certain embodiments, tire sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 4586-4620, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 4586-4620 having at least 1, 2. 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 4586-4620 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4586-462. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA643 - sgRNA677 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises tire scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid P262 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 4621-4623, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 4621-4623 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4627-4629. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 4627-4629. or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 4627-4629 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 4627-4629 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4627-4629. In certain embodiments, the extension sequence is the sequence set forthSEQ ID NOs: 4627-4629, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 4624-4626, or a variant thereof. In certain embodiments, the epegRNA comprises tire combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA 1550 - epegRNA 1552 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 4624-4626 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises tire sequence set forth in SEQ ID NO: 4624-4626 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in SEQ ID NO: 4624-4626. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid H253 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in SEQ ID NO: 4630 or 4631, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of SEQ ID NO: 4630 or 4631 having at least 1, 2, 3, 4. 5, 6, 7, 8. 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in SEQ ID NO: 4630 or 4631. In certain embodiments, tire epegRNA comprises the extension sequence set forth in any one of SEQ ID NO: 4634 or 4635, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in SEQ ID NO: 4634 or 4635 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' tenninus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in SEQ ID NO: 4634 or 4635 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, or 15 mismatches as compared to the sequence set forth in SEQ ID NO: 4634 or 4635. In certain embodiments, the extension sequence is the sequence set forth in SEQ ID NO: 4634 or 4635, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in SEQ ID NO: 4632 or 4633, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as epegRNA1553 or epegRNA1554 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 4632 or 4633 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in in SEQ ID NO: 4632 or 4633 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in SEQ ID NO: 4632 or 4633. Suitable scaffold sequences can be identified by those skilled in the art depending on. for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6. 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6. 7, 8, 9, 10, 11, 12, 13. 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid A255 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 4636-4643, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 4636-4643 having at least 1. 2, 3, 4, 5. 6, 7, 8, 9. 10, 11, 12, 13,14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4636-4643. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 4648-4655, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 4648-4655 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncatednucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 4648-4655 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4648-4655. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 4648-4655. or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 4644-4647, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA 1555 - epegRNA 1562 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 4644-4647 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, tire spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 4644-4647 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4644-4647. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4. 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids T257-P275 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 4656-4748, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 4656-4748 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4656-4748. In certain embodiments, tire epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 4863-4955, or a variant thereof, in combination with a spacersequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 4863-4955 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 4863-4955 having at least 1, 2. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4863-4955. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 4863-4955, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 4859-4862, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA1550 - epegRNA1655 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 4859-4862 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth i in any of SEQ ID NOs: 4859-4862 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4859-4862. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids T257-P275 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 4749-4858, or a variant thereof. In certain embodiments, the sgRNA comprises tire sequence of any of SEQ ID NOs: 4749-4858 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4749-4858. In certain embodiments, the sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 4859-5065, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 4956-5065 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, tire spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 4956-5065 having at least 1, 2, 3. 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 4956-5065. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA644 - sgRNA753 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids L264-G280 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 5066-5582, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 5066-5582 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to tire sequence set forth in any of SEQ ID NOs: 5066-5582. In certain embodiments, tire epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 5657-6173, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 5657-6173 having at least 1, 2, 3. 4, 5, 6, 7. 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises tire sequence set forth in any of SEQ ID NOs: 5657-6173 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 5657-6173. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 5657-6173, or a variant thereof, that has been modified toinclude synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 5657-6173, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA1656 - epegRNA2172 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 5648-5656 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 5648-5656 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 5648-5656. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, tire epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, tire structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids L264-G280 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 5583-5647, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 5583-5647 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 5583-5647. In certain embodiments, the sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 6174-6238, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 6174-6238 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 6174-6238 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 6174-6238. In certain embodiments,the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA 1088 or sgRNA754 - sgRNA817 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids S267-L288 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 6239-6625, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 6239-6625 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to tire sequence set forth in any of SEQ ID NOs: 6239-6625. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 6706-7092, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 6706-7092 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises tire sequence set forth in any of SEQ ID NOs: 6706-7092 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 6706-7092. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 6706-7092, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 6706-7092, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA2273 - epegRNA2659 in Table 1. In certain embodiments, the spacer sequence comprises tire sequence set forth in any of SEQ ID NOs: 6695-6705 having at least 1, 2,3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 6695-6705 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 6695-6705. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, tire epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, tire structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX 1 gene or a sequence complementary thereto that encodes amino acids S267-L288 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, tire sgRNA comprises tire sequence set forth in any of SEQ ID NOs: 6626-6694, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 6626-6694 having at least 1, 2, 3, 4, 5, 6. 7, 8, 9, 10, 11, 12,13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 6626- 6694. In certain embodiments, the sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 7093-7161, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 7093-7161 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 7093-7161 having at least 1, 2, 3, 4, or 5 mismatches as compared to tire sequence set forth in any of SEQ ID NOs: 7093-7161. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA887 - sgRNA955 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22. ora variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to tire sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids V276-S283 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 7162-7260, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 7162-7260 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 7162-7260. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 7335-7433, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 7335-7433 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises tire sequence set forth in any of SEQ ID NOs: 7335-7433 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 7335-7433. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 7335-7433, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 7330-7334, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of cpcgRNA2174 - cpcgRNA2272 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 7330-7334 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 7330-7334 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 7330-7334. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises thescaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX 1 gene or a sequence complementary thereto that encodes amino acids V276-S283 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 7261-7329, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 7261-7329 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 7261-7329. In certain embodiments, the sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 7434-7502, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 7434-7502 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises tire sequence set forth in any of SEQ ID NOs: 7434-7502 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 7434-7502. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA956 - sgRNA 1024 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22. or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example. SEQ ID NO: 22 having at least 1. 2, 3, 4, 5. 6. 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids L277-T298 of TREX1 as provided inSEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 7503-8183, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 7503-8183 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 7503-8183. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 8258-8938, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 8258-8938 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises tire sequence set forth in any of SEQ ID NOs: 8258-8938 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 8258-8938. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 8258-8938, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 8248-8257, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA8258 - epegRNA3341 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 8248-8257 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 8248-8257 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 8248-8257. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises tire scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX 1 gene or a sequence complementary thereto that encodes amino acids L277-T298 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 8184-8247, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 8184-8247 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 8184-8247. In certain embodiments, the sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 8939-9002, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 8939-9002 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, tire spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 151-195 having at least 1, 2, 3, 4. or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 151-195. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA 1024 - sgRNA 1087 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in tire art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2. 3, 4, 5, 6. 7. 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, an sgRNA is provided for targeting a region of a TREX1 gene or a sequence complementary thereto that encodes amino acids L277-T298 of TREX 1 as provided in SEQ ID NO: 9209. In certain embodiments, tire sgRNA comprises the sequence set forth in any of SEQ ID NOs: 8184-8247, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 8184-8247 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 8184-8247. In certain embodiments, tire sgRNA comprises the spacer sequence set forth in any one of SEQ ID NOs: 8939-9002, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in anyone of SEQ ID NOs: 8939-9002 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises tire sequence set forth in any of SEQ ID NOs: 151-195 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 151-195. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to a construct identified as any one of sgRNA1024 - sgRNA1087 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7. 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid V235 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 9003-9032 or 9058-9061. or a variant thereof. In certain embodiments, tire epegRNA comprises the sequence of any of SEQ ID NOs: 9003-9032 or 9058-9061 having at least 1, 2. 3, 4, 5, 6. 7, 8, 9, 10, 11, 12. 13. 14. or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9003-9032 or 9058-9061. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 9125-9154 or 9180-9183, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 9125-9154 or 9180-9183 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9. 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 9125-9154 or 9180-9183 having at least 1, 2, 3. 4. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9125-9154 or 9180-9183. In certain embodiments, the extension sequence is the sequence set forth in any of SEQ ID NOs: 9125-9154 or 9180-9183, or a variant thereof, that has been modified to include synonymous mutations that encode for tire same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in SEQ ID NOs:9087 or 9113-9116, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA3342 - epegRNA3371 or epegRNA3397 - epegRNA3400 in Table 1. In certain embodiments, tire spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 9087 or 9113-9116 having at least 1, 2, 3. 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 9087 or 9113-9116 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth i in any of SEQ ID NOs: 9087 or 9113-9116. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, tire epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, tire structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, an sgRNA is provided for targeting a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid V235 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the sgRNA comprises the sequence set forth in any of SEQ ID NOs: 9078-9086, or a variant thereof. In certain embodiments, the sgRNA comprises the sequence of any of SEQ ID NOs: 9078-9086 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9078-9086. In certain embodiments, the sgRNA comprises tire spacer sequence set forth in any one of SEQ ID NOs: 9200-9208, or a variant thereof, in combination with a scaffold sequence. In certain embodiments, the spacer sequence comprises the sequence set forth in any one of SEQ ID NOs: 9200-9208 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 9200-9208 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9200-9208. In certain embodiments, the sgRNA comprises the combination of spacer sequence and scaffold sequence, or variants thereof, corresponding to aconstruct identified as any one of sgRNA3 - sgRNA 11 set forth in Table 1. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the sgRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the sgRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid R268 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 9035-9038, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 9035-9038 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9035-9038. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 9157-9160, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 9157-9160 having at least 1. 2, 3, 4, 5. 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 9157-9160 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9157-9160. In certain embodiments, the extension sequence is the sequence set forth SEQ ID NOs: 9157-9160, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, tire spacer sequence is the sequence set forth in any of SEQ ID NOs: 9090-9093, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA3374 - epegRNA3377 in Table 1. In certain embodiments, tire spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 9090-9093 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises tire sequence set forth in any of SEQ ID NOs: 9090-9093 having at least 1, 2,3, 4, or 5 mismatches as compared to the sequence set forth i in any of SEQ ID NOs: 9090-9093. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of tire prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid D278 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 9039-9044, or a variant thereof. In certain embodiments, the epegRNA comprises tire sequence of any of SEQ ID NOs: 9039-9044 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9039- 9044. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 9161-9166, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 9161-9166 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 9161-9166 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9161-9166. In certain embodiments, the extension sequence is tire sequence set forth in any of SEQ ID NOs: 9161-9166, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 9094-9099, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA3378 - epegRNA3383 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 9094-9099 having at least 1, 2,3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 9094-9099 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9094-9099. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, tire epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, tire structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid E266 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 9045-9049, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 9045-9049 having at least 1. 2, 3, 4, 5. 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9045-9049. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 9167-9171, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 9167-9171 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 9167-9171 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9167-9171. In certain embodiments, the extension sequence is the sequence set forth in any of SEQ ID NOs: 9167-9171, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 9100-9104, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified asany one of epegRNA3384 - epegRNA3388 in Table 1. In certain embodiments, the spacer sequence comprises tire sequence set forth in any of SEQ ID NOs: 9100-9104 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 9100-9104 having at least 1, 2. 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9100-9104. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, tire epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2. 3. 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid A255 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 9050-9057, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 9050-9057 having at least 1. 2, 3, 4. 5. 6, 7, 8, 9. 10. 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9050-9057. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 9172-9183, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 9172-9183 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, tire extension sequence comprises the sequence set forth in any of SEQ ID NOs: 9172-9183 having at least 1, 2, 3. 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9172-9183. In certain embodiments, the extension sequence is the sequence set forth in any of SEQ ID NOs: 9172-9183, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 9105-9116, ora variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA3389 - epegRNA3396 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 9105-9116 having at least 1, 2,3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 9105-9116 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9105-9116. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises tire scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6,7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid T249 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in SEQ ID NO: 9062, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of SEQ ID NO: 9062 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in SEQ ID NO: 9062. In certain embodiments, the epegRNA comprises the extension sequence set forth in SEQ ID NO: 9184, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in SEQ ID NO: 9184 having at least 1, 2, 3. 4, 5, 6, 7.8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in SEQ ID NO: 9184 having at least 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in SEQ ID NO: 9184. In certain embodiments, the extension sequence is the sequence set forth in SEQ ID NO: 9184, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence isthe sequence set forth in SEQ ID NO: 9117, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as epegRNA3401 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 9117 having at least 1. 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, tire spacer sequence comprises the sequence set forth in SEQ ID NO: 9117 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in SEQ ID NOs: 9117. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises tire scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4. 5, 6, 7, 8. 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, tire structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid D272 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 9063-9071, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 9063-9071 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9063- 9071. In certain embodiments, the epegRNA comprises the extension sequence set forth in anyone of SEQ ID NOs: 9172-9183, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 9185-9193 having at least 1. 2, 3, 4, 5. 6, 7, 8, 9. 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 9185-9193 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9185-9193. In certain embodiments, the extension sequence is the sequence set forth in any of SEQ ID NOs: 9185-9193, or a variant thereof, that has been modified to includesynonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in SEQ ID NO: 9118, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA3402 - epegRNA3410 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 9118 having at least 1, 2. 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 9118 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in SEQ ID NO: 9118. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, tire epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid R268 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 9063-9071, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of any of SEQ ID NOs: 9063-9071 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9063-9071. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 9172-9183. or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 9185-9193 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises the sequence set forth in any of SEQ ID NOs: 9185-9193 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQID NOs: 9185-9193. In certain embodiments, the extension sequence is the sequence set forth in any of SEQ ID NOs: 9185-9193, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is tire sequence set forth in SEQ ID NO: 9118, or a variant thereof. In certain embodiments, tire epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA3402 - epegRNA3410 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 9118 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 9118 having at least 1, 2, 3, 4, or 5 mismatches as compared to the sequence set forth in SEQ ID NO: 9118. Suitable scaffold sequences can be identified by those skilled in the art depending on. for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to tire sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid K277 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in any of SEQ ID NOs: 9072-9076. or a variant thereof. In certain embodiments, tire epegRNA comprises the sequence of any of SEQ ID NOs: 9072-9076 having at least 1, 2, 3, 4, 5, 6. 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9072- 9076. In certain embodiments, the epegRNA comprises the extension sequence set forth in any one of SEQ ID NOs: 9194-9198, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises the sequence set forth in any one of SEQ ID NOs: 9194-9198 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequencecomprises the sequence set forth in any of SEQ ID NOs: 9194-9198 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9194-9198. In certain embodiments, the extension sequence is the sequence set forth in any of SEQ ID NOs: 9194-9198, or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in any of SEQ ID NOs: 9119-9123, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as any one of epegRNA3411- epegRNA3416 in Table 1. In certain embodiments, the spacer sequence comprises die sequence set forth in any of SEQ ID NOs: 9119-9123 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in any of SEQ ID NOs: 9119-9123 having at least 1, 2. 3, 4, or 5 mismatches as compared to the sequence set forth in any of SEQ ID NOs: 9119-9123. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2. 3. 4, 5, 6. 7. 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.In certain embodiments, the targeted mutation is in a region of a TREX1 gene or a sequence complementary thereto that encodes amino acid R284 of TREX1 as provided in SEQ ID NO: 9209. In certain embodiments, the epegRNA comprises the sequence set forth in SEQ ID NO: 9077, or a variant thereof. In certain embodiments, the epegRNA comprises the sequence of SEQ ID NO: 9077 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in SEQ ID NO: 9077. In certain embodiments, the epegRNA comprises the extension sequence set forth in SEQ ID NO: 9199, or a variant thereof, in combination with a spacer sequence and scaffold sequence. In certain embodiments, the extension sequence comprises die sequence set forth in SEQ ID NO: 9199 having at least 1, 2, 3, 4, 5, 6, 7,8, 9, 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the extension sequence comprises tire sequence set forth in SEQ ID NO: 9199 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches as compared to the sequence set forth in SEQ ID NO: 9199. In certain embodiments, the extension sequence is the sequence set forth in SEQ ID NO: 9199. or a variant thereof, that has been modified to include synonymous mutations that encode for the same desired amino acid sequence. In certain embodiments, the spacer sequence is the sequence set forth in SEQ ID NO: 9124, or a variant thereof. In certain embodiments, the epegRNA comprises the combination of spacer sequence and extension sequence, or variants thereof, corresponding to a construct identified as epegRNA3416 in Table 1. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 9124 having at least 1, 2, 3, 4, or 5 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, the spacer sequence comprises the sequence set forth in SEQ ID NO: 9124 having at least 1. 2, 3, 4, or 5 mismatches as compared to the sequence set forth in SEQ ID NOs: 9124. Suitable scaffold sequences can be identified by those skilled in the art depending on, for example, selection of the prime editing system and / or Cas enzyme. Thus, in certain embodiments, the epegRNA comprises an alternative scaffold sequence for use in combination with alternative prime editing enzymes. In certain embodiments, the epegRNA comprises the scaffold sequence set forth in SEQ ID NO: 22, or a variant thereof. In certain embodiments, variants of SEQ ID NO: 22 include, for example, SEQ ID NO: 22 having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 truncated nucleotides at its 5' terminus and / or 3' terminus. In certain embodiments, variants of SEQ ID NO: 22 include SEQ ID NO: 22 having at least 1, 2, 3. 4. 5, 6, 7. 8. 9, 10. 11. 12. 13, 14, or 15 mismatches as compared to the sequence set forth SEQ ID NO: 22. In certain embodiments, the epegRNA further comprises a structural RNA motif at its 3' terminus. In certain embodiments, the structural RNA motif comprises the sequence set forth in SEQ ID NO: 23.Table 1IllCas ProteinsMethods and compositions described herein can utilize Cas proteins, such as a Cas9 nickase. Cas proteins are RNA-guided DNA endonuclease enzymes associated with the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), widely used in genetic engineering applications, as they can be used to induce site-directed double-strand breaks in DNA based on the complementarity to the guide RNA. RNA-guided Cas enzymes can be dual (e.g., Cas9, Cas 12b) and have a 2-part guide RNA in the native system, as opposed to single-RNA guided ones (e.g., Casl2a). A Cas nuclease can be mutated in a variety of ways to improve specificity and control. Nuclease domains can be mutated independently of each other to generate Cas nickases having only one catalytically active domain (either the HNH domain or the RuvC domain). Cas9 nickases retain DNA binding based on gRNA specificity, but are capable of cutting only one strand of DNA resulting in a single-strand break (e.g. a "nick”).Non-limiting examples of RNA-guided DNA endonuclease proteins include Cask Casl B, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas9 (also known as Csnl and Csxl2), CaslO, Csyl, Csy2, Csy3, Csel, Cse2, Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csxl7, Csxl4, CsxlO, Csxl6, CsaX, Csx3, Csxl, Csxl5, Csfl, Csf2, Csf3, Csf4, Cas-Phi, homologs thereof, variants thereof, or modified versions thereof, such as modification to generate nickases.The range of sequences recognized by Cas nucleases is constrained by the need for a specific protospacer adjacent motif (PAM). For example, Cas from different bacterial species can recognize different PAM sequences. For example, the SpCas9 nuclease cuts upstream of the PAM sequence 5'-NGG-3' (where “N” can be any nucleotide base), while the PAM sequence 5'- NNGRR(N)-3' (where “N” can be any nucleotide base and “R” can be either A or G) is required for SaCas9 (from Staphylococcus aureus) to target a DNA region for editing. While the PAM sequence itself is necessary for cleavage, it is not included in the single guide RNA sequence.Because RNA-programmable nucleases (e.g., Cas9) use RNA:DNA hybridization to target DNA cleavage sites, these proteins are able to be targeted, in principle, to any sequence specified by the guide RNA. Methods of using RNA-programmable nucleases, such as Cas9, for site-specific cleavage (e.g., to modify a genome) are known in the art (see e.g., Cong, L. et al., Multiplex genome engineering using CRISPR / Cas systems. Science 339, 819-823 (2013); Mali, P. et al., RNA-guided human genome engineering via Cas9. Science 339, 823-826 (2013); Hwang. W. Y. et al., Efficient genome editing in zebrafish using a CRISPR-Cas system. NatureBiotechnology 31, 227-229 (2013); Jinek, M. et al., RNA-programmed genome editing in human cells. eLife 2, e00471 (2013); Dicarlo, J. E. et al., Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems. Nucleic Acids Research (2013); Jiang, W. et al. RNA- guided editing of bacterial genomes using CRISPR-Cas systems. Nature Biotechnology 31, 233- 239 (2013); the entire contents of each of which are incorporated herein by reference).As a result, the engineering of Cas derivatives with purposefully altered PAM specificities address this limitation. Such Cas enzymes (i.e., PAM modified Cas), can also be used in the prime editors described herein.High fidelity Cas enzymes, with improved specificity, developed to reduce the frequency of off-target events associated with wild type Cas can also be used in the prime editors described herein.In certain embodiments, the catalytically active RNA-guided DNA endonuclease protein can be a CRISPR associated protein 9 (Cas9) nickase. The Cas9 nickase can a Cas9 protein having an amino acid substitution at position 10 or at position 840 or at position 863. Any amino acid substitution that removes the aspartic acid at position 10 (D10), as well as any amino acid substitution that removes the histidine at position 840 (H840) can be used to alter the catalytic activity of the enzyme. For example, the introduction of a H840A substitution in a Cas9 nuclease, through which the 840 amino acid histidine is replaced by an alanine, inactivates one of the nuclease domains. With only one functioning domain, the catalytically impaired Cas9 (H840A Cas9) can only introduce a single strand nick.

[0082] Various alterations of Cas9 can lead to the generation of a Cas9 nickase; non-limiting examples of Cas9 nickases include D10A Cas9, DION Cas9, H840N Cas9, H840Y Cas9, H840A Cas9, or N863A Cas9. Equivalent modifications can be applied to Cas9 variants, as well as to any alternative Cas protein.Reverse TranscriptaseA reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by retroviruses to replicate their genomes, by retrotransposon mobile genetic elements to proliferate within the host genome, by eukaryotic cells to extend the telomeres at the ends of their linear chromosomes, and by some non-retroviruses such as the hepatitis B vims, a member of the Hepadnaviridae, which are dsDNA-RT viruses.Retroviral RT has three sequential biochemical activities: RNA-dependent DNA polymerase activity, ribonuclease H (RNAse H), and DNA-dependent DNA polymerase activity.Collectively, these activities enable the enzy me to convert single-stranded RNA into doublestranded cDNA. In retroviruses and retrotransposons, this cDNA can then integrate into the host genome, from which new RNA copies can be made via host-cell transcription. The same sequence of reactions is widely used to convert RNA to DNA for use in molecular cloning, RNA sequencing, polymerase chain reaction (PCR), or genome analysis. Prime editor and genome editing in general rely on the use of RTases for their ability to generate DNA using an RNA template. Any RTase that synthesizes DNA from an RNA template can be used, including engineered RT, any protein that can generate DNA based on a RNA template, variants thereof and mutants thereof. Non-limiting examples or RTases include Rous sarcoma virus reverse transcriptase; HIV-1 reverse transcriptase from human immunodeficiency virus type 1; M-MLV reverse transcriptase from the Moloney murine leukemia virus; AMV reverse transcriptase from the avian myeloblastosis; Marathon reverse transcriptase; telomerase reverse transcriptase, and any variant thereof.A reverse transcriptase can be an engineered RTase, comprising mutations in the polynucleotide sequence of the enzy me, that are responsible for enhancing the binding of the enzyme to the template, the enzyme processivity, and the enzyme thermostability.In certain embodiments, a reverse transcriptase of a prime editor can be an M-MLV reverse transcriptase (e.g., accession number M32803) or a Marathon reverse transcriptase. M- MLV reverse transcriptase is known for its ability to synthesize DNA from a single-stranded RNA template.In certain embodiments, the prime editor is the PEmax fusion protein, which includes an SpCas9 nickase and a reverse transcriptase from Moloney murine leukemia virus. See, for example, Chen PJ, et al. Enhanced prime editing systems by manipulating cellular determinants of editing outcomes. Cell. 2021 Oct 28;184(22):5635-5652.e29, which is incorporated herein by reference. In certain embodiments, the PEmax fusion protein is encoded by the sequence set forth in SEQ ID NO: 9214, or a sequence at least 95% identical thereto that encodes a functional enzyme.PEMax (SEQ ID NO: 9214) augaaacggacagccgacggaagcgaguucgagucaccaaagaagaagcggaaagucgacaagaaguacagcaucggccuggac aucggcaccaacucugugggcugggccgugaucaccgacgaguacaaggugcccagcaagaaauucaaggugcugggcaacac cgaccggcacagcaucaagaagaaccugaucggagcccugcuguucgacagcggcgaaacagccgaggccacccggcugaagag aaccgccagaagaagauacaccagacggaagaaccggaucugcuaucugcaagagaucuucagcaacgagauggccaaggugga cgacagcuucuuccacagacuggaagaguccuuccugguggaagaggauaagaagcacgagcggcaccccaucuucggcaaca ucguggacgagguggccuaccacgagaaguaccccaccaucuaccaccugagaaagaaacugguggacagcaccgacaaggccgaccugcggcugaucuaucuggcccuggcccacaugaucaaguuccggggccacuuccugaucgagggcgaccugaaccccgac aacagcgacguggacaagcuguucauccagcuggugcagaccuacaaccagcuguucgaggaaaaccccaucaacgccagcggc guggacgccaaggccauccugucugccagacugagcaagagcagaaagcuggaaaaucugaucgcccagcugcccggcgagaa gaagaauggccuguucggaaaccugauugcccugagccugggccugacccccaacuucaagagcaacuucgaccuggccgagg augccaaacugcagcugagcaaggacaccuacgacgacgaccuggacaaccugcuggcccagaucggcgaccaguacgccgacc uguuucuggccgccaagaaccuguccgacgccauccugcugagcgacauccugagagugaacaccgagaucaccaaggcccccc ugagcgccucuaugaucaagagauacgacgagcaccaccaggaccugacccugcugaaagcucucgugcggcagcagcugccu gagaaguacaaagagauuuucuucgaccagagcaagaacggcuacgccggcuacauugacggcggagccagccaggaagaguu cuacaaguucaucaagcccauccuggaaaagauggacggcaccgaggaacugcucgugaagcugaagagagaggaccugcugc ggaagcagcggaccuucgacaacggcagcaucccccaccagauccaccugggagagcugcacgccauucugcggcggcaggaag auuuuuacccauuccugaaggacaaccgggaaaagaucgagaagauccugaccuuccgcauccccuacuacgugggcccucug gccaggggaaacagcagauucgccuggaugaccagaaagagcgaggaaaccaucacccccuggaacuucgaggaaguggugga caagggcgcuuccgcccagagcuucaucgagcggaugaccaacuucgauaagaaccugcccaacgagaaggugcugcccaagca cagccugcuguacgaguacuucaccguguauaacgagcugaccaaagugaaauacgugaccgagggaaugagaaagcccgccu uccugagcggcgagcagaaaaaggccaucguggaccugcuguucaagaccaaccggaaagugaccgugaagcagcugaaagag gacuacuucaagaaaaucgagugcuucgacuccguggaaaucuccggcguggaagaucgguucaacgccucccugggcacaua ccacgaucugcugaaaauuaucaaggacaaggacuuccuggacaaugaggaaaacgaggacauucuggaagauaucgugcuga cccugacacuguuugaggacagagagaugaucgaggaacggcugaaaaccuaugcccaccuguucgacgacaaagugaugaag cagcugaagcggcggagauacaccggcuggggcaggcugagccggaagcugaucaacggcauccgggacaagcaguccggcaa gacaauccuggauuuccugaaguccgacggcuucgccaacagaaacuucaugcagcugauccacgacgacagccugaccuuuaa agaggacauccagaaagcccagguguccggccagggcgauagccugcacgagcacauugccaaucuggccggcagccccgccau uaagaagggcauccugcagacagugaaggugguggacgagcucgugaaagugaugggccggcacaagcccgagaacaucguga ucgaaauggccagagagaaccagaccacccagaagggacagaagaacagccgcgagagaaugaagcggaucgaagagggcauca aagagcugggcagccagauccugaaagaacaccccguggaaaacacccagcugcagaacgagaagcuguaccuguacuaccugc agaaugggcgggauauguacguggaccaggaacuggacaucaaccggcuguccgacuacgauguggacgcuaucgugccucag agcuuucugaaggacgacuccaucgacaacaaggugcugaccagaagcgacaagaaccggggcaagagcgacaacgugcccucc gaagaggucgugaagaagaugaagaacuacuggcggcagcugcugaacgccaagcugauuacccagagaaaguucgacaaucu gaccaaggccgagagaggcggccugagcgaacuggauaaggccggcuucaucaagagacagcugguggaaacccggcagauca caaagcacguggcacagauccuggacucccggaugaacacuaaguacgacgagaaugacaagcugauccgggaagugaaagug aucacccugaaguccaagcugguguccgauuuccggaaggauuuccaguuuuacaaagugcgcgagaucaacaacuaccacca cgcccacgacgccuaccugaacgccgucgugggaaccgcccugaucaaaaaguacccuaagcuggaaagcgaguucguguacg gcgacuacaagguguacgacgugcggaagaugaucgccaagagcgagcaggaaaucggcaaggcuaccgccaaguacuucuuc uacagcaacaucaugaacuuuuucaagaccgagauuacccuggccaacggcgagauccggaagcggccucugaucgagacaaac ggcgaaaccggggagaucgugugggauaagggccgggauuuugccaccgugcggaaagugcugagcaugccccaagugaaua ucgugaaaaagaccgaggugcagacaggcggcuucagcaaagagucuauccugcccaagaggaacagcgauaagcugaucgcc agaaagaaggacugggacccuaagaaguacggcggcuucgacagccccaccguggccuauucugugcuggugguggccaaagu ggaaaagggcaaguccaagaaacugaagagugugaaagagcugcuggggaucaccaucauggaaagaagcagcuucgagaaga aucccaucgacuuucuggaagccaagggcuacaaagaagugaaaaaggaccugaucaucaagcugccuaaguacucccuguuc gagcuggaaaacggccggaagagaaugcuggccucugccggcgaacugcagaagggaaacgaacuggcccugcccuccaaaua ugugaacuuccuguaccuggccagccacuaugagaagcugaagggcucccccgaggauaaugagcagaaacagcuguuugugg aacagcacaagcacuaccuggacgagaucaucgagcagaucagcgaguucuccaagagagugauccuggccgacgcuaaucug gacaaagugcuguccgccuacaacaagcaccgggauaagcccaucagagagcaggccgagaauaucauccaccuguuuacccugaccaaucugggagccccugccgccuucaaguacuuugacaccaccaucgaccggaagagguacaccagcaccaaagaggugcug gacgccacccugauccaccagagcaucaccggccuguacgagacacggaucgaccugucucagcugggaggugacuccggcgg aagcucugguggcagcaagcggaccgccgacggcucugaauucgagagcccuaagaagaaaagaaaggugagcggaggcucua gcggcggaagcacccugaacauugaagacgaguauagacugcaugaaacaagcaaggaacccgacgugucccugggcuccaccu ggcuguccgacuuuccccaggccugggccgagacaggaggaaugggccuggccgugcggcaggcaccccugaucaucccucug aaggccaccucuacacccgugagcaucaagcaguacccuaugucucaggaggccagacugggcaucaagccucacauccagagg cugcuggaccagggcauccuggugccaugccagagccccuggaacacaccacugcugcccgugaagaagccaggcaccaaugac uauagacccgugcaggaucugagagaggugaacaagaggguggaggauauccaccccaccgugcccaacccuuacaaucugcu guccggccugcccccuucucaccagugguauacagugcuggaccugaaggaugccuucuuuugucugagacugcacccuacca gccagccacuguucgccuuugaguggagggacccugagaugggcaucucuggccagcugaccuggacacgccugccucagggc uucaagaauagcccaacacuguuuaacgaggcccugcaccgcgaccuggcagauuuccggauccagcacccagaucugauccug cugcaguacguggacgaucugcugcuggccgccaccagcgagcuggauugccagcagggaacacgcgcccugcugcagacccu gggaaaccugggauauagggcauccgccaagaaggcccagaucugucagaagcaggugaaguaccugggcuaucugcugaagg agggccagagauggcugacagaggccaggaaggagacagugaugggccagccaacacccaagaccccaagacagcugagggag uuccugggcaaagcaggauuuugcaggcuguucaucccaggauucgcagagauggcagcaccucuguacccacugaccaagcc gggcacccuguuuaauuggggcccugaccagcagaaggccuaucaggagaucaagcaggcccugcugacagcaccagcccugg gccugccagaccugaccaagccuuucgagcuguuuguggaugagaagcagggcuacgccaagggcgugcugacccagaagcug ggaccauggagacggcccguggccuaucuguccaagaagcuggacccaguggcagcaggauggccaccaugccugaggauggu ggcagcaaucgccgugcugacaaaggaugccggcaagcugaccaugggacagccacuggucauccuggcaccacacgcagugg aggcccuggugaagcagccuccagaucgcuggcugucuaacgcccggaugacacacuaccaggcccugcugcuggacaccgau cgcgugcaguuuggcccugugguggcccugaauccagccacccugcugccucugccagaggagggccugcagcacaacugucu ggacauccuggcagaggcacacggaacaaggccagaccugaccgaucagccccugccugacgccgaucacacaugguauaccga uggaagcucccugcugcaggagggccagaggaaggcaggagcagcagugaccacagagacagaagugaucugggccaaggccc ugccagcaggcacauccgcccagcgggccgagcugaucgcccugacccaggcccugaagauggccgagggcaagaagcugaac guguacacagacuccagauaugccuucgccaccgcacacauccacggagagaucuacaggcgccggggcuggcugaccucuga gggcaaggagaucaagaacaaggaugagauccuggcccugcugaaggcccuguuucugcccaagcggcugagcaucauccacu guccuggacaccagaagggacacuccgccgaggcaaggggcaaucggauggccgaccaggccgccagaaaggcugcuauuacu gaaacucccgacacuuccacucugcugauugaaaacuccuccccuucuggcggcucaaaaagaaccgccgacggcagcgaauuc gagucucccaagaagaagaggaaagucggcucuggcccugccgcuaagagagugaagcuggacuaaA reverse transcriptase can be at the N-tenninus of a polynucleotide of a prime editor, or a reverse transcriptase can be at the C-terminus of a polynucleotide of a prime editor. A reverse transcriptase sequence can also be inserted in the sequence of the Cas protein, at the N-termius or at tire C-terminus of a polynucleotide. sgRNAPrime editing can further include a single guide RNA (sgRNA) in addition to a pegRNA.The sgRNA interacts with the Cas enzyme and promotes second strand nicking. In certain embodiments, the inclusion of the sgRNA improves editing efficiency. Table 1 identifies sequences corresponding to sgRNAs that include spacer sequences for targeting TREX1 and ascaffold sequence required for Cas-binding. In certain embodiments, the sgRNA is includes a spacer sequence and / or scaffold sequence identified in Table 1.Human TREX1 geneThe wild-type protein translated from the TREX1 gene (three prime repair exonuclease 1) consists of 314 amino acids (~ 32 kDa) and is encoded by a single exon on chromosome 3p21. TREX1 consists of three domains important for its role as a DNA repair enzyme (i.e., exonuclease domains I, II, and III). TREX1 also has an extended C-terminal “tail” domain of ~ 80 amino acids containing a leucine-rich sequence required for its endoplasmic reticulum (ER) localization. RVCL patients harbor three types of mutations, all of which are located at or beyond valine-235 of the 314 amino acid protein. The most dominant mutations are frame-shift mutations of TREX1 that produce a truncated protein, with V235G fs*6 being the most common. Other RVCL-causing mutations that have been identified so far include T236Nfs, T249Nfs, T249Sfs, T250Nfs, H253Qfs, A255Efs, E266X, P262Gfs, S267Efs, S267Rfs, S267Qfs, S268Gfs, T270Nfs, K271Qfs, D272Lfs, D272Ifs, P275Qfs, K277X, D278Efs, R284Kfs, E285X, L287Afs, P290_A310del, and A310Efs (see, e.g., FIG. 26). In certain embodiments, the compositions and methods provided are suitable for correction of one or more of these mutations. Further, it is to be understood that additional mutations that are not included in this list, including not yet identified or characterized mutations, can be RVCL-causing, and corrected using the compositions and methods provided.As used, the terms “correction” or “editing” with respect to a targeted Trexl gene or Trexl sequence encompasses not only reversion to a reference wild-type sequence or Trexl encoding sequence. For example, correction can include substitutions at the target site that introduce sequences encoding an alternative amino acid residue or residues that would restore expression of a full-length Trexl protein (e.g., as in correcting reading frame of a mutant TREX1 to restore expression the C-terminal transmembrane domain).TREX1 Coding Sequence ATGGGCTCGCAGGCCCTGCCCCCGGGGCCCATGCAGACCCTCATCTTTTTCGACATG GAGGCCACTGGCTTGCCCTTCTCCCAGCCCAAGGTCACGGAGCTGTGCCTGCTGGCT GTCCACAGATGTGCCCTGGAGAGCCCCCCCACCTCTCAGGGGCCACCTCCCACAGTT CCTCCACCACCGCGTGTGGTAGACAAGCTCTCCCTGTGTGTGGCTCCGGGGAAGGCC TGCAGCCCTGCAGCCAGCGAGATCACAGGTCTGAGCACAGCTGTGCTGGCAGCGCAT GGGCGTCAATGTTTTGATGACAACCTGGCCAACCTGCTCCTAGCCTTCCTGCGGCGCC AGCCACAGCCCTGGTGCCTGGTGGCACACAATGGTGACCGCTACGACTTCCCCCTGCTCCAAGCAGAGCTGGCTATGCTGGGCCTCACCAGTGCTCTGGATGGTGCCTTCTGTGT GGATAGCATCACTGCGCTGAAGGCCCTGGAGCGAGCAAGCAGCCCCTCAGAACACG GCCCAAGGAAGAGCTATAGCCTAGGCAGCATCTACACTCGCCTGTATGGGCAGTCCC CTCCAGACTCGCACACGGCTGAGGGTGATGTCCTGGCCCTGCTCAGCATCTGTCAGT GGAGACCACAGGCCCTGCTGCGGTGGGTGGATGCTCACGCCAGGCCTTTCGGCACCA TCAGGCCCATGTATGGGGTCACAGCCTCTGCTAGGACCAAGCCAAGACCATCTGCTG TCACAACCACTGCACACCTGGCCACAACCAGGAACACTAGTCCCAGCCTTGGAGAGA GCAGGGGTACCAAGGATCTTCCTCCAGTGAAGGACCCTGGAGCCCTATCCAGGGAG GGGCTGCTGGCCCCACTGGGTCTGCTGGCCATCCTGACCTTGGCAGTAGCCACACTG TATGGACTATCCCTGGCCACACCTGGGGAGTAG (SEQ ID NO: 9210)TREX1 Amino Acid Sequence MGSQALPPGPMQTLIFFDMEATGLPFSQPKVTELCLLAVHRCALESPPTSQGPPPTVPPPP RVVDKLSLCVAPGKACSPAASEITGLSTAVLAAHGRQCFDDNLANLLLAFLRRQPQPWC LVAHNGDRYDFPLLQAELAMLGLTSALDGAFCVDSITALKALERASSPSEHGPRKSYSLG SIYTRLYGQSPPDSHTAEGDVLALLSICQWRPQALLRWVDAHARPFGTIRPMYGVTASA RTKPRPSAVTTTAHLATTRNTSPSLGESRGTKDLPPVKDPGALSREGLLAPLGLLAILTLA VATLYGLSLATPGE (UniProt: Q9NSU2 ■ TREX1 HUMAN) (SEQ ID NO: 9209)Nucleic Acids and Expression CassettesIn one aspect, provide herein are nucleic acids that encode elements of a prime editing system. These nucleic acids include RNA species as well as DNA encoding the RNA species. In certain embodiments, the nucleic acids are included in expression cassettes, wherein the coding sequences are operably linked to expression control sequences. In certain, embodiments the nucleic acids are included in a vector or composition for delivery to a target cell or for administration to a subject.The terms “nucleic acid,” “nucleotide sequence,” and “nucleic acid molecule,” as used herein interchangeably, refer to a compound comprising a nucleobase and an acidic moiety, e.g.. a nucleoside, a nucleotide, or a polymer of nucleotides. Typically, polymeric nucleic acids, e.g., nucleic acid molecules comprising three or more nucleotides are linear molecules, in which adjacent nucleotides are linked to each other via a phosphodiester linkage. In some embodiments, “nucleic acid” refers to individual nucleic acid residues (e.g., nucleotides and / or nucleosides). In some embodiments, “nucleic acid” refers to an oligonucleotide chain comprising three or more individual nucleotide residues. As used herein, the terms “oligonucleotide” and “polynucleotide” can be used interchangeably to refer to a polymer of nucleotides (e.g., a string of at least three nucleotides). In some embodiments, “nucleic acid” encompasses RNA as well as single and / ordouble-stranded DNA. Nucleic acids may be naturally occurring, for example, in the context of a genome, a transcript, an mRNA, tRNA, rRNA, siRNA, snRNA, a plasmid, cosmid, chromosome, chromatid, or other naturally occurring nucleic acid molecule. On the other hand, a nucleic acid molecule may be a non-naturally occurring molecule, e.g.. a recombinant DNA or RNA, an artificial chromosome, an engineered genome, or fragment thereof, or a synthetic DNA, RNA, DNA / RNA hybrid, or including non-naturally occurring nucleotides or nucleosides.Furthermore, the terms ‘'nucleic acid,’’ “DNA,” “RNA,” and / or similar terms include nucleic acid analogs, e g., analogs having other than a phosphodiester backbone. Nucleic acids can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, nucleic acids can comprise nucleoside analogs such as analogs having chemically modified bases or sugars, and backbone modifications. A nucleic acid sequence is presented in the 5’ to 3’ direction unless otherwise indicated. In some embodiments, a nucleic acid is or comprises natural nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxy cytidine); nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, 2-aminoadenosine, C5-bromouridine, C5 -fluorouridine, C5- iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5 -methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars (e.g., 2'-fluororibose, ribose. 2'-deoxyribose. arabinose, and hexose); and / or modified phosphate groups (e.g., phosphorothioates and 5'-N-phosphoramidite linkages).As used herein, an “expression cassette” refers to a nucleic acid molecule encoding one or more elements of a prime editing system (e.g., prime-editing enzyme and / or pcgRNA) that includes regulatory sequences operably linked thereto which direct or modulate transcription, translation, and / or expression of the nucleic acid sequences. Such an expression cassette may be administered to a subject for therapeutic purposes. Expression cassettes can also be used for generating a viral vector for therapeutic delivery of the nucleotide sequences described.As used herein, the term “regulatory sequence”, or “expression control sequence” refers to nucleic acid sequences, such as initiator sequences, enhancer sequences, and promoter sequences, which induce, repress, or otherwise control the transcription of nucleic acid sequences to which they are operably linked.As used herein, “operably linked” sequences include both expression control sequences that are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control expression of a coding sequence.The regulatory control elements typically contain a promoter sequence as part of the expression control sequences. In certain embodiments, the promoter is a chicken beta actin promoter with CMV enhancer elements, e.g., the CB7 promoter.Other suitable promoters include, e.g., constitutive promoters, regulatable promoters [see, e.g., WO 2011 / 126808 and WO 2013 / 04943], or a promoter responsive to physiologic cues. The promoter can be selected from different sources, e.g., human cytomegalovirus (CMV) immediate- early enhancer / promoter, the SV40 early enhancer / promoter, the JC polymovirus promoter, myelin basic protein (MBP) or glial fibrillary acidic protein (GFAP) promoters, herpes simplex virus (HSV-1) latency associated promoter (LAP), rouse sarcoma virus (RSV) long terminal repeat (LTR) promoter, neuron-specific promoter (NSE), platelet derived growth factor (PDGF) promoter, melanin-concentrating hormone (MCH) promoter, CBA, matrix metalloprotein promoter (MPP), and the chicken beta-actin promoter.In addition to a promoter, an expression cassette may contain one or more other appropriate transcription initiation, termination, enhancer sequences, efficient RNA processing signals such as splicing and polyadenylation (poly A) signals; sequences that stabilize cytoplasmic mRNA for example WPRE; sequences that enhance translation efficiency (i.e., Kozak consensus sequence); sequences that enhance protein stability-; and when desired, sequences that enhance secretion of the encoded product. An example of a suitable enhancer is the CMV enhancer. Other suitable enhancers include those that are appropriate for desired target tissue indications. In one embodiment, the expression cassette comprises one or more expression enhancers. In one embodiment, the expression cassette contains t vo or more expression enhancers. These enhancers may be tire same or may differ from one another. For example, an enhancer may include a CMV immediate early enhancer. This enhancer may be present in tw o copies which are located adjacent to one another. Alternatively, the dual copies of the enhancer may be separated by one or more sequences. In still another embodiment, the expression cassette further contains an intron, e.g., the chicken beta-actin intron. Other suitable introns include those known in the art, e g., such as are described in WO 2011 / 126808. Examples of suitable poly A sequences include, e.g., rabbit beta globin, SV40, SV50, bovine growth hormone (bGH), human growth hormone, HSV TK, and synthetic poly As. Optionally, one or more sequences may be selected to stabilize mRNA. An example of such a sequence is a modified WPRE sequence,which may be engineered upstream of tire poly A sequence and downstream of the coding sequence (see, e.g., MA Zanta-Boussif, et al, Gene Therapy (2009) 16: 605-619).As described herein, regulatory elements comprise but not limited to: promoter; enhancer; transcription factor; transcription terminator; efficient RNA processing signals such as splicing and polyadenylation signals (poly A); sequences that stabilize cytoplasmic mRNA, for example Woodchuck Hepatitis Virus (WHP) Posttranscriptional Regulatory Element (WPRE); sequences that enhance translation efficiency (i.e., Kozak consensus sequence).In certain embodiments, a suitable promoter may include without limitation, an elongation factor 1 alpha (EFl alpha) promoter (see, e.g., Kim DW et al, Use of the human elongation factor 1 alpha promoter as a versatile and efficient expression system. Gene. 1990 Jul 16;91(2):217-23) or a CB6 promoter (see, e g., Large-Scale Production of Adeno-Associated Viral Vector Serotype-9 Carrying the Human Survival Motor Neuron Gene, Mol Biotechnol. 2016 Jan;58(l):30-6. doi: 10. 1007 / sl2033-015-9899-5). Other suitable promoters include CAG promoter, which comprises (C) the cytomegalovirus (CMV) early enhancer element, (A) the promoter, the first exon and the first intron of chicken beta-actin gene, and (G) the splice acceptor of the rabbit beta-globin gene. See, e.g., Alexopoulou, Annika N., et al. BMC cell biology 9.1 (2008): 2. Although less desired, other promoters, such as viral promoters, constitutive promoters, inducible promoters, regulatable promoters (see, e.g., WO 2011 / 126808 and WO 2013 / 04943), or a promoter responsive to physiologic cues may be used may be utilized in the vectors described herein. In certain embodiments, the expression cassette includes an U6 promoter. In another embodiment, the regulatory elements comprise an enhancer. In a further embodiment, the enhancer(s) is selected from one or more of an APB enhancer, an ABPS enhancer, an alpha mic / bik enhancer, a TTR enhancer, an en34 enhancer, an ApoE enhancer, a CMV enhancer, or an RSV enhancer. In yet another embodiment, the regulatory' elements comprise an intron. In a further embodiment, the intron is selected from CBA, human beta globin, IVS2, SV40, bGH, alpha-globulin, beta-globulin, collagen, ovalbumin, or p53. In one embodiment, the regulatory elements comprise a poly A. In a further embodiment, the poly A is a synthetic poly A or from bovine growth hormone (bGH). human growth hormone (hGH). SV40, rabbit P-globin (RGB), or modified RGB (mRGB). In another embodiment, the regulatory elements may comprise a WPRE sequence. In yet another embodiment, the regulatory' elements comprise a Kozak sequence.Expression cassettes can be delivered via any suitable delivery' system. Suitable non-viral delivery' systems are known in the art (see, e.g., Ramamoorth and Narvekar. J Clin Diagn Res. 2015 Jan; 9(l):GE01-GE06, which is incorporated herein by reference) and can be readilyselected by one of skill in the art and may include, e.g., naked DNA, naked RNA, dendrimers, PLGA, polymethacrylate, an inorganic particle, a lipid particle (e.g., a lipid nanoparticle or LNP), or a chitosan-based formulation. In certain embodiments, the nucleic acids or expression cassettes provided are in a plasmid.Nucleoside-Modifled mRNAIn certain embodiments, the compositions provided contain a nucleic acid molecule that is a nucleoside-modified mRNA. Nucleoside-modified mRNA have particular advantages over nonmodified mRNA, including for example, increased stability, low or absent innate immunogenicity, and enhanced translation. Nucleoside-modifications useful in the present invention is further described in U.S. Patent No. 8,278,036, which is incorporated by reference herein in its entirety.An mRNA may include one or more modified nucleobases, nucleosides, or nucleotides. In some embodiments, the mRNA in the compositions comprise at least one modification which confers increased or enhanced stability to the nucleic acid, including, for example, improved resistance to nuclease digestion in vivo. An mRNA may include any number of base pairs, including tens, hundreds, or thousands of base pairs. Any number (e.g., all, some, or none) of nucleobases, nucleosides, or nucleotides may be an analog of a canonical species, substituted, modified, or otherwise non-naturally occurring. In certain embodiments, all of a particular nucleobase type may be modified. For example, all cytosine in an mRNA may be 5- methylcytosine.In certain embodiments, the nucleoside-modified RNA comprises the naturally occurring modified-nucleoside pseudouridine. In certain embodiments, inclusion of pseudouridine makes the mRNA more stable, non-immunogenic, and highly translatable (Kariko et al., 2008, Mol Ther 16: 1833-1840; Anderson et al., 2010, Nucleic Acids Res 38:5884-5892; Anderson et al., 2011, Nucleic Acids Research 39:9329-9338; Kariko ct al., 2011, Nucleic Acids Research 39:cl42; Kariko et al., 2012, Mol Ther 20:948-953; Kariko et al., 2005, Immunity 23: 165-175).As used herein, the terms "‘modification'’ and “modified” as such terms relate to the nucleic acids provided herein, include at least one alteration which preferably enhances stability and renders the mRNA more stable (e.g., resistant to nuclease digestion) than the wild-type or naturally occurring version of the mRNA. As used herein, the terms “stable” and “stability” as such terms relate to the nucleic acids of the present invention, and particularly with respect to the mRNA, refer to increased or enhanced resistance to degradation by, for example nucleases (i.e., endonucleases or exonucleases) which are normally capable of degrading such mRNA. Increasedstability can include, for example, less sensitivity to hydrolysis or other destruction by endogenous enzymes (e.g., endonucleases or exonucleases) or conditions within the target cell or tissue, thereby increasing or enhancing the residence of such mRNA in the target cell, tissue, subject and / or cytoplasm. Also contemplated by the terms “modification” and “modified” as such terms related to the mRNA of the present invention are alterations which improve or enhance translation of mRNA nucleic acids, including for example, the inclusion of sequences which function in the initiation of protein translation (e.g., the Kozak consensus sequence).In certain embodiments, tire non-viral del i \ cr system comprises an RNA molecule which is a messenger RNA (mRNA) molecule. In certain embodiments, the mRNA molecule is an in vitro transcribed (IVT) mRNA molecule. In certain embodiments, the IVT mRNA molecule is a nucleoside-modified mRNA molecule. An mRNA may include a 5' untranslated region, a 3' untranslated region, and / or a coding or translating sequence.In certain embodiments, the nucleoside-modified mRNA of the invention is IVT mRNA. For example, in certain embodiments, the nucleoside-modified mRNA is synthesized by T7 phage RNA polymerase. In another embodiment, the nucleoside-modified mRNA is synthesized by SP6 phage RNA polymerase. In another embodiment, the nucleoside-modified RNA is synthesized by T3 phage RNA polymerase.In some embodiments, the number of C and / or U residues in an mRNA sequence is reduced. In another embodiment, the number of C and / or U residues is reduced by substitution of one codon encoding a particular amino acid for another codon encoding the same or a related amino acid. Contemplated modifications to the mRNA nucleic acids disclosed herein include the incorporation of pseudouridine (y) or 5 -methylcytosine (m5C). Substitutions and modifications to the mRNA of the present invention may be performed by methods readily known to one or ordinary skill in tire art.In certain embodiments, tire modified nucleoside is mlacp3T (l-mcthyl-3-(3-amino-3- carboxypropyl) pseudouridine. In another embodiment, the modified nucleoside is m IT (1- methylpseudouridine). In another embodiment, the modified nucleoside is Tm (2"-O- methylpseudouridine. In another embodiment, the modified nucleoside is m5D (5- methyldihydrouridine). In another embodiment, the modified nucleoside is m3 (3- methylpseudouridine). In another embodiment, the modified nucleoside is a pseudouridine moiety that is not further modified. In another embodiment, the modified nucleoside is a monophosphate, diphosphate, or triphosphate of any of the above pseudouridines. In anotherembodiment, the modified nucleoside is any other pseudouridine-like nucleoside known in tire art.In another embodiment, the modified nucleoside of the present invention is m5C (5- methylcytidine). In another embodiment, the modified nucleoside is m5U (5 -methyluridine). In another embodiment, the modified nucleoside is m6A (N6-methyladenosine). In another embodiment, the modified nucleoside is s2U (2-thiouridine). In another embodiment, the modified nucleoside is (pseudouridine). In another embodiment, the modified nucleoside is Um (2 ’ -O-methy luridine) .In other embodiments, the modified nucleoside is mlA (1-methyladenosine); m2A (2- methyladenosine); Am (2’-O-methyladenosine); ms2m6A (2-methylthio-N6-methyladenosine); i6A (N6-isopentenyladenosine); ms2i6A (2-metliyltliio-N6isopentenyladenosine); io6A (N6-(cis- hydroxyisopentenyl)adenosine); ms2io6A (2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine): g6A (N6-glycinylcarbamoyladenosine): t6A (N6-threonylcarbamoyladenosine); ms2t6A (2-methylthio-N6-threonyl carbamoyladenosine); m6t6A (N6-methyl-N6- threonylcarbamoyladenosine): hn6A(N6-hydroxynon alylcarbamoyladcnosinc): ms2hn6A (2- methyhhio-N6-hydroxynorvalyl carbamoyladenosine); Ar(p) (2’-O-ribosyladenosine (phosphate)); I (inosine); mil (1 -methylinosine); mllm (l,2’-O-dimethylinosine); m3C (3- methylcytidine); Cm (2’-O-methylcytidine); s2C (2-thiocytidine); ac4C (N4-acetylcytidine); f5C (5-fonnylcytidine); m5Cm (5.2'-O-dimethylcytidine); ac4Cm (N4-acetyl-2’-O-methylcytidine); k2C (lysidine); mlG (1-methylguanosine); m2G (N2-methylguanosine): m7G (7- methylguanosine); Gm (2?-O-methylguanosine); m22G (N2,N2-dimethylguanosine); m2Gm (N2,2’-O-dimethylguanosine); m22Gm (N2,N2,2’-O-trimethylguanosine); Gr(p) (2’-O- ribosylguanosine (phosphate)); yW (wybutosine); o2yW (peroxywybutosine); OHyW (hydroxywybutosine); OHyW* (undermodified hydroxy wybutosine); imG (wyosinc): mimG (mcthylwyosinc); Q (qucuosinc); oQ (epoxy qucuosinc); galQ (galactosyl-qucuosinc); manQ (mannosyl-queuosine); preQO (7-cyano-7-deazaguanosine); preQi (7-aminomethyl-7- deazaguanosine); G+ (archaeosine): D (dihydrouridine): m5Um (5,2’-O-dimethyluridine); s4U (4-thiouridine); m5s2U (5-methyl-2-thiouridine); s2Um (2-thio-2’ -O-methy luridine); acp3U (3- (3-amino-3-carboxypropyl)uridine); ho5U (5 -hydroxy uridine); mo5U (5-methoxyuridine); cmo5U (uridine 5-oxyacetic acid): mcmo5U (uridine 5-oxyacetic acid methyl ester); chm5U (5- (carboxyhydroxymethyl)uridine)); mchm5U (5-(carboxyhydroxymethyl)uridine methyl ester); mcm5U (5-methoxycarbonylmethyluridine); mcm5Um (5-methoxycarbonylmethyl-2’-O- methy luridine); mcm5s2U (5-methoxycarbonyhnethyl-2-thiouridine); nm5s2U (5-aminomethyl-2 -thiouridine); mnm5U (5-methylaminomethyluridine); mnm5s2U (5-methylaminomethyl-2- thiouridine); mnm5se2U (5-methylaminomethyl-2-selenouridine); ncm5U (5- carbamoylmethyluridine); ncm5Um (5-carbamoylmethyl-2’-O-methyluridine); cmnm5U (5- carboxymethylaminomethyluridine); cmmn5Um (5-carboxymetliylaminomethyl-2’-O- methyluridine); cmnm5s2U (5-carboxymethylaminomethyl-2-thiouridine); m62A (N6,N6- dimethyladenosine); Im (2’-O-methylinosine); m4C (N4-methylcytidine); m4Cm (N4.2’-O- dimethylcytidine); hm5C (5-hydroxymethylcytidine); m3U (3-methyluridine); cm5U (5- carboxymethyluridine); m6Am (N6,2’-O-dimethyladenosine); m62Am (N6,N6,O-2’- trimethyladenosine); m2,7G (N2,7-dimethylguanosine); m2,2,7G (N2,N2,7-trimethylguanosine); m3Um (3,2’-O-dimethyluridine); m5D (5 -methyldihydrouridine); f5Cm(5-formyl-2'-O- methylcytidine); mlGm (l,2’-O-dimethylguanosine); mlAm (1.2?-O-dimethyladenosine); rm5U (5-taurinomethyluridine); rm5s2U (5-taurinomethyl-2-thiouridine)); imG-14 (4- demethylwyosine); imG2 (isowyosine); or ac6A (N6-acetyladenosine).In another embodiment, a nucleoside-modified mRNA comprises a combination of 2 or more of the above modifications. In another embodiment, the nucleoside-modified mRNA comprises a combination of 3 or more of the above modifications. In another embodiment, the nucleoside-modified RNA comprises a combination of more than 3 of the above modifications.In another embodiment, between 0. 1% and 100% of the residues in the nucleoside- modified RNA are modified (e.g.. either by the presence of pseudouridine or a modified nucleoside base). In another embodiment. 0. 1% of the residues are modified. In another embodiment, the fraction of modified residues is 0.2%. In another embodiment, the fraction is 0.3%. In another embodiment, the fraction is 0.4%. In another embodiment, the fraction is 0.5%. In another embodiment, the fraction is 0.6%. In another embodiment, the fraction is 0.8%. In another embodiment, the fraction is 1%. In another embodiment, the fraction is 1.5%. In another embodiment, the fraction is 2%. In another embodiment, the fraction is 2.5%. In another embodiment, the fraction is 3%. In another embodiment, the fraction is 4%. In another embodiment, the fraction is 5%. In another embodiment, the fraction is 6%. In another embodiment, the fraction is 8%. In another embodiment, tire fraction is 10%. In another embodiment, the fraction is 12%. In another embodiment, the fraction is 14%. In another embodiment, the fraction is 16%. In another embodiment, the fraction is 18%. In another embodiment, the fraction is 20%. In another embodiment, the fraction is 25%. In another embodiment, the fraction is 30%. In another embodiment, the fraction is 35%. In another embodiment, the fraction is 40%. In another embodiment, tire fraction is 45%. In anotherembodiment, the fraction is 50%. In another embodiment, the fraction is 60%. In another embodiment, the fraction is 70%. In another embodiment, the fraction is 80%. In another embodiment, the fraction is 90%. In another embodiment, tire fraction is 100%.In certain embodiments, the mRNA includes a polyA sequence. A polyA sequence may be comprised entirely or mostly of adenine nucleotides or analogs or derivatives thereof. In certain embodiments, the polyA sequence is a tail located adjacent to a 3’ untranslated region (3’ UTR) of an mRNA.Typically, a mature mRNA comprises a ’-cap, optionally a 5 ’-UTR, an open reading frame, optionally a 3’-UTR and a poly(A) sequence. The term “UTR” refers to an “untranslated region” flanking the coding sequence of a recombinant nucleic acid as defined herein. In certain embodiments, a 5 ’-UTR starts with the transcriptional start site and ends one nucleotide before the start codon of the open reading frame. The 5’ -UTR may comprise elements for controlling gene expression, also called “regulatory elements”. Such regulatory elements may be, for example, ribosomal binding sites. The 5’-UTR may be post-transcriptionally modified, for example by addition of a 5’ cap. Thus, 5’-UTRs may preferably correspond to the sequence of a nucleic acid, in particular a mature mRNA, which is located between the 5’-Cap and the start codon, and more specifically to a sequence, which extends from a nucleotide located 3’ to the 5’- Cap, preferably from the nucleotide located immediately 3’ to tire 5 '-Cap, to a nucleotide located 5 ’ to the start codon of tire protein coding sequence (transcriptional start site), preferably to the nucleotide located immediately 5’ to the start codon of tire protein coding sequence (transcriptional start site). The nucleotide located immediately 3’ to the 5 ’-Cap of a mature mRNA typically corresponds to the transcriptional start site. 5’ UTRs typically have a length of less than 500, 400, 300, 250 or less than 200 nucleotides. In some embodiments its length may be in the range of at least 10, 20, 30 or 40, preferably up to 100 or 150, nucleotides. In certain embodiments, the at least one 5 ’-UTR clement comprises of a nucleic acid sequence derived from the 5' UTR of a mammalian gene, preferably a human gene. A 3’-UTR corresponds to a sequence which is located between the stop codon of the protein coding sequence, preferably immediately 3 ’ to the stop codon of the protein coding sequence, and the poly(A) sequence of the artificial nucleic acid molecule, e.g., RNA. In certain embodiments, the at least one 3 ’-UTR element comprises a nucleic acid sequence derived from the 3 ’-UTR of a mammalian gene, preferably a human gene.In certain embodiments, tire regulator}' sequence of an mRNA transcript comprises of a cap structure at 5' end, an untranslated region at 5’ end (5 ’UTR), an untranslated region at 3’ end(3’UTR), and poly(A) tail at 3 ’end. In certain embodiments, the nucleic acid sequence of an mRNA transcript comprises modified nucleosides of 5 -Methylcytosine, and / or pseudouridine. In certain embodiments, tire 5' cap is 5’ cap analog. See e.g., WO 2017 / 053297, which is incorporated herein by reference in its entirety. In certain embodiments, a 5' cap analog comprises cap analog comprises m7GpppN. optionally wherein the 5; cap analog is commercially available 5 ’cap. e.g., CleanCap® AU. CleanCap® AG, CleanCap® AG (3’OMe) (TriLink Biotechnologies, San Diego, CA, USA). In certain embodiments, the poly(A) tail comprises of at least 100 to at least 250 adenine nucleotides. In one embodiment, the poly(A) tail is at least 150 to at least 200 adenine nucleotides. In certain embodiments, the poly(A) tail is at least 120 adenine nucleotides.In certain embodiments, the mRNA transcript sequence is 5 'cap- coding sequence- 3’poly(A)tail. In certain embodiments, tire mRNA transcript sequence is 5’cap-5’UTR- coding sequence -3'UTR-3’poly(A)tail. In certain embodiments, the mRNA transcript sequence is 5'cap analog- coding sequence -3’poly(A)tail. In certain embodiments, the mRNA transcript sequence is 5’cap analog-5’UTR- coding sequence -3’UTR-3’poly(A)tail.In certain embodiments, tire mRNA transcript sequence is 5’cap- coding sequence (nucleoside -modified)-3 ’poly(A)tail. In certain embodiments, the mRNA transcript sequence is 5’cap-5’UTR- coding sequence (nucleoside-modified)-3’UTR-3’poly(A)tail. In certain embodiments, the mRNA transcript sequence is 5’cap analog- coding sequence (nucleoside- modified -3’poly(A)tail. In certain embodiments, the mRNA transcript sequence is 5’cap analog- 5’UTR- coding sequence (nucleoside-modified -3’UTR-3’poly(A)tail.In one example, a non-viral vector genome comprising an mRNA transcript comprising at a minimum, from 5’ to 3’, 5’ cap, a 5’ UTR, a coding sequence, a 3’UTR and a poly (A) tail.In certain embodiments, tire mRNA transcript comprises nucleic acid described herein, further comprising a 5’ cap and a polyA tail. In certain embodiments, the mRNA transcript comprises nucleic acid described herein, further comprising a 5' cap, Kozak sequence, and a polyA tail. In certain embodiments, the mRNA transcript comprises nucleic acid sequence described herein, further comprising a 5’ cap which is a cap analog and a polyA tail comprising at least 100 adenine nucleotides. In certain embodiments, the mRNA transcript comprises nucleic acid sequence described herein, further comprising a 5’ cap analog which is a CleanCap® AG cap analog (TriLink Biotechnologies), and a polyA tail comprising at least 120 adenine nucleotides. In certain embodiments, the mRNA transcript comprises nucleic acid sequence which is nucleoside modified nucleic acid sequence described herein. In certain embodiments, themRNA transcript comprises nucleic acid sequence which is nucleoside modified nucleic acid sequence of described herein, further comprising a 5’ cap and a polyA tail of at least 100 adenine nucleotides. In certain embodiments, the mRNA transcript comprises nucleic acid sequence which is nucleoside modified nucleic acid sequence of described herein, further comprising a 5 ’ cap analog (e.g., CleanCap® AG cap analog) and a polyA tail of at least 120 adenine nucleotides. In certain embodiments, the mRNA transcript comprises nucleic acid sequence, which is nucleoside modified nucleic acid sequence described herein, further comprising a 5’ cap analog (e.g., CleanCap® AG cap analog), a 5’ UTR, a 3’ UTR, and a polyA tail of at least 120 adenine nucleotides.Lipid NanoparticlesIn certain embodiments, the compositions and methods provided herein require a nucleic acid molecule, wherein the nucleic acid molecule is encapsulated in a lipid nanoparticle (LNP). The encapsulated nucleic acids include DNA and / or RNA sequences that encode components of a prime editing system, including, for example, prime editing fusion proteins, pegRNA, sgRNA.The term “lipid nanoparticle”, also referred to as LNP, refers to a particle having at least one dimension on the order of nanometers (e.g., 1-1,000 nm) which includes one or more lipids (e.g., cationic lipids, non- cationic lipids, and PEG-modified lipids). In some embodiments, such lipid nanoparticles comprise a cationic lipid and one or more excipient selected from neutral lipids, charged lipids, steroids and polymer conjugated lipids (e.g., a pegylated lipid). In some embodiments, the DNA, or a portion thereof, is encapsulated in the lipid portion of tire lipid nanoparticle or an aqueous space enveloped by some or all of the lipid portion of the lipid nanoparticle, thereby protecting it from enzymatic degradation or other undesirable effects induced by the mechanisms of the host organism or cells. In some embodiments, the DNA or a portion thereof is associated with the lipid nanoparticles. Preferably, the lipid nanoparticles are formulated to deliver one or more DNA to one or more target cells (e.g., tumor cells).In the context of the present disclosure, lipid nanoparticles are not restricted to any particular morphology, and should be interpreted as to include any morphology generated when a cationic lipid and optionally one or more further lipids are combined, e.g.. in an aqueous environment and / or in the presence of a nucleic acid compound. For example, a liposome, a lipid complex, a lipoplex and the like are within the scope of a lipid nanoparticle.In various embodiments, the lipid nanoparticles have a mean diameter of from about 30 nm to about 150 nm, from about 40 nm to about 150 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 70 nm to about 110 nm, from about 70 nm toabout 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 mn, 70 nm, 75 nm, 80 nm, 85 mn, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, or 150 nm. and are substantially non-toxic. In certain embodiments, the DNA, when present in the lipid nanoparticles, is resistant in aqueous solution to degradation with a nuclease. As used herein, the mean diameter may be represented by the z-average as determined by dynamic light scattering.An LNP may comprise any lipid capable of forming a particle to which the one or more nucleic acid molecules are attached, or in which the one or more nucleic acid molecules are encapsulated. The term “lipid'’ refers to a group of organic compounds that are derivatives of fatty acids (e.g., esters) and are generally characterized by being insoluble in water but soluble in many organic solvents. Lipids are usually divided in at least three classes: (1) “simple lipids” which include fats and oils as well as waxes; (2) “compound lipids” which include phospholipids and glycolipids; and (3) “derived lipids” such as steroids.In certain embodiments, the LNP comprises one or more ionizable cationic lipids as described herein, cholesterol, a helper phospholipid, and a polyethylene glycol-modified lipid.As mentioned, the LNP comprises an ionizable cationic lipid. The cationic lipid is preferably ionizable, i.e., it becomes protonated as the pH is lowered below the pKa of the ionizable group of the lipid, but is progressively more neutral at higher pH values. When positively charged, the lipid is then able to associate with negatively charged nucleic acids. In certain embodiments, the cationic lipid comprises a zwitterionic lipid that assumes a positive charge on pH decrease. The LNP may comprise any lipid capable of forming a particle to which the one or more nucleic acid molecules are attached, or in which tire one or more nucleic acid molecules arc encapsulated.In certain embodiments, the LNP may comprise any fur tlrer cationic or ionizable lipid, i.e.. any of a number of lipid species which carry a net positive charge at a selective pH, such as physiological pH. Such lipids include, but are not limited to, N,N-dioleyl-N.N- dimethylammonium chloride (DODAC); N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA); N,N-distearyl-N,N-dimethylammonium bromide (DDAB); N- (2,3dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP); 3-(N — (N',N'dimethylaminoethane)-carbamoyl)cholesterol (DC-Chol), N-(l-(2,3-dioleoyloxy)propyl)N- 2-(sperminecarboxamido)ethyl)-N,N-dimethylammonium trifluoracetate (DOSPA),dioctadecylamidoglycyl carboxyspermine (DOGS), l,2-dioleoyl-3-dimethylammonium propane (DODAP), N.N-dimcthyl-2.3-diolcoyloxy)propylaminc (DODMA), and N- (l,2dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl ammonium bromide (DMRIE).Other useful lipids include, without limitation. 98N12-5, C 12-200. PLGA, PEG, PEG- DMG, PEGylated lipids, amino alcohol lipids, and KL22.Additionally, a number of commercial preparations of cationic lipids are available which can be used in the present invention. These include, for example, LIPOFECTIN® (commercially available cationic liposomes comprising DOTMA and l,2-dioleoyl-sn-3phosphoethanolamine (DOPE), from GIBCO / BRL, Grand Island, N.Y.); LIPOFECTAMINE® (commercially available cationic liposomes comprising N-(l-(2,3dioleyloxy)propyl)-N-(2-(sperminecarboxamido)ethyl)- N,N-diniethylanimonium trifluoroacetate (DOSPA) and (DOPE), from GIBCO / BRL); and TRANSFECTAM® (commercially available cationic lipids comprising dioctadecylamidoglycyl carboxyspermine (DOGS) in ethanol from Promega Corp., Madison, Wis.). The following lipids are cationic and have a positive charge at below physiological pH: DODAP, DODMA, DMDMA, 1 ,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), l,2-dilinolenyloxy-N,N- dimethylaminopropane (DLenDMA).In one embodiment, the further cationic lipid is an amino lipid. Suitable amino lipids useful in the invention include those described in W02012 / 016184, incorporated herein by reference in its entirety. Representative amino lipids include, but are not limited to, 1,2- dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1 ,2-dilinoleyoxy- 3morpholinopropane (DLin-MA). l,2-dilinoleoyl-3 -dimethylaminopropane (DLinDAP). 1,2- dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), l-linoleoyl-2-linoleyloxy- 3dimethylaminopropane (DLin-2-DMAP), l,2-dilinoleyloxy-3 -trimethylaminopropane chloride salt (DLin-TMA.Cl), l,2-dilinoleoyl-3 -trimethylaminopropane chloride salt (DLin-TAP.Cl), 1,2- diIinoIcyIoxy-3-(N-mcthyIpipcrazino)propanc (DLin-MPZ), 3-(N,Ndilinolcylamino)-l,2- propanediol (DLinAP), 3-(N,N-dioleylamino)-l,2-propanediol (DOAP), l,2-dilinoleyloxo-3-(2- N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), and 2,2-dilinoleyl-4- dimethylaminomethyl-[ 1.3] -dioxolane (DLin-K-DMA). 4-(dimethylamino)-butanoic acid. ( 10Z, 13Z)- 1 -(9Z, 12Z)-9, 12-octadecadien- 1 -yl- 10, 13-nonadecadien- 1 -yl ester (DLin-MC3- DMA), N,N-dimethyl-2,2-di-(9Z,12Z)-9,12-octadecadien-l-yl-l,3-dioxolane-4-ethanamine (DLin-KC2-DMA). See also, e.g., WO2014 / 089486, US 2018 / 0353616A1, and US 8,853,377B2, which are incorporated by reference.In certain embodiments, LNP formulation is performed using routine procedures comprising cholesterol, ionizable lipid, helper lipid, PEG-lipid and polymer forming a lipid bilayer around encapsulated mRNA (Kowalski et al., 2019, Mol. Ther. 27(4):710-728). In some embodiments, LNP comprises a cationic lipid (i.e. N-[l-(2,3-dioleoyloxy)propyl]-N.N,N- trimethylammonium chloride (DOTMA), or 1,2-dioleoy 1-3 -trimethylammonium -propane (DOTAP)) with helper lipid DOPE. In some embodiments, LNP comprises an ionizable lipid Dlin-MC3-DMA ionizable lipids, or diketopiperazine-based ionizable lipids (cKK-E12). In some embodiments, polymer comprises a polyethyleneimine (PEI), or a poly(P-amino)esters (PBAEs). In some embodiments, the LNP comprises C14-4 / DOPE / Chol / PEG-lipid. See, Rybakova Y., Kowalski P. S., Huang Y., Gonzalez J. T., Heartlein M. W., DeRosa F., et al. . (2019). mRNA delivery for therapeutic anti-HER2 antibody expression in vivo. Mol. Ther. 27 , 1415-1423 which is incorporated by reference. In other embodiments, the LNP comprises L319 / DSPC / Chol / PEG- DMG. See, Thran M., Mukherjee J., Pdnisch M., Fiedler K.. Thess A.. Mui B. L. (2017). mRNA mediates passive vaccination against infectious agents, toxins, and tumors. EMBO Mol. Med. 9, 1434-1447 which is incorporated by reference. See also, e.g., WO2014 / 089486, US 2018 / 0353616A1, US2013 / 0037977A1, W02015 / 074085A1, US9670152B2, and US 8,853,377B2, which are incorporated by reference.Certain LNPs useful herein include those that are described in WO 2021 / 077066 and WO 2021 / 055892. each of which is incorporated herein by reference in its entirety. Useful LNPs include those that show enhanced delivery to tumor cells. LNP formulations may be varied to enhance tumor delivery. For example, the type and ionizable lipid:mRNA ratio, the mRNA:sgRNA ratio, molar ratio of ionizable lipid, phosopholipid, cholesterol, and PEG-lipid, etc. may be varied. In one embodiment, the LNP is one described by Kauffman, K. J.; Dorkin, J. R.; Yang, J. H.; Heartlein, M. W.; DeRosa, F.; Mir, F. F.; Fenton, O. S.; Anderson, D. G., Optimization of lipid nanoparticlc formulations for mRNA delivery in vivo with fractional factorial and definitive screening designs. Nano letters 2015, 15 (11), 7300-7306, which is incorporated herein by reference. In certain embodiments, the LNPs are designed with ionizable lipid: mRNA weight ratios varying betw een 5: 1 to 25: 1. In certain embodiments, tire ionizable lipid: mRNA weight ratio is 5: 1, 10: 1, 12.5: 1, 15: 1, 20: 1, or 25: 1. In certain embodiments, the mRNA:sgRNA weight ratio is 1: 1, 1:2, 2: 1, or 1:4.Other LNPs have been described and are useful herein. See, e.g., WO 2016 / 118724, US 10,413,618B2, US 10,723,692B2, and US8754062B2, each of which is incorporated herein by reference.In certain embodiments, the LNP comprises one or more additional lipids which stabilize the formation of particles during their formation. Exemplary neutral lipids include, for example, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG). dipalmitoylphosphatidylglycerol (DPPG). dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE) and dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-lcarboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidylethanolamine (DSPE), 16-0-monom ethyl PE, 16-O-dimethyl PE, 18-1-trans PE, l-stearioyl-2-oleoylphosphatidyedianol amine (SOPE), and 1,2-dielaidoyl-sn- glycero-3-phophoetlianolamine (transDOPE). In one embodiment, the neutral lipid is 1,2- distearoyl-sn-glycero-3phosphocholine (DSPC).In some embodiments, the LNPs comprise a neutral lipid selected from DSPC. DPPC, DMPC, DOPC, POPC, DOPE and SM. In various embodiments, the molar ratio of the cationic lipid to the neutral lipid ranges from about 2: 1 to about 8: 1.In various embodiments, the LNPs further comprise a steroid or steroid analogue. In certain embodiments, the steroid or steroid analogue is cholesterol. In some of these embodiments, the molar ratio of the cationic lipid to cholesterol ranges from about 5: 1 to 1 : 1.The term ‘‘anionic lipid'’ refers to any lipid that is negatively charged at physiological pH. These lipids include phosphatidylglycerol, cardiolipin, diacylphosphatidylserine, diacylphosphatidic acid, Ndodecanoylphosphatidylethanolamines. N- succinylphosphatidylethanolamines, Nglutarylphosphatidylethanolamines, lysylphosphatidylglycerols, palmitoyloleyolphosphatidylglycerol (POPG), and other anionic modifying groups joined to neutral lipids.In certain embodiments, the LNP comprises glycolipids (c.g., monosialogangliosidc GM1).In some embodiments, tire LNPs comprise a polymer conjugated lipid. The term “polymer conjugated lipid" refers to a molecule comprising both a lipid portion and a polymer portion. An example of a polymer conjugated lipid is a pegylated lipid. The term “pegylated lipid” refers to a molecule comprising both a lipid portion and a polyethylene glycol portion. Pegylated lipids are known in the art and include l-(monomethoxy-polyetiiyleneglycol)-2,3- dimyristoylglycerol (PEG-s-DMG) and the like.In certain embodiments, the LNP comprises an additional, stabilizing-lipid which is a polyethylene glycol-lipid (pegylated lipid). Suitable polyethylene glycollipids include PEG- modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramides (e.g., PEG-CerC14 or PEG-CerC20), PEG-modified dialkylamines, PEG-modified diacylglycerols. PEG-modified dialkylglycerols. Representative polyethylene glycol-lipids include PEG-c-DOMG. PEG-c-DMA, and PEG-s-DMG. In one embodiment, the polyethylene glycol-lipid is N-[(methoxy polyethylene gtycol)2000)carbamyl]-l,2-dimyristyloxlpropyl-3- amine (PEG-c-DMA). In one embodiment, the polyethylene glycol-lipid is PEG-c-DOMG). In other embodiments, the LNPs comprise a pegylated diacylglycerol (PEG-DAG) such as 1- (monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG), a pegylated phosphatidylethanoloamine (PEG-PE), a PEG succinate diacylglycerol (PEG-S-DAG) such as 4- O-(2',3'-di(tetradecanoyloxy)propyl-l-O-(<n-methoxy(polyethoxy)ethyl)butanedioate (PEG-S- DMG), a pegylated ceramide (PEG-cer), or a PEG dialkoxypropylcarbamate such as m- methoxy (poly ethoxy)ethyl-N-(2,3di (tetradeca noxy)propyl)carba mate or 2,3- di(tetradecanoxy)propyl-N-(w-methoxy(polyethoxy)ethyl)carbamate. In various embodiments, the molar ratio of the cationic lipid to the pegylated lipid ranges from about 100: 1 to about 25: 1.Other exemplary LNPs and their manufacture are described in the art, for example in U.S. Patent Application Publication No. U520120276209, Semple et al., 2010, Nat Biotechnol., 28(2): 172-176; Akinc et al.. 2010, Mol Then, 18(7): 1357-1364; Basha et al., 2011, Mol Ther, 19(12): 2186-2200; Leung et al., 2012, J Phys Chem C Nanomater Interfaces, 116(34): 18440- 18450; Lee et al.. 2012. Int J Cancer.. 131(5): E78L90; Belliveau et al.. 2012. Mol Ther nucleic Acids, 1: e37; Jayaraman et al., 2012, Angew Chem Int Ed Engl., 51(34): 8529-8533; Mui et al., 2013, Mol Ther Nucleic Acids. 2, el39; Maier et al., 2013, Mol Ther., 21(8): 1570-1578; and Tam et al., 2013, Nanomedicine, 9(5): 665-74, each of which are incorporated by reference in their entirety.In certain embodiments, the LNP is associated with a targeting moiety that binds to a target on the surface of the target cell, e g., an endothelial cell. In certain embodiments, tire targeting moiety is an antibody or an antigen binding fragment thereof, and the target is an antigen on the surface of the target cell. In other embodiments, the target is a cell surface receptor, and the targeting moiety is its cognate ligand. In certain embodiments, the targeting moiety binds specifically to ICAM. In other embodiments, the targeting moiety binds specifically to PECAM. In other embodiments, the targeting moiety’ binds specifically to VC AM.By the term “antibody” or “antibody molecule” is any immunoglobulin, including antibodies and fragments thereof, that binds to a specific antigen. As used herein, antibody or antibody molecule contemplates intact immunoglobulin molecules, immunologically active portions of an immunoglobulin molecule, and fusions of immunologically active portions of an immunoglobulin molecule.The antibody may be a naturally occurring antibody or may be a synthetic or modified antibody (e.g., a recombinantly generated antibody; a chimeric antibody; a bispecific antibody; a humanized antibody; a camelid antibody; and the like). The antibody may comprise at least one purification tag. In a particular embodiment, the framework antibody is an antibody fragment. The term “antibody fragment” includes a portion of an antibody that is an antigen binding fragment or single chains thereof. An antibody fragment can be a synthetically or genetically engineered polypeptide. Examples of binding fragments encompassed within the term “antigenbinding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment, which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although tire two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding fragment” of an antibody. These antibody fragments are obtained using conventional techniques known to those in the art, and the fragments can be screened for utility in the same manner as whole antibodies. Antibody fragments include, without limitation, immunoglobulin fragments including, without limitation: single domain (Dab; e.g., single variable light or heavy chain domain), Fab, Fab', F(ab')2. and F(v); and fusions (e.g., via a linker) of these immunoglobulin fragments including, without limitation: scFv. scFv2, scFv-Fc, minibody, diabody, triabody. and tetrabody. The antibody may also be a protein (e.g., a fusion protein) comprising at least one antibody or antibody fragment.As used herein, “specifically binding,” “binds specifically to,” “specific binding” refer, for example, to an antibody selectively or preferentially binding to an antigen. For example, with respect to a targeting moiety’ (such as an antibody), specifically binding refers to preferentialbinding refers to the ability of the antibody to bind one or more epitopes of an antigen or binding partner of interest without substantially recognizing and binding other molecules in a sample or environment containing a mixed population of antigens. Specific binding interactions are mediated by one or. typically, more nonco valent bonds between the binding molecules or binding partners.As noted above, the LNP described herein can encapsulate a DNA cargo. The DNA cargo comprises an expression cassette that include sequences encoding one or more elements of prime editing system as provided herein under control of regulatory sequences.The regulatory sequences can include any of those conventionally used, such as a promoter, appropriate transcription initiation, termination, enhancer sequences, efficient RNA processing signals such as splicing and polyadenylation (polyA) signals: TATA sequences; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (l.e., Kozak consensus sequence); introns; sequences that enhance protein stability, etc. The expression cassette or vector may contain none, one or more of any of the elements described herein. In certain embodiments, the expression cassette further includes viral LTRs or ITRs.The promoter may be selected based on the desired expression of the DNA cargo. In certain embodiments, the promoter is cell-specific, such as for delivery' to the target cell. The target cell may, in certain embodiments, include any mammalian cell type, such as neurons, glia, hepatocytes, endothelial cells, epithelial cells, fibroblasts, muscle cells, adipocytes, chondrocytes, osteocytes, keratinocytes, melanocytes, t lymphocytes, b lymphocytes, macrophages, dendritic cells, granulocytes, NK cells, mast cells, hematopoietic stem cells, pancreatic islet cells, spermatocytes, oocytes, thyroid follicular cells, pituitary cells, astrocytes, microglia, Schwann cells, IPSCs, primary neurons, ocular cells, etc.In another embodiment, the promoter is a ubiquitous or constitutive promoter. An example of a suitable promoter is a hybrid chicken [Lactin (CBA) promoter with cytomegalovirus (CMV) enhancer elements. In another embodiment, the promoter is the CB7 promoter. Other suitable promoters include tire human [Lactin promoter, the human elongation factor- la promoter, the cytomegalovirus (CMV) promoter, the simian virus 40 promoter, and the herpes simplex virus thymidine kinase promoter. See, e.g., Damdindorj et al, (August 2014) A Comparative Analysis of Constitutive Promoters Located in Adeno-Associated Viral Vectors. PLoS ONE 9(8): e 106472. Still other suitable promoters include viral promoters, constitutive promoters, regulatable promoters [see, e.g., WO 2011 / 126808 and WO 2013 / 04943], In another embodiment, die promoter is an inducible promoter. The inducible promoter may be selectedfrom known promoters including the rapamycin / rapalog promoter, the ecdysone promoter, tire estrogen-responsive promoter, and the tetracycline -responsive promoter, or heterodimeric repressor switch.The use of RNA or DNA viral based systems for the delivery of nucleic acids take advantage of highly evolved processes for targeting a virus to specific cells in the body and trafficking the viral payload to the nucleus. Viral vectors can be administered directly to patients (in vivo) or they can be used to treat cells in vitro, and the modified cells may optionally be administered to patients (ex vivo). Conventional viral based systems could include retroviral, lentivirus, adenoviral, adeno-associated and herpes simplex virus vectors for gene transfer. Integration in the host genome is possible with the retrovirus, lentivirus, and adeno-associated virus gene transfer methods, often resulting in long term expression of the inserted transgene. Additionally, high transduction efficiencies have been observed in many different cell types and target tissues.The tropism of a retrovirus can be altered by incorporating foreign envelope proteins, expanding the potential target population of target cells. Lentiviral vectors are retroviral vectors that are able to transduce or infect non-dividing cells and typically produce high viral titers. Selection of a retroviral gene transfer system would therefore depend on the target tissue.Retroviral vectors comprise cis-acting long terminal repeats with packaging capacity for up to 6-10 kb of foreign sequence. The minimum cis-acting LTRs are sufficient for replication and packaging of the vectors, which are then used to integrate the therapeutic gene into the target cell to provide permanent transgene expression. Widely used retroviral vectors include those based upon murine leukemia virus (MuLV), gibbon ape leukemia vims (GaLV), simian immuno deficiency vims (SIV), human immuno deficiency vims (HIV), and combinations thereof (see, e.g., Buchscher et al., J. Virol. 66:2731-2739 (1992); Johann et al., J. Virol. 66: 1635-1640 (1992); Sommncrfclt et al., Virol. 176:58-59 (1990); Wilson et al., J. Virol. 63:2374-2378 (1989); Miller et al., J. Virol. 65:2220-2224 (1991); PCT / US94 / 05700).In applications where transient expression is preferred, adenoviral based systems may be used. Adenoviral based vectors are capable of very high transduction efficiency in many cell types and do not require cell division. With such vectors, high titer and levels of expression have been obtained. This vector can be produced in large quantities in a relatively simple system.Adeno-associated vims (“AAV”) vectors may also be used to transduce cells with target nucleic acids, e.g., in the in vitro production of nucleic acids and peptides, and for in vivo and ex vivo gene therapy procedures (see, e.g., West et al., Virology 160:38-47 (1987); U.S. Pat. No.4,797,368; WO 93 / 24641; Kotin, Human Gene Therapy 5:793-801 (1994); Muzyczka, J. Clin. Invest. 94: 1351 (1994). Several different AAV serotypes have been used to advantage for transduction of mammalian cells, these include, for example AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8, and AAV9 tliat have different tropisms for cell types of interest. Construction of recombinant AAV vectors is described in a number of publications, including U.S. Pat. No. 5.173.414; Tratschin et al., Mol. Cell. Biol. 5:3251-3260 (1985); Tratschin, et al., Mol. Cell. Biol. 4:2072-2081 (1984); Hermonat & Muzyczka, PNAS 81:6466-6470 (1984); and Samulski et al., J. Virol. 63:03822-3828 (1989). In certain preferred embodiments, the viral vector is a split AAV8 vector or a split AAV9 vector.Packaging cells are typically used to form virus particles tliat are capable of infecting a host cell. Such cells include HEK 293 cells, which package adenovirus, and y2 cells or PA317 cells, which package retrovirus. Viral vectors used in gene therapy are usually generated by producing a cell line that packages a nucleic acid vector into a viral particle. The vectors typically contain the minimal viral sequences required for packaging and subsequent integration into a host, other viral sequences being replaced by an expression cassette for the polynucleotide(s) to be expressed. The missing viral functions are typically supplied in trans by the packaging cell line.For example, AAV vectors used in gene therapy typically only possess ITR sequences from the AAV genome which are required for packaging and integration into the host genome. Viral DNA is packaged in a cell line, which contains a helper plasmid encoding the other AAV genes, namely rep and cap, but lacking ITR sequences. The cell line may also be infected with adenovirus as a helper. The helper virus promotes replication of the AAV vector and expression of AAV genes from the helper plasmid. The helper plasmid is not packaged in significant amounts due to a lack of ITR sequences. Contamination with adenovirus can be reduced by, e.g., heat treatment to which adenovirus is more sensitive than AAV.In some embodiments, a host cell is transiently or non-transiently transfected with one or more vectors described herein. In some embodiments, a cell is transfected as it naturally occurs in a subject. In some embodiments, a cell that is transfected is taken from a subject. In some embodiments, the cell is derived from cells taken from a subject, such as a cell line.In one aspect, the invention provides for methods of modifying a target polynucleotide in a eukaryotic cell, which may be in vivo, ex vivo or in vitro. In some embodiments, the method comprises sampling a cell or population of cells from a human or non-human animal, andmodifying the cell or cells. Culturing may occur at any stage ex vivo. The cell or cells may be reintroduced into the human or non-human animal.In certain embodiments, one or more nucleic acid sequences provided herein are delivered to target cells by a vector or a viral vector, of which many are known and available in the art. In one embodiment, provided is a vector comprising an expression cassette as described herein. In one embodiment, the vector is a non-viral vector. In a further embodiment, tire non-viral vector is a plasmid. In another embodiment, the vector is a viral vector. Viral vectors include any vims suitable for gene therapy, including but not limited to a bocavirus, adenovirus, adeno-associated vims (AAV), herpes virus, lentivims, retrovirus, or parvovirus. However, for ease of understanding, the adeno-associated virus is referenced herein as an exemplar}' viral vector.As used herein, a recombinant viral vector is any suitable viral vector which targets tire desired cell(s). Thus, the recombinant viral vectors described herein preferably target one or more of the cells and tissues affected by RCVL. The examples provide illustrative recombinant adeno- associated viruses (rAAV). However, other suitable viral vectors may include, e.g., a recombinant adenovirus, a recombinant parvovirus such a recombinant bocavirus, a hybrid A AV / bocavims, a recombinant herpes simplex vims, a recombinant retrovirus, or a recombinant lentivims. In preferred embodiments, these recombinant viruses are replication-defective.As used herein, the terms ‘‘recombinant AAV’, “rAAV’', and “AAV vector’' used interchangeably, mean, without limitation, an AAV vector comprising a capsid protein and a vector genome packaged therein, wherein the vector genome comprises a nucleic acid heterologous to the AAV. In one embodiment, tire capsid protein is a non-naturally occurring capsid. Such an artificial capsid may be generated by any suitable technique, using a selected AAV sequence (e.g., a fragment of a vpl capsid protein) in combination with heterologous sequences which may be obtained from a different selected AAV, non-contiguous portions of the same AAV, from a non-AAV viral source, or from a non-viral source. An artificial AAV may be, without limitation, a pseudotyped AAV, a chimeric AAV capsid, a recombinant AAV capsid, or a “humanized” AAV capsid. Pseudotyped vectors, wherein the capsid of one AAV is replaced with a heterologous capsid protein, are useful in the invention. In one embodiment. AAV2 / 5 and AAV 2 / 8 are exemplary pseudotyped vectors. The selected genetic element may be delivered by any suitable method, including transfection, electroporation, liposome deliver}', membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion. The methods used to make such constructs are known to those with skill in nucleic acid manipulation and include genetic engineering, recombinant engineering, and synthetic techniques. See, e.g., Greenand Sambrook, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY (2012).In certain embodiments, elements of a prime editing system (including sequences encoding a pegRNA, prime editing fusion enzyme, and / or a sgRNA) are included in single AAV vector. Alternatively, to accommodate the loading capacity of AAV vectors, dual vector approach can be utilized. See, for example, Davis JR. et al. Efficient prime editing in mouse brain, liver and heart with dual AAVs. Nat Biotechnol. 2024 Feb;42(2):253-264, which is incorporated herein by reference. Also, FIG. 22A - FIG. 22F, which provide maps and sequences for AAV production plasmids.A “replication-defective” virus or viral vector refers to a synthetic or artificial viral particle in which an expression cassette containing a gene of interest is packaged in a viral capsid or envelope, where any viral genomic sequences also packaged within the viral capsid or envelope are replication-deficient; i.e., they cannot generate progeny virions but retain the ability to infect target cells. In one embodiment, the genome of the viral vector does not include genes encoding the enzymes required to replicate (the genome can be engineered to be “gutless” - containing only the gene of interest flanked by the signals required for amplification and packaging of the artificial genome), but these genes may be supplied during production. Therefore, it is deemed safe for use in gene therapy since replication and infection by progeny virions cannot occur except in the presence of the viral enzyme required for replication. Such replication-defective viruses may be adeno-associated viruses (AAV), adenoviruses, lentiviruses (integrating or non-integrating), or another suitable virus source.“Plasmid” or “plasmid vector” generally is designated herein by a lower-case p preceded and / or followed by a vector name. Plasmids, other cloning and expression vectors, properties thereof, and constructing / manipulating methods thereof that can be used in accordance with the present invention arc readily apparent to those of skill in the art. In certain embodiments, the expression cassettes described herein are engineered into a suitable genetic element (a vector) useful for generating viral vectors and / or for delivery to a host cell, e.g., naked DNA, phage, transposon, cosmid. episome, etc., which transfers the sequences carried thereon. The selected vector may be delivered by any suitable method, including transfection, electroporation, liposome delivery, membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion. The methods used to make such constructs are known to those with skill in nucleic acid manipulation and include genetic engineering, recombinant engineering, andsynthetic techniques. See, e.g., Sambrook et al, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY.As used herein, the term “host cell” may refer to the packaging cell line in which a vector (e.g., a recombinant AAV) is produced from a production plasmid. In the alternative, the term “host cell” may refer to any target cell for prime editing. Thus, a “host cell,” refers to a prokaryotic or eukaryotic cell that contains exogenous or heterologous DNA that has been introduced into the cell by any means, e.g., electroporation, calcium phosphate precipitation, microinjection, transformation, viral infection, transfection, liposome delivery, membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion. In certain embodiments herein, the term “host cell” refers to cultures of cells of various mammalian species for in vitro assessment of the compositions described herein. In other embodiments herein, the term “host cell” refers to tire cells employed to generate and package tire viral vector or recombinant virus.As used herein, a “vector genome” refers to the nucleic acid sequence packaged inside a viral vector. In one example, a vector genome contains, at a minimum, from 5’ to 3’, a vectorspecific sequence, a nucleic acid sequence as provided herein encoding a pegRNA, sgRNA and / or prime editing fusion enzyme, where the vector-specific sequence may be a terminal repeat sequence that specifically packages the vector genome into a viral vector capsid or envelope protein. In certain embodiments, the vector genome contains, at a minimum, from 5' to 3’, a 5’ AAV ITR sequence, an expression cassette, and a 3’ AAV inverted terminal repeat (ITR) sequence, including interv ening sequences. In certain embodiments. For example. AAV inverted terminal repeats are utilized for packaging into AAV and certain other parvovirus capsids. Lentivirus long terminal repeats may be utilized where packaging into a lentiviral vector is desired. Similarly, other terminal repeats (e.g., a retroviral long terminal repeat), or the like may be selected.An AAV vector is an AAV nuclease (e.g., DNase)-resistant particle having an AAV protein capsid into which is packaged expression cassette flanked by AAV inverted terminal repeat sequences (ITRs) for delivery to target cells. A nuclease-resistant recombinant AAV (rAAV) indicates that the AAV capsid has fully assembled and protects these packaged vector genome sequences from degradation (digestion) during nuclease incubation steps designed to remove contaminating nucleic acids which may be present from the production process. In many instances, the rAAV described herein is DNase resistant.An AAV capsid is composed of 60 capsid (cap) protein subunits, VP1, VP2, and VP3, that are arranged in an icosahedral symmetry in a ratio of approximately 1 : 1 : 10 to 1 : 1 :20, depending upon the selected AAV. Various AAVs may be selected as sources for capsids of AAV vectors as identified above. See, e.g., US Published Patent Application No. 2007-0036760- Al: US Published Patent Application No. 2009-0197338-Al; EP 1310571. See also, WO 2003 / 042397 (AAV7 and other simian AAV). US Patent 7790449 and US Patent 7282199 (AAV8), WO 2005 / 033321 and US 7,906,111 (AAV9), and WO 2006 / 110689, and WO 2003 / 042397 (AAVrhlO). These documents also describe other AAV which may be selected for generating AAV and are incorporated by reference. Among the AAVs isolated or engineered from human or non-human primates (NHP) and well characterized, human AAV2 is tire first AAV that was developed as a gene transfer vector; it has been widely used for efficient gene transfer experiments in different target tissues and animal models. Unless otherwise specified, the AAV capsid, ITRs, and other selected AAV components described herein, may be readily selected from among any AAV, including, without limitation, the AAV s commonly identified as AAV 1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV8bp, AAV7m8 and AAVAnc80. See, e.g., WO 2005 / 033321, which is incorporated herein by reference.The rAAV particles provided herein may be of any AAV serotype, including any derivative or pseudotype (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 2 / 1, 2 / 5, 2 / 8, or 2 / 9). As used herein, tire serotype of an rAAV viral vector (e g., an rAAV particle) refers to the serotype of the capsid proteins of the recombinant virus. In some embodiments, the rAAV particle is not AAV2. In certain embodiments, the rAAV particle is AAV2. In some embodiments, the rAAV particle is AAV6. In some embodiments, the rAAV particle is an AAV6 serotype comprising an rAAV capsid protein as described herein. Non-limiting examples of derivatives and pseudotypes include rAAV2 / l , rAAV2 / 5, rAAV2 / 8, rAAV2 / 9, AAV2-AAV3 hybrid, AAVrh. 10, AAVhu. 14, AAV3a / 3b, AAVrh32.33, AAV-HSC15, AAV-HSC17, AAVhu.37, AAVrh.8, CHt-P6, AAV2.5, AAV6.2, AAV2i8, AAV-HSC15 / 17, AAVM41, AAV9.45, AAV6(Y445F / Y731F), AAV2.5T, AAV-HAE1 / 2, AAV clone 32 / 83, AAVShHIO. AAV2 (Y->F), AAV8 (Y733F), AAV2.15, AAV2.4, AAVM41, and AAVr3.45. Such AAV serotypes and derivatives / pseudotypes, and methods of producing such derivatives / pseudotypes are known in the art (see, e.g.. Mol Ther. 2012 Apr:20(4):699-708. doi: 10. 1038 / mt.2011.287. Epub 2012 Jan 24. The AAV vector toolkit: poised at the clinical crossroads. Asokan Al, Schaffer DV, Samulski RJ.). In certain embodiments, the rAAV particle is a pseudotyped rAAV particle, which comprises (a) a nucleic acid vector comprising ITRs from one serotype (e g., AAV2) and (b) a capsid comprised ofcapsid proteins derived from another serotype (e.g., AAV1, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, or AAV10). Methods for producing and using pseudotyped rAAV vectors are known in the art (see, e.g.. Duan et al., J. Virol., 75:7662-7671, 2001; Halbert et al., J. Virol., 74: 1524-1532, 2000; Zolotukhin et al., Methods, 28: 158-167, 2002; and Auricchio et al., Hum. Molec. Genet., 10:3075-3081, 2001).As used herein, relating to AAV, the term "variant” means any AAV sequence which is derived from a known AAV sequence, including those sharing at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or greater sequence identity over the amino acid or nucleic acid sequence. In another embodiment, the AAV capsid includes variants which may include up to about 10% variation from any described or known AAV capsid sequence. That is, the AAV capsid shares about 90% identity to about 99.9% identity, about 95% to about 99% identity or about 97% to about 98% identity to an AAV capsid provided herein and / or known in the art. In one embodiment, the AAV capsid shares at least 95% identity with an AAV capsid. When determining the percent identity of an AAV capsid, the comparison may be made over any of the variable proteins (e.g., vpl, vp2, or vp3). In one embodiment, the AAV capsid shares at least 95% identity with the AAV8 vp3. In another embodiment, a self-complementary AAV is used.The ITR sequences or other AAV components may be readily isolated or engineered using techniques available to those of skill in tire art from an AAV. Such AAV may be isolated, engineered, or obtained from academic, commercial, or public sources (e.g., the American Type Culture Collection, Manassas. VA). Alternatively, the AAV sequences may be engineered through synthetic or other suitable means by reference to published sequences such as are available in the literature or in databases such as, e.g., GenBank, PubMed, or the like. AAV vectors may be engineered by conventional molecular biology7techniques, making it possible to optimize these particles for cell specific delivery’ of nucleic acid sequences, for minimizing immunogenicity, for tuning stability and particle lifetime, for efficient degradation, for accurate delivery to the nucleus, etc.The ITRs are the genetic elements responsible for the replication and packaging of the genome during vector production and are the only viral cis elements required to generate rAAV. In one embodiment, the ITRs are from an AAV different than that supplying a capsid. In a preferred embodiment, the ITR sequences from AAV2, or the deleted version thereof (AITR), which may be used for convenience and to accelerate regulatory approval. However, ITRs from other AAV sources may be selected. Where tire source of the ITRs is from AAV2 and the AAVcapsid is from another AAV source, tire resulting vector may be termed pseudotyped. Typically, AAV vector genome comprises an AAV 5 ’ ITR, the nucleic acid sequences encoding the gene product(s) and any regulatory sequences, and an AAV 3’ ITR. However, other configurations of these elements may be suitable. In one embodiment, a self-complementary AAV is provided. A shortened version of tire 5' ITR. termed AITR, has been described in which the D-sequence and terminal resolution site (trs) are deleted. In certain embodiments, the vector genome includes a shortened AAV2 ITR of 130 base pairs, wherein the external ‘ a” element is deleted. The shortened ITR is reverted back to the wild-type length of 145 base pairs during vector DNA amplification using the internal A element as a template. In other embodiments, the full-length AAV 5’ and 3’ ITRs are used.The recombinant adeno-associated virus (AAV) described herein may be generated using techniques which are known. See. e.g., WO 2003 / 042397: WO 2005 / 033321, WO 2006 / 110689: US 7588772 B2. Such a method involves culturing a host cell which contains a nucleic acid sequence encoding an AAV capsid; a functional rep gene; an expression cassette as described herein flanked by AAV inverted terminal repeats (ITRs): and sufficient helper functions to permit packaging of the expression cassette into the AAV capsid protein. Also provided herein is the host cell which contains a nucleic acid sequence encoding an AAV capsid; a functional rep gene; a vector genome as described; and sufficient helper functions to permit packaging of the vector genome into the AAV capsid protein. In one embodiment, the host cell is a HEK 293 cell. These methods are described in more detail in WO2017160360 A2, which is incorporated by reference herein.Other methods of producing recombinant AAV available to one of skill in the art may be utilized. Suitable methods may include without limitation, baculovirus expression system or production via yeast. See, e.g., Robert M. Kotin, Large-scale recombinant adeno-associated virus production. Hum Mol Genet. 2011 Apr 15; 2O(R1): R2-R6. Published online 2011 Apr 29. doi: 10. 1093 / hmg / ddrl41; Aucoin MG et al., Production of adeno-associated viral vectors in insect cells using triple infection: optimization of baculovirus concentration ratios. Biotechnol Bioeng. 2006 Dec 20:95(6): 1081-92; SAMI S. THAKUR. Production of Recombinant Adeno-associated viral vectors in yeast. Thesis presented to the Graduate School of the University of Florida, 2012; Kondratov O et al. Direct Head-to-Head Evaluation of Recombinant Adeno-associated Viral Vectors Manufactured in Human versus Insect Cells, Mol Ther. 2017 Aug 10. pii: S1525- 0016(17)30362-3. doi: 10. 1016 / j.ymthe.2017.08.003. [Epub ahead of print]; Mietzsch M et al, OneBac 2.0: Sf9 Cell Lines for Production of AAV1, AAV2, and AAV8 Vectors with MinimalEncapsidation of Foreign DNA. Hum Gene Ther Methods. 2017 Feb;28(l): 15-22. doi:10. 1089digtb.2016.164.; Li L et al. Production and characterization of novel recombinant adeno- associated virus replicative-form genomes: a eukaryotic source of DNA for gene transfer. PLoS One. 2013 Aug l:8(8):e69879. doi: 10. 1371 / joumal. pone.0069879. Print 2013; Galibert L et al, Latest developments in the large-scale production of adeno-associated virus vectors in insect cells toward the treatment of neuromuscular diseases. J Invertebr Pathol. 2011 Jul;107 Suppl:S80-93. doi: 10. 1016 / j.jip.2011.05.008; and Kotin RM, Large-scale recombinant adeno-associated vims production. Hum Mol Genet. 2011 Apr 15;20(Rl):R2-6. doi: 10. 1093 / hmg / ddrl41. Epub 2011 Apr 29.Pharmaceutical CompositionsIn another aspect, provided herein are pharmaceutical compositions containing the described nucleic acids and a pharmaceutically acceptable carrier. In certain embodiments, the nucleic acids are encapsulated in an LNP formulation or included in a viral or non-viral vector.As used herein, '‘carrier” includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. The use of such media and agents for pharmaceutical active substances is well known in tire art. Supplementary active ingredients can also be incorporated into tire compositions. The phrase “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an allergic or similar untoward reaction when administered to a host.In one embodiment, a composition includes a final formulation suitable for delivery to a subject, e.g., is an aqueous liquid suspension buffered to a physiologically compatible pH and salt concentration. Optionally, one or more surfactants are present in tire formulation. In another embodiment, the composition may be transported as a concentrate which is diluted for administration to a subject. In other embodiments, the composition may be ly ophilized and reconstituted at the time of administration.Methods and agents well known in the art for making formulations are described, for example, in “Remington's Pharmaceutical Sciences,” Mack Publishing Company, Easton, Pa. Formulations may, for example, contain excipients, carriers, stabilizers, or diluents such as sterile water, saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes, preservatives (such as octadecyldimethylbenzyl, ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzylalcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3- pentanol, and m-cresol), low molecular weight polypeptides, proteins such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, histidine, arginine, and lysine, monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, and dextrins, chelating agents such as EDTA, sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).A suitable surfactant, or combination of surfactants, may be selected from among nonionic surfactants that are nontoxic. In one embodiment, a difunctional block copolymer surfactant terminating in primary hydroxyl groups is selected, e.g., such as Pluronic® F68 [BASF], also known as Poloxamer 188. which has a neutral pH. has an average molecular weight of 8400. Other surfactants and other Poloxamers may be selected, i.e., nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly (ethylene oxide)), SOLUTOL HS 15 (Macrogol-15 Hydroxystearate), LABRASOL (Polyoxy capryllic glyceride), polyoxy 10 oleyl ether, TWEEN (polyoxyethylene sorbitan fatty acid esters), ethanol and polyethylene glycol. In one embodiment, the formulation contains a poloxamer. These copolymers are commonly named with the letter “P"’ (for poloxamer) followed by three digits: the first two digits x 100 give the approximate molecular mass of the polyoxypropylene core, and the last digit x 10 gives the percentage polyoxyethylene content. In one embodiment Poloxamer 188 is selected. The surfactant may be present in an amount up to about 0.0005 % to about 0.001% of the suspension.These above compositions may be administered in a variety of volumes of carrier, excipient or buffer formulation, ranging from about 25 to about 1000 microliters, or higher volumes, including all numbers within the range, depending on the size of the area to be treated, the viral titer used, the route of administration, and tire desired effect of the method.MethodsIn certain embodiments, the methods are provided comprising administration of one or more polynucleotides, such as or one or more vectors as described herein, one or more transcripts thereof, and / or one or proteins transcribed therefrom, to a host cell. Conventional viral and non- viral based gene transfer methods can be used to introduce nucleic acids in mammalian cells ortarget tissues. Such methods can be used to administer nucleic acids encoding components of a prime editing system to cells in culture, or in a host organism.The terms “treatment,” “treat,” and “treating,” refer to a clinical intervention aimed to reverse, alleviate, delay the onset of, or inhibit the progress of a disease or disorder, or one or more symptoms thereof, as described herein. As used herein, the terms “treatment.” “treat.” and “treating” refer to a clinical intervention aimed to reverse, alleviate, delay the onset of. or inhibit the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed and / or after a disease has been diagnosed. In other embodiments, treatment may be administered in the absence of symptoms, e.g., to prevent or delay onset of a symptom or inhibit onset or progression of a disease. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.Symptoms of RVCL usually begin in middle age (-35-50 years) with eye issues such as an increasing number of “floaters” and “blind spots.” The main pathologic process of RVCL is that small blood vessels prematurely drop out; that is, deteriorate and disappear. This leads to mini strokes (or “micro-infarcts”) in tissues. The loss of blood supply affects both the eye (retina) and the brain (white matter) since these organs serve key functions and are sensitive to even small disruptions in blood flow. As more vessels drop out, there is development of increased vision loss and larger brain infarcts (or tumor-like lesions), especially if the mini-strokes are clustered. Disease-related symptoms including visual loss, brain disease producing stroke-like symptoms, mental impairment, migraine, psychiatric disturbances and seizures. Additional systemic effects includedliver and kidney disease, anemia, high blood pressure and, less commonly, Raynaud’s phenomenon, and intestinal bleeding. These features likely arise primarily because small blood vessels progressively deteriorate in tire organs (e.g., liver, kidney, skin, intestine). Some RVCL patients also develop thyroid disease (hypothyroidism) or bone problems caused by loss of small blood vessels (osteonecrosis).In certain embodiments, methods of treating RVCL in a subject in need thereof are provided, the method comprising administering to the subject a therapeutically effective a compositions comprising nucleic acid sequences encoding elements of a prime editing system. In certain embodiments, the nucleic acid sequences are included in an LNP formulation. In other embodiments, the nucleic acid sequences are delivered using a viral vector, such as an AAVvector or dual AAV vector system. In certain embodiments, the subject has a mutation in a TREX1 allele that is V235G fs*6, T236Nfs, T249Nfs, T249Sfs, T250Nfs, H253Qfs, E266*, S267Efs, S267Rfs, S267Qfs, S268Gfs, T270Nfs, K271Qfs, D272Lfs, D272Ifs, P275Qfs, K277, D278Efs, R284Kfs, E285*, L287Afs, or A310Efs.The term "‘therapeutically effective amount,” as used herein, refers to an amount of a biologically active agent that is sufficient to elicit a desired biological response. For example, in certain embodiments, an effective amount may refer to the amount of the prime editing components that is sufficient to induce correction of a target site specifically bound and mutated by the prime editor. As will be appreciated by the skilled artisan, the effective amount of an composition, e.g., an LNP formulation or viral vector for delivery elements of prime editing components, may vary depending on various factors as, for example, on the desired biological response, e.g., on the specific allele, genome, or target site to be edited, on the cell or tissue being targeted, or on the agent being used.The compositions provided herein may be administered locally or systemically, as needed to treat the specific aspects of RVCL. Acceptable routes of administration include, but are not limited to, direct delivery to a desired organ (e.g., the liver (optionally via the hepatic artery), lung, heart, eye, kidney,), oral, inhalation, intranasal, intrathecal, intratracheal, intraarterial, intraocular, intravenous, intramuscular, subcutaneous, intradermal, ICM, and other parental routes of administration. Routes of administration may be combined, if desired.Non-viral vector delivery systems include DNA plasmids, RNA (e.g., a transcript of a vector described herein), naked nucleic acid, and nucleic acid complexed with a delivery vehicle, such as a liposome. Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes after delivery to the cell. For a review of gene therapy procedures, see Anderson, Science 256:808-813 (1992); Nabel & Feigner, TIBTECH 11:211-217 (1993); Mitani & Caskey, TIBTECH 11: 162-166 (1993); Dillon, TIBTECH 11: 167-175 (1993); Miller, Nature 357:455-460 (1992); Van Brunt, Biotechnology 6(10): 1149-1154 (1988); Vigne, Restorative Neurology and Neuroscience 8:35-36 (1995); Kremer & Perricaudet, British Medical Bulletin 51( 1):31-44 (1995); Haddada et al., in Current Topics in Microbiology and Immunology Doerfler and Bihm (eds) (1995); and Yu et al., Gene Therapy 1: 13-26 (1994).Methods of non-viral delivery of nucleic acids include lipofection, nucleofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipid-nucleic acid conjugates, lipid nanoparticles, artificial virions, virus-like particles, naked DNA, and agent- enhanced uptake of DNA. Lipofection is described in e.g., U.S. Pat. Nos. 5,049,386, 4,946,787;and 4,897,355) and lipofection reagents are sold commercially (e.g., Transfectam™ and Lipofectin™). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those of Feigner, WO 91 / 17424; WO 91 / 16024. Delivery can be to cells (e.g.. in vitro or ex vivo administration) or target tissues (e.g.. in vivo administration).The invention is now described with reference to the following examples. These examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these examples but rather should be construed to encompass any and all variations that become evident as a result of the teaching provided herein.EXAMPLESExample 1 : Materials and MethodsEstablishment of transgenic Drosophila for expressing human TREX1. For tire wild-type human TREX1, as well as RVCL mutant TREX1 (TREX1 V235Gfs) and AExo RVCL mutant TREX1 (TREX1 R62A / V235Gfs), PCR was used to amplify the insert fragments. Using the DNA Ligation Kit Mighty Mix (Takara Bio, Shiga, Japan), these fragments were incorporated into the 20 UAS-IVS-P 10 vector. During this process, a Myc tag (EQKLISEEDL) was added to the N- tenninus of each inserted human TREX1. The constructed recombinant vectors were then injected into fly embryos and inserted into the ZH86Fb landing site (Wellgenetics, Taipei, Taiwan).Evaluation of the rough eye phenotype. Each human TREX1 variant was expressed under the control of the GMR-Gal4 driver and the resulting flies were reared at 29°C. After eclosion, adult flies were frozen and stored at -80°C for later use. To photograph the compound eyes of the flies, a DP23 camera (Olympus, Japan) was attached to an Olympus BX53 microscope (Olympus. Japan) to capture images at 20x magnification. The area was photographed, including the compound eye, shifting the focus incrementally by 1.87 pm for each shot. These images were then depth-composited for each focus slice and the resulting phenotypic score was calculated using Flynotyper. This phenotypic score reflects structural abnormalities in the compound eye, with a higher score indicating a greater degree of disorder in eye arrangement. A gene knockdown screen to alleviate the rough eye phenotype caused by the RVCL mutant TREX1 was performed using the following procedure. First, primary screening by visual inspection using atleast three samples for each candidate gene was performed under blinded conditions. Based on the primary screening, 67 genes were identified. Furthermore, quantitative secondary screening was performed on these 67 genes using Flynotyper. Statistical analysis of the 67 samples was performed using Prism 9 software. For comparative analysis, one-way analysis of variance (ANOVA) was initially attempted. Subsequently, a nonparametric test with a Kruskal-Wallis test was performed to determine if there were statistically significant differences between the groups. GO enrichment analysis was performed on a group of genes with reduced toxicity of the mutant TREX1 (geneontology .org). Assignment of human ortholog to fly genes was performed using the DRSC integrative ortholog prediction tool (DIOPT) (flymai.org / cgi-bin / DRSC_orthologs.pl).Immunohistochemistry and imaging of Drosophila. The following antibodies were used: mouse anti-myc (9B11) (1:2,000; Cell Signaling Technology, CST. 2276S), rabbit anti-Histone H2AvD pS 137 (Rockland, 600-401-914), anti-mouse Alexa Fluor 568 (Thermo Fisher Scientific, A- 11004) and anti-rabbit Alexa Fluor 633 (Thermo Fisher Scientific. A-21071). The specimens were mounted using the Vectashield mounting medium (Vector Laboratories). To visualize the nucleus, 4',6-diamidino-2-phenylindole (DAPI, Bio-Rad, 13 1303) was used. Images were scanned using an FV3000 confocal microscope (Olympus, Tokyo, Japan) and captured using Imaris soft are (Oxford Instruments, Zurich, Switzerland). To quantify the localization pattern of each human TREX1 transgene, one- to two-day-old adult female flies were dissected. Referring to the DAPI signal, the region of the nucleus was selected using freehand selection in Fiji, an open-source image analysis software. The nucleus was selected by experimenters who were blind to the genotype. The average fluorescence intensities of the nuclear and non-nuclear regions were calculated. To quantitatively evaluate the localization of myc-tagged human TREX1, the range stained by DAPI was considered the intranuclear signal and compared with the extranuclear signal to calculate the ratio of nuclear to cytoplasmic TREX1.Ribonucleoprotein electroporation forHDR induction. To examine tire efficiency of HDR and NHEJ, the ribonucleoprotein (RNP) complex was electroporated into the Flp-In 293T cells. Briefly, the gRNA complex was prepared by mixing equal amounts of Alt-R CRISPR Cas9 crRNA and tracrRNA at equal concentrations (50 pM) in duplex buffer (IDT), heated 95°C for 5 minutes, and allowed to cool to room temperature. The prepared gRNA (120 pmol) was mixed with 100 pmol Alt-R Cas9 Nuclease V3 and allowed to form an RNP complex for 5 minutes at room temperature. Next, 4 pl of RNP complex was added to 1 x 106cells suspended in 100 pl Opti-MEM with 1.2 pl of 100 pM (120 pmol) electroporation enhancer (IDT) and 1 pL of 100pM (100 pmol) HDR single-strand donor oligo and incorporated by electroporation using a NEPA21 electroporator (NEPAGene). For single-strand donor oligos, ultramer DNA oligonucleotides were used in which the bonds between the five bases at tire 3’ and 5’ ends were modified with phosphorothioate to protect from degradation by nucleases, including TREX1. In addition, a two-base mutation immediately upstream of the stop codon was introduced into the donor oligo to detect the HDR repair allele (FIG. 7A) specifically. After electroporation, the cells were divided into two groups, one of which was induced to express TREX 1 by the addition of doxycycline. Seventy -two hours after electroporation of RNP, genomic DNA was extracted and cleaned using a DNeasy Blood & Tissue Kit (Qiagen) and AMPure XP (Beckman coulter). The effect of each mutated TREX1 on HDR and NHEJ efficiency was assessed as the percentage change from dox-free cells between split pairs after electroporation.Quantification of HDR efficiency using droplet digital PCR (ddPCR). In tiiis assay, the primer was set upstream of the complementation region with the donor oligo and inside die donor oligo, so that the mutation within die donor oligo was included in the amplified product. To quantify the total PCR amplification product and HDR allele-derived product in the same amplicon, two types of probes were designed in a single amplicon (FIG. 7A). The first is a FAM-labeled reference probe that does not overlap with the cut site and always binds to the amplicon regardless of the presence of the mutation insertion. The second is a HEX-labelled probe that binds specifically to amplification products derived from alleles undergoing HDR repair. To ensure specificity of the donor oligo-derived mutant sequence by HDR repair, this probe is chimerically modified w ith locked nucleic acids (LNA). This HDR probe-positive amplicon w as detected only when the donor oligo was introduced during genome editing. Droplets enclosing the PCR mix were formed using the Bio-Rad QX-100 emulsification device. After PCR cycling, droplets were analyzed immediately using QuantaSoft v. 1.6 (Bio-Rad). Frequencies of HDR in each sample are calculated as FHDR = CHDR X 100 / Gotai, where F = allelic frequency (%), CHD = the HDR-repaired allelic (HDR specific probe positive) concentration, and Ctotai = the total allelic (reference probe positive) concentration (FIG. 7A).Mismatch cleavage assay. The genomic DNA sequence region containing the CRISPR Cas9 cut site was amplified by PCR using PrimeSTAR GXL DNA Polymerase. PCR products were denatured by heating at 95 °C for 5 minutes and then cooled using a thermocycler at rates of 2°C / s to 85°C and l°C / s to 25°C to form heteroduplexes. Heteroduplex DNA digestion was performed using Guide-it Resolvase (TaKaRa) for 30 minutes at 37°C. Digested PCR amplicons wereseparated by capillary gel electrophoresis and uncut amplicons and cleaved fragments were detected and quantified using an Agilent 2200 TapeStation system. The NHEJ efficiency was calculated as the ratio of the cleaved fragment signal to the total DNA fragment signal.Plasmid construction. The full-length coding region of human TREX1 cDNA was amplified by PCR from a human cDNA library (Clontech) with an N-terminal myc-His tag and subcloned into the multiple cloning site of the pcDNATM5 / FRT / TO vector (BamHI / XhoI)(Thermo Fisher) or pRetroX TRE 3G vector (BamHI / MluI) (Clontech). Each mutant construct was produced using the GeneArt site-directed mutagenesis system (Thenno Fisher). A consensus MAPKK NES-fused TREX1 was created by PCR using specific primers from the cDNA library and subcloned into the pcDNATM5 / FRT / TO vector.Establishment of cells with stable gene expression. Stable gene-expressing cells were produced using the Flp-In system (Thermo Fisher) or Retro X Tet-On 3G Inducible Expression System (Clontech). In the Flp-In system, T-Rex-293 Cells (Thermo Fisher) were seeded at approximately 60% confluent in 35 mm dishes one day before transfection. Then, 150 ng of pcDNA5 / FRT / TO vector with each human TREX1 mutant cDNA and 850 ng of pOG44 was transfected into T-Rex- 293 Cells by X-tremeGENE HP DNA Transfection Reagent (Roche). The medium was replaced with selection medium containing 250 pg / mL hygromycin B. Each surviving colony was picked up and used for each experiment after confirming normal growth capacity and doxycycline- induced gene-of-interest expression. The RetroX Tet-On 3G inducible expression system was established in two steps. For retrovirus production, GP2-293 packaging cells were seeded at 60% confluence in 100 mm dishes 24 hours before transfection. pAmpho vector (15 pg) and pRetroX Tet-3G vector (15 pg) or pRetroX TRE-3G vector (15 pg) with each human TREX1 mutant cDNA were transfected into the cells using the Xfect Transfection Reagent (Takara). After 4 hours of incubation, the medium was replaced with a fresh medium. The medium was collected after 48 hours and 72 hours. After filtration of the harvested medium to remove cell debris, a Retro-X concentrator was added to the medium and incubated overnight 4°C. The processed medium was centrifuged at 1500 xg for 45 minutes at 4°C and the supernatant was discarded. The precipitated virus products were dissolved in a fresh medium. For retroviral transfection into target cells, 1.4 *10’ IMR-90 cells were seeded in 6-well plates 24 hours before transfection. The seeded cells were co-transduced with RetroX-Tet3G and RetroX-TRE3G retroviruses at a ratio of 2: 1 with polybrene (8 pg / ml) and centrifuged at 1500 xg for 60 minutes at room temperature, followed by overnight incubation in a humidified incubator. After virus transduction, tire cellswere exposed to 2 pg / ml puromycin (Thermo Fisher) and 600 pg / ml geneticin (Thermo Fisher) for 6 days and used for each experiment. Cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM, Gibco) supplemented with 10% Tet System Approved FBS (Clontech). As a positive control to analyze the behavior of the SET complex, IMR-90 cells were treated with granzyme A (2.5 pM) and perforin (40 ng / ml) for 20 minutes before analysis. All the cells were negative for mycoplasma.Neutral comet assay. Cellular DNA damage w as assessed by a neutral comet assay using a comet assay kit (Trevigen). LMAgarose was melted by heating prior to the experiment. Briefly, 1 pl of SYBR Gold was dissolved in 30 m of Tris-EDTA buffer (pH 7.5). The dissociated cells were adjusted to 1 x 105per ml with cold PBS. 30 pl of the cell solution and 300 pl of Comet LMAgarose were combined and 50 pl of the mixture was evenly placed on the designated slides. The slides were placed on ice for 5 minutes and incubated at 4°C for 30 minutes. Afterw ards, the slides were incubated in lysis solution at 4°C for 60 minutes and then in 1 xNeutral Electrophoresis Buffer (50 mM Tris, 150 niM Sodium Acetate, pH 9.0) at 4°C for 30 minutes without light exposure. Electrophoresis was conducted in 1 *Neutral Electrophoresis Buffer at 4°C and 17 volts for 45 minutes. Slides were incubated in DNA precipitation buffer (1 M ammonium acetate in ethanol) at room temperature for 30 minutes and then in 70% ethanol at room temperature for 30 minutes. The slides were dried and incubated with diluted SYBR Gold [1:30000 in 10 mM Tris-HCl, 1 mM EDTA (pH 7.5)] for 30 minutes without light exposure. The slides w ere observed under an all-in-one microscope (Keyence; BioRevo BZ-9000) with a 40x objective lens. These images were analyzed using OpenComet, an open-source plugin for the image-processing program ImageJ. 20-30 cells were analyzed per assay, and five independent assays were performed.EdU proliferation assay. Proliferation of IMR-90 cells was determined using tire Click-iT EdU Imaging Kit (ThermoFisher) according to the manufacturer’s protocol. Briefly, IMR-90 cells with inducible TREX1 expression were seeded at 50% confluency one day before adding EdU solution. Half of the medium was replaced with I OpM EdU solution and the cells were incubated in a humidified incubator for 24 hours. The cells were fixed with 4% paraformaldehyde (PFA) (Fujifilm) in phosphate buffer solution for 15 minutes and permeabilized with 0.5% Triton X-100 (Sigma Aldrich) for 20 minutes. EdU and azide were reacted with a copper catalyst for 30 minutes. Cell nuclei w ere visualized using Hoechst 33342 (Thermo Fisher). The percentage ofEdU-positive cells relative to doxycycline-untreated cells, after doxycycline-induction of the indicated form of TREX1 in IMR90 cells, was calculated each day after doxycycline addition.Mice. A targeting sgRNA was designed with specificity to tire location of the codon encoding threonine 235 of mouse TREX1, and site-specific cleavage was assessed in vitro. spCAS9 and sgRNAs were in vitro- transcribed from PCR amplicons purified by Qiaquick PCR purification spin columns (Qiagen) using the MEGAshortscript T7 kit (Thermo Fisher) for sgRNA and mMESSAGE mMACHINE T7 ultra kit (Thermo Fisher) for Cas9 mRNA. In vztro-transcribed Cas9 RNA was purified via lithium chloride precipitation and sgRNA was purified using the MEGAclear RNA purification kit (Life technologies) and diluted in nuclease free injection buffer. The TREX1 T235Gfs frameshift was introduced using a single-stranded DNA oligonucleotide donor (ssODN) which include tire 5 aberrant C-terminal amino acid residues found in human TREX1 V235Gfs with 99 nucleotide flanking sequences homologous to the TREX1 open reading frame. Four-week-old female C57BL / 6J mice were super-ovulated with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotrophin (HCG) and mated with C57BL / 6J male mice. Fertilized single-cell embryos (embryonic day 0.5 [E0.5]) were isolated and microinjected with a combined mixture of 50 ng / pl Cas9, 25 ng / pl sgRNA and 100 ng / pl ssODN or 25 ng Cas9, 13 ng / pl sgRNA and 100 ng / pl ssODN in Dnasc / Rnasc free microinjection buffer (1 mM Tris. 0.25 niM EDTA, pH 7.4). Following microinjection -80-100 modified embryos per day, over a period of 6 days, were transferred into E0.5 pseudo-pregnant ICR / CD1 female recipient mice. Colonies were established from two independent founder mice backcrossed to wild-type C57BL / 6J mice for five generations, wild-type litter control mice were used for all experiments. Experiments were performed on mice of both sexes between (2 - 12 months) of age, matched with littermate control animals. Sample sizes were derived from previously published studies. Mice w ere randomly allocated for all experiments. Human TREX1 mutant mice were generated at Cyagen / Taconic. Briefly, a CAG promoter, a transcriptional stop sequence flanked by loxP sequences, and N-temiinal HA-tagged WT or RVCL human TREX1 cDNAs were cloned into ROSA26 targeting vectors. In v / tro-transcribed Cas9 mRNA, sgRNAs. and targeting vectors were microinjected into fertilized embryos and implanted into C57BL / 6J mice. Coloni...

Claims

1. WHAT IS CLAIMED IS:

1. A prime editing guide RNA (pegRNA) comprising, from 5' to 3': a) a spacer that is complementary to a target sequence on a first strand of a TREX1 gene; b) a scaffold sequence capable of binding to a Cas9 protein; and c) an extension sequence comprising: i) an editing template that comprises a region of complementarity to an editing target sequence on a second strand of the TREX1 gene, and ii) a primer binding site, wherein the first strand and the second strand are complementary to each other, and wherein the editing target sequence on the second strand comprises or is complementary to a portion of the TREX1 gene comprising a mutation.

2. The pegRNA of claim 1, wherein the editing target sequence of the second strand comprises or is complementary to a sequence in a region of tire TREX1 gene that encodes amino acids 231-236, amino acids 251-256, amino acids 249-255, amino acids 263-269, amino acids 270-275, amino acids 273-278, amino acids 223-249, amino acids 242-251, amino acids 257-275, amino acids 264-280, amino acids 267-288, amino acids 276-283, or amino acids 277-298 corresponding to a TREX 1 protein lacking the mutation, optionally SEQ ID NO: 9209.

3. The pegRNA of claim 1 or 2, wherein the editing target sequence of the second strand comprises or is complementary to a sequence in a region of the TREX1 gene comprising a mutation in amino acid 235, 236, 249. 249, 250. 253, 262, 266, 267, 267, 267, 268, 270, 271, 272, 272, 275, 277, 278, 284, 285, 287, 290, or 310 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209.4 The pegRNA of any one of claims 1 to 3, wherein the mutation is V235Gfs, T236Nfs, T249Nfs, T249Sfs, T250Nfs, H253Qfs, P262Gfs, E266X, S267Efs, S267Rfs, S267Qfs, S268Gfs, T270Nfs, K271Qfs, D272Lfs, D272Ifs, P275Qfs, K277X, D278Efs, R284Kfs, E285X, L287Afs, P290_A310deI and / or A3 lOEfs.

5. The pegRNA of any one of claims 1 to 4, wherein the spacer sequence and / or the extension sequence comprise RNA sequences, or variants thereof, of a pegRNA set forth in Table 1.

6. The pegRNA of any one of claims 1 to 5, wherein the scaffold sequence comprises (5'-3') GUUUUAGAGCUAGAAAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGA AAAAGUGGCACCGAGUCGGUGC (SEQ ID NO:22), or a variant thereof.

7. The pegRNA of any one of claims 1 to 6, wherein the extension sequence further comprises a nucleic acid moiety linked thereto that is a toe-loop, hairpin, stem-loop, pseudoknot, aptamer, G-quadraplex, tRNA, riboswitch, or ribozyme, optionally wherein tire nucleic acid moiety is a tevopreQ 1 motif.

8. The pegRNA of claim 7, wherein the nucleic acid moiety is 3' to the end of the extension sequence.

9. The pegRNA of any one of claims 1 to 8, wherein the pegRNA includes nucleoside modifications.

10. An sgRNA having a sequence that targets a prime editor to nick a non-edited strand of a TREX1 gene, wherein the sgRNA comprises a spacer sequence, or variant thereof, corresponding to an sgRNA set forth in Table 1, optionally^ wherein the sgRNA includes nucleoside modifications.

11. An mRNA encoding a prime editor, wherein the prime editor is a PEI, PE2, PE3, PE3b, or PEmax fusion enzyme, optionally wherein the mRNA includes nucleoside modifications.

12. The mRNA acceding to claim 11. comprising the modified RNA sequence set forth in SEQ ID NO: 9214, or a sequence at least 95% identical thereto, encoding the PEmax fusion enzyme.

13. A nucleic acid comprising a sequence encoding the pegRNA of any one of claims 1 to 9 and / or the sgRNA of claim 10.

14. The nucleic acid of claim 13, wherein the sequence encoding the pegRNA is operably linked to a U6 promoter sequence and / or the sequence encoding the sgRNA is operably linked to a U6 promoter sequence.

15. A nucleic acid comprising a sequence encoding the pegRNA of any one of claims 1 to 9. the sgRNA of claim 10, and / or the mRNA of claim 11 or 12.

16. The nucleic acid of any one of claims 13 to 15, which is a plasmid.

17. An in vitro host cell comprising the nucleic acid of any one of claims 13 to 16.

18. A composition comprising a lipid nanoparticle (LNP), the LNP encapsulating the pegRNA of any one of claims 1 to 9, the sgRNA of claim 10, the mRNA of claim 11 or 12, and / or the nucleic acid of any one of claims 13 to 16.

19. The composition of claim 18, wherein tire LNP comprises targeting moieties, optionally wherein the targeting moieties are antibodies or fragments thereof that bind PECAM or ICAM.

20. A composition for editing one or more RVCL-causing mutations in a TREX1 polynucleotide comprising one or more recombinant viral vectors for delivery of a) a nucleic acid sequence encoding a Cas nickase-reverse transcriptase prime editor and b) a nucleic acid sequence encoding a prime editing guide RNA (pegRNA) of any one of claims 1 to 9.

21. The composition of claim 20, further comprising a sequence encoding the sgRNA of claim 10.

22. The composition of claim 20 or 21, wherein the prime editor is PEL PE2, PE3, PE3b, or PEmax fusion enzyme.

23. The composition of any one of claims 20 to 22, wherein the one or more recombinant vectors are lentivirus, retrovirus, adenovirus, adeno-associated virus, or herpes simplex virus vectors.

24. The composition of any one of claims 20 to 23, comprising dual AAV vectors.

25. A cultured cell produced by introducing into a cell the composition of any one of claims 18 to 24.

26. A method of treating RVCL in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 18 to 24.

27. The method of claim 26, wherein the subject has a mutation in a TREX1 gene in a region that encodes amino acids 231-236, amino acids 2 1-256, amino acids 249-255, amino acids 263- 269, amino acids 270-275, amino acids 273-278, amino acids 223-249, amino acids 242-251, amino acids 257-275, amino acids 264-280, amino acids 267-288, amino acids 276-283, or amino acids 277-298 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209.

28. The method of claim 26 or 27 , wherein the subject has a mutation in a TREX1 allele that is a mutation in ammo acid 235, 236, 249. 249, 250. 253, 262, 266, 267, 267, 267, 268, 270, 271, 272, 272, 275, 277, 278, 284, 285, 287, 290, or 310 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209.

29. The method of any one of claims 26 to 28, wherein the mutation is V235Gfs, T236Nfs, T249Nfs, T249Sfs, T250Nfs, H253Qfs, P262Gfs, E266X, S267Efs, S267Rfs, S267Qfs, S268Gfs, T270Nfs, K271Qfs, D272Lfs, D272Ifs, P275Qfs, K277X, D278Efs, R284Kfs, E285X, L287Afs, P290_A310del and / or A3 lOEfs.

30. The method of any one of claims 26 to 29, wherein the composition is administered intraocularly, intravenously, and / or intramuscularly.

31. The method of any one of claims 26 to 30, wherein the subject is a mammal, optionally a human.

32. A method for editing a TREX1 gene comprising one or more RVCL-causing mutations, the method comprising contacting tire TREX1 gene with a prime editing system comprising a Cas nickase and a prime editing guide RNA (pegRNA) of any one of claims 1 to 8, wherein pegRNA targets the prime editor to effect a correction of the one or more RVCL-causing mutations in the TREX1 gene.

33. The method of claim 32, wherein the TREX1 gene has a mutation in a region that encodes amino acids 231-236, amino acids 251-256, amino acids 249-255, amino acids 263-269, amino acids 270-275, amino acids 273-278, amino acids 223-249, amino acids 242-251, amino acids 257-275, amino acids 264-280, amino acids 267-288, amino acids 276-283, or amino acids 277-298 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209.

34. The method of claim 32 or 33, wherein the TREX1 gene has a mutation in amino acid 235, 236, 249, 249, 250, 253, 262, 266, 267, 267, 267, 268, 270, 271, 272, 272, 275, 277, 278, 284, 285, 287, 290, or 310 corresponding to a TREX1 protein lacking the mutation, optionally SEQ ID NO: 9209.

35. The method of any one of claims 32 to 34, wherein the mutation is V235Gfs, T236Nfs, T249Nfs, T249Sfs, T250Nfs, H253Qfs, P262Gfs, E266X, S267Efs, S267Rfs, S267Qfs, S268Gfs, T270Nfs. K271Qfs. D272Lfs. D272Ifs, P275Qfs, K277X. D278Efs. R284Kfs. E285X, L287Afs, P290_A31 Odel and / or A31 OEfs.

36. The method of any one of claims 32 to 35, wherein the prime editor is a PEI, PE2, PE3, PE3b, or PEmax fusion enzyme.

37. The method of any one of claims 32 to 36, wherein the prime editing system further comprises an sgRNA of claim 10.

38. The method of any one of claims 32 to 37, wherein the contacting is in a eukaryotic cell, optionally a mammalian cell or a human cell.

39. The method of claim 38, wherein the cell is in vivo.

40. The method of claim 38, wherein the cell is ex vivo.

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