Transmembrane receptor gene editing

Abstract

Provided herein are compositions and methods for ablating intracellular signaling through specific cell surface receptors as means of treatment for various conditions of a pro- inflammatory character. In some aspects, the compositions and methods are to prevent the progression of osteoarthritis and other arthritides and to treat osteoarthritis and other arthritides in a mammalian joint. In some aspects, the compositions and method are for treating or preventing localized nociception, inflammation, degeneration, or morphological changes associated with back or spine conditions or disorders.

Description

TRANSMEMBRANE RECEPTOR GENE EDITINGCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No.63 / 301,033, filed January 19, 2022, U.S. Provisional Patent Application No. 63 / 303,479, filed January 26, 2022, and U.S. Provisional Patent Application No. 63 / 390,222, filed July 18, 2022, the contents of which are hereby incorporated by reference herein, in their entireties, for all purposes.BACKGROUND OF THE INVENTION

[0002] Receptor-ligand interactions are responsible for transmission of various signals across the plasma membrane of a receptor-expressing cell. In most instances, a circulating ligand will bind to a particular receptor anchored into cellular membrane (with or without coreceptors), which, by different mechanisms and often through activity of the receptor’s cytoplasmic domain, results in the transduction of signaling pathways from the cell surface to the interior. Such signaling events can, in turn, impact a variety of cellular activities, including modulation of expression of various gene products that can further impact cellular functions.

[0003] The ubiquity of the receptor-ligand paradigm in cellular biology means that numerous diseases, illnesses, and conditions are caused, wholly or in part, by aberrant or excessive signaling through various cellular receptors, and various approaches have been utilized to address this. Small and large molecules can be used to disrupt receptor-ligand interactions, though issues of off-target effects and potential immunogenicity remain.

[0004] More recently, genetic approaches have been explored to either transiently reduce (i.e., knockdown), e.g., in the case of siRNA, or permanently ablate (i.e. , genetic knockout), the expression of a given ligand or receptor. In both instances, such reduction or ablation can result in ‘leakiness.’ For example, a lower-affinity receptor may bind ligand present in excess in the absence of the native receptor, or conversely, unoccupied receptors may bind other ligands in absence of its native ligand. In either instance, this leakiness can result in additional issues at the organismal level. Therefore, more advanced genetic tools are needed to address the myriad of diseases, illnesses and conditions without the leakiness observed with traditional genetic knockdown or knockout.BRIEF SUMMARY OF THE INVENTION

[0005] Provided herein are compositions and methods for silencing the signaling functionality of one or more cellular receptors in an animal in need thereof to treat a disease, illness or condition caused by aberrant or excessive signaling through said receptor.

[0006] In some embodiments, receptor signaling is silenced by CRISPR editing of the gene encoding the receptor. In some embodiments, the CRISPR editing results in ablation of a transmembrane domain (e.g., generation of soluble decoy receptor). In some embodiments, the CRISPR editing results in ablation of a cytoplasmic domain (e.g., generation of a membrane-bound decoy receptor). In some embodiments, the CRISPR editing results targetes the extracellular domain (e.g., generation of a complete knock out).

[0007] In contrast to complete ablation or transient knockdown of gene expression of a receptor or ligand, which has been associated with potentially important off-target effects and leakiness, the targeting of a receptor’s transmembrane domain or cytoplasmic domain, as described herein, comprises a novel approach for blocking intracellular signaling of one or more receptor-ligand interactions without the issues of excess ligand or unoccupied receptors to contribute to more deleterious outcomes.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The presently disclosed embodiments will be further explained with reference to the attached drawings. The drawings shown are not necessarily to scale, with emphasis instead generally being placed upon illustrating the principles of the presently disclosed embodiments.

[0009] Figure 1 illustrates the exons to be edited by CRISPR methods herein described to generate the indicated type of interference (e.g., genetic knockout, soluble decoy receptor, or membrane-bound decoy receptor) for the indicated exemplary gene targets.

[0010] Figures 2A and 2B illustrate the different types of CRISPR edits to (A) canine IL1RAP gene and (B) human TNFRSF4 gene. For cILlRAP, the splicing map at top indicates which exons are edited with sgRNA shown, aligned with the corresponding domains in the full length cILlRAP protein, such that OCP02 edits in the ectodomain, OCP07 edits in the transmembrane domain, and OCP10 edits in the TIR domain (bottom). For TNFRSF4, the splicing map at bottom is labeled with the encoded protein domains andaligned with the sgRNA binding sites and the interference type generated. For instance, those sgRNAs that generate soluble decoy receptors cluster within the area encoding the transmembrane domain, while those generating transmembrane decoy receptors cluster within the encoded cytoplasmic domain and ablate the TRAF binding sites. In either case, synthesis of the ectodomain is unimpacted, allowing binding of the ligand.

[0011] Figures 3A and 3B illustrate a non-exhaustive list of disease states associated with IL1R1 and IL 1 RAP activity.

[0012] Figures 4A and 4B illustrate a non-exhaustive list of disease states associated with (A) IL6R and (B) IL6ST activity.

[0013] Figure 5 illustrates a non-exhaustive list of disease states associated with TNFRSF1A activity.

[0014] Figure 6 illustrates a non-exhaustive list of disease states associated with TNFRSF1B activity.

[0015] Figure 7 illustrates a non-exhaustive list of disease states associated with TNFRSF3 activity.

[0016] Figure 8 illustrates a non-exhaustive list of disease states associated with TNFRSF4 activity.

[0017] Figure 9 illustrates a non-exhaustive list of disease states associated with TNFRSF 11 A activity .

[0018] Figures 10A and 10B illustrate a non-exhaustive list of disease states associated with (A) TGFRB1 and (B) TGFBR2 activity.

[0019] Figures 11 A and 1 IB illustrate the design of exemplary sgRNAs that target canine IL1R1, including (A) a summary of select sgRNAs based on off-target risks, on-target efficacy, and frameshift likelihood and (B) AlphaFold2 models of wild-type and decoy IL1R1 receptors, as predicted to be generated by OCR13 and OCR14.

[0020] Figure 12 illustrates the in vitro performance of the tested sgRNA candidates that target canine IL1RAP, as deduced from Sanger traces. ND, not determined.

[0021] Figures 13A, 13B, 13C, and 13D illustrate the effect of various Cas9 variants on the in-vitro editing performance of select candidate sgRNAs that target canine IL1R1.

[0022] Figures 14A and 14B illustrate the design of exemplary sgRNAs that target canine IL1RAP, including (A) a summary of select sgRNAs based on off-target risks, on-target efficiency and frameshift likelihood and (B) AlphaFold2 -predicted models of the 3D structure of normal and OCP07-edited IL 1 RAP.

[0023] Figure 15 illustrates the in vitro performance of the tested sgRNA candidates that target canine IL 1 RAP, as deduced from Sanger traces.

[0024] Figures 16A, 16B, 16C illustrate (A) select sgRNAs targeting IL1RAP for testing and their editing efficacy with wildtype Cas9, (B) the effect of the indicated Cas9 variants on editing efficacy in canine monocytes and (C) a comparison of editing efficacy between AR- Cas9 and WT-Cas9 in canine synovial fibroblasts.

[0025] Figures 17A, 17B, and 17C illustrate the editing efficacy of the indicated IL 1 RAP- directed sgRNAs in (A) canine monocytes, (B) canine chondrocytes and (C) canine synovial fibroblasts.

[0026] Figure 18 illustrates the impact of IL1R1 editing on silencing transcriptional induction of PTGS2 in response to 4 hours exposure to ILip in canine synoviocytes.

[0027] Figure 19 illustrates the impact of IL1R1 editing on silencing transcriptional induction of IL6 in response to 4 hours exposure to IL 1 [3 in canine synoviocytes.

[0028] Figure 20 illustrates the experimental design underlying transcriptome analyses, among other assays. Generally, ILip treatment will induce pro-inflammatory signaling exclusively through the IL1 receptor, whereas MSU crystals and LPS trigger inflammation by different means (in addition to inducing IL1 signaling).

[0029] Figures 21A and 21B illustrate the transcriptional upregulation of PTGS2 (COX-2) in wild type control and IL1RAP- edited canine monocytes at (A) 4 and (B) 24 hours of exposure to LPS (1 ug / ml), ILip (100 pM), MSU crystals (400 ug / ml), and PBS (IX).

[0030] Figure 22A and 22B illustrate the impact of IL1RAP editing on silencing transcriptional induction of PTGS2 in (A) canine chondrocytes and (B) canine synoviocytes in response to 4 hours exposure to ILip.

[0031] Figures 23A and 23B illustrate luciferase activity levels (RLU) of (A) canine synovial fibroblasts at 8 hours and (B) canine chondrocytes at 24 hours post exposure to luciferase mRNA containing LNPs at the indicated concentration.

[0032] Figures 24A and 24B illustrate results of synovial fluid cytology assays collected (A) at baseline and (B) at 4 weeks after injection of saline, low dose LNP formulation A and low-dose LNP formulation B.

[0033] Figures 25A, 25B, 25C, 25D, 25E, 25F, 25G, and 25H collectively illustrate, for control and IL 1 RAP-edited cells, (A) a principal component analysis plot of normalized gene counts following IL 1 [3 or MSU treatment. Two heatmaps of select gene expression as result of (B) ILip or (C) MSU treatment, and Venn diagrams of upregulated or downregulated genes following (D, E) ILip or (F, G) MSU treatment. (H) Transcriptome analysis of the top 500 ILip-responsive genes in ILlRAP-edited canine monocytes DH82.

[0034] Figures 26A, 26B, 26C, 26D, 26E, and 26F collectively illustrate SEQ ID NOs: 680-824 (A-D) the crRNA sequences generated by the bioinformatic methods herein described that target human IL1R1 to generate a genetic knockout, a soluble decoy receptor, a membrane-bound decoy receptor, or other form and (E-H) additional information regarding the choromosome 2 genomic coordinates (assembly hg38) of the bound DNA, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0035] Figures 27A, 27B, 27C, 27D, 27E, 27F, 27G, and 27H collectively illustrate SEQ ID NOs: 825-892 and SEQ ID NOs: 3336-3420 (A-D) the crRNA sequences generated by the bioinformatic methods herein described that target canine IL1R1 to generate a genetic knockout, a soluble decoy receptor, or a membrane-bound decoy receptor, or other form and (E-H) additional information includes the chromosome 10 genomic coordinates (assembly canFam3) of the bound DNA, the DNA strand targeted, the exon targeted, and several predicted performance metrics.

[0036] Figures 28A, 28B, and 28C collectively illustrate SEQ ID NOs: 893-967, the crRNA sequences generated by the bioinformatic methods herein described that target equine IL1R1 to generate (A) a genetic knockout, (B) a soluble decoy receptor, or (C) a membranebound decoy receptor. Additional information includes the chromosome 15 genomic coordinates (assembly equCab3) of the bound DNA, the DNA strand targeted, the exon targeted, and several predicted performance metrics.

[0037] Figures 29A, 29B, and 29C collectively illustrate SEQ ID NOs: 968-1039, the crRNA sequences generated by the bioinformatic methods herein described that target feline IL1R1 to generate (A) a genetic knockout, (B) a soluble decoy receptor, or (C) a membranebound decoy receptor. Additional information includes the chromosome A3 genomiccoordinates (assembly felCat9) of the bound DNA, the DNA strand targeted, the exon targeted, and several predicted performance metrics.

[0038] Figures 30A, 30B, 30C, 30D, 30E, 30F, 30G, and 30H collectively illustrate SEQ ID NOs: 1040-1203, (A-D) the crRNA sequences generated by the bioinformatic methods herein described that target human IL1RAP to generate a genetic knockout, a soluble decoy receptor, a membrane-bound decoy receptor or other form and (E-H) additional information regarding the chromosome 3 genomic coordinates (assembly hg38) of the bound DNA, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0039] Figures 31A, 31B, 31C, 31D, 31E, and 31F collectively illustrate SEQ ID NOs: 1204-1271 and SEQ ID NOs: 3421-3490 (A-C) the crRNA sequences generated by the bioinformatic methods herein described that target canine IL1RAP to generate a genetic knockout, a soluble decoy receptor, a membrane-bound decoy receptor, or other form and (D- F) additional information includes the chromosome 34 genomic coordinates (assembly canFam3) of the bound DNA, the DNA strand targeted, the exon targeted, and several predicted performance metrics.

[0040] Figures 32A, 32B, and 32C collectively illustrate SEQ ID NOs: 1272-1348, the crRNA sequences generated by the bioinformatic methods herein described that target equine IL1RAP to generate (A) a genetic knockout, (B) a soluble decoy receptor, or (C) a membrane-bound decoy receptor. Additional information includes the chromosome 19 genomic coordinates (assembly equCab3) of the bound DNA, the DNA strand targeted, the exon targeted, and several predicted performance metrics.

[0041] Figures 33A, 33B, and 33C collectively illustrate SEQ ID NOs: 1349-1424, the crRNA sequences generated by the bioinformatic methods herein described that target feline IL1RAP to generate (A) a genetic knockout, (B) a soluble decoy receptor, or (C) a membrane-bound decoy receptor. Additional information includes where the chromosome C2 genomic coordinates (assembly felCat9) bound, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0042] Figures 34A, 34B, 34C, 34D, 34E, and 34F collectively illustrate SEQ ID NOs: 1425-1546, (A-C) the crRNA sequences generated by the bioinformatic methods herein described that target human TGFBR1 to generate a genetic knockout, a soluble decoy receptor, a membrane-bound decoy receptor or other form and (D-F) additional informationregarding the chromosome 9 genomic coordinates (assembly hg38) of the bound DNA, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0043] Figures 35A, 35B, 35C, 35D, 35E, 35F, 35G, and 35H collectively illustrate SEQ ID NOs: 1547-1745, (A-E) the crRNA sequences generated by the bioinformatic methods herein described that target human TGFBR2 to generate a genetic knockout, a soluble decoy receptor, a membrane-bound decoy receptor or other form and (F-J) additional information regarding the chromosome 3 genomic coordinates (assembly hg38) of the bound DNA, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0044] Figures 36A, 36B, 36C, 36D, 36E, 36F, 36G, 36H, 361, and 36J collectively illustrate SEQ ID NOs: 1746-1968, (A-E) the crRNA sequences generated by the bioinformatic methods herein described that target human IL6R to generate a genetic knockout, a soluble decoy receptor, a membrane-bound decoy receptor or other form and (F- J) additional information regarding the chromosome 1 genomic coordinates (assembly hg38) of the bound DNA, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0045] Figures 37A, 37B, 37C, 37D, 37E, 37F, 37G, 37H, 371, and 37J collectively illustrate SEQ ID NOs: 1969-2178, (A-E) the crRNA sequences generated by the bioinformatic methods herein described that target human IL6ST to generate a genetic knockout, a soluble decoy receptor, a membrane-bound decoy receptor or other form and (F- J) additional information regarding the chromosome 5 genomic coordinates (assembly hg38) of the bound DNA, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0046] Figures 38A, 38B, 38C, 38D, 38E, 38F, 38G, 38H, 381, and 38J collectively illustrate SEQ ID NOs: 2179-2395, (A-E) the crRNA sequences generated by the bioinformatic methods herein described that target human TNFRSF1 A to generate a genetic knockout, a soluble decoy receptor, a membrane-bound decoy receptor or other form (F-J) additional information regarding the chromsome 12 genomic coordinates (assembly hg38) of the bound DNA, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0047] Figures 39A, 39B, 39C, 39D, 39E, 39F, 39G, 39H, 391, and 39J collectively illustrate SEQ ID NOs: 2396-2642, (A-E) the crRNA sequences generated by the bioinformatic methods herein described that target human TNFRSF1B to generate a geneticknockout, a soluble decoy receptor, a membrane-bound decoy receptor or other form and (F- J) additional information regarding the chromsome 1 genomic coordinates (assembly hg38) of the bound DNA, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0048] Figures 40A, 40B, 40C, 40D, 40E, 40F, 40G, 40H, 401, and 40J collectively illustrate SEQ ID NOs: 2643-2866, (A-E) the crRNA sequences generated by the bioinformatic methods herein described that target human TNFRSF3 to generate a genetic knockout, a soluble decoy receptor, a membrane-bound decoy receptor or other form and (F- J) additional information regarding the chromsome 12 genomic coordinates (assembly hg38) of the bound DNA, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0049] Figures 41A, 41B, 41C, 41D, 41E, 41F, 41G, and 41H collectively illustrate SEQ ID NOs: 2867-3041, (A-D) the crRNA sequences generated by the bioinformatic methods herein described that target human TNFRSF4 to generate a genetic knockout, a soluble decoy receptor, a membrane-bound decoy receptor or other form and (E-H) additional information regarding the chromsome 1 genomic coordinates (assembly hg38) of the bound DNA, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0050] Figures 42A, 42B, 42C, 42D, 42E, 42F, 42G, 42H, 421, 42J, 42K, and 42L collectively illustrate SEQ ID NOs: 3042-3335, (A-F) the crRNA sequences generated by the bioinformatic methods herein described that target human TNFRSF11 A to generate a genetic knockout, a soluble decoy receptor, a membrane-bound decoy receptor or other form and (G- L) additional information regarding the chromsome 18 genomic coordinates (assembly hg38) of the bound DNA, DNA strand targeted, exon targeted, and several predicted performance metrics.

[0051] Figures 43A and 43B illustrate (A) a schematic view showing the targeted domains of TGFBR1 and the orientation of various sgRNAs predicted to generate knockouts, membrane-bound decoy receptors, and soluble decoy receptors (ECD: Extracellular Domain; TMD: Transmembrane Domain; ICD: Intracellular Domain; GSM: GS rich Motif); and (B) a set of parameters considered for designing sgRNAs against TGFBR1, as well as example crRNA sequences.

[0052] Figures 44A and 44B illustrate (A) a schematic view showing the targeted domains of TGFBR2 and the orientation of various sgRNAs predicted to generate knockouts,membrane-bound decoy receptors, and soluble decoy receptors (ECD: Extracellular Domain; TMD: Transmembrane Domain; ICD: Intracellular Domain; GSM: GS rich Motif); and (B) a set of parameters considered for designing sgRNAs against TGFBR2, as well as example crRNA sequences.

[0053] Figures 45A and 45B show a summary of the efficiency for editing the human TGFBR1 gene in THP-1 cells using the identified guides and (A) wild type SpCas9 or (B)ARCas9.

[0054] Figures 46A and 46B show a summary of the efficiency for editing the human TGFBR2 gene in THP-1 cells using the identified guides and (A) wild type SpCas9 or (B)ARCas9.

[0055] Figures 47A, 47B, 47C, and 47D illustrate relative levels of (A, C) TGFB1 and (B, D) TIMP1 gene expression in THP-1 cells that are unedited (WT) or edited to knock out TGFB1 (OHTG), TGFBR1 (OHTIR), or TGFBR2 (OHTIIR) following challenge by LPS (panels A and B) or TGF-beta (panels C and D) for 6 hours.

[0056] Figures 48A, 48B, 48C, 48D, 48E, 48F, 48G, 48H, 481, 48J, and 48K collectively illustrate human-directed crRNA sequences targeting (A) hILlRl (SEQ ID NOs: 3491-3513), (B) hILlRAP (SEQ ID NOs: 3514-3543), (C) hIL6R (SEQ ID NOs: 3544-3566), (D) hIL6ST (SEQ ID NOs: 3567-3606), (E) hTNFRSFl A (SEQ ID NOs: 3607-3647), (F) hTNFRSFIB (SEQ ID NOs: 3648-3692), (G) hTNFRSF3 (SEQ ID NOs: 3693-3713), (H) hTNFRSF4 (SEQ ID NOs: 3714-3740), (I) hTNFRSFl 1A (SEQ ID NOs: 3741-3788), (J) hTGFBRl (SEQ ID NOs: 3789-3813), and (K) hTGFBR2 (SEQ ID NOs: 3814-3865) for use in sgRNAs to validate in vitro editing with different modes of delivery.DETAILED DESCRIPTION OF THE INVENTIONI. Introduction

[0057] Provided herein are compositions and methods for silencing the signaling functionality of one or more cellular receptors in an animal in need thereof to treat a disease, illness or condition caused by aberrant or excessive signaling through said receptor.

[0058] In some embodiments, receptor signaling is silenced by CRISPR editing of the gene encoding the receptor. In some embodiments, the CRISPR editing results in ablation of a transmembrane domain (i.e., generation of a soluble decoy receptor). In some embodiments,the CRISPR editing results in ablation of a cytoplasmic domain (i.e., generation of a membrane-bound decoy receptor).II. Definitions

[0059] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entireties.

[0060] The terms “Interleukin 1 receptor type 1” or “IL1R1” refer to the genes (NCBI Gene ID: 3554 [human], NCBI Gene ID: 481328 [canine], NCBI Gene ID: 100009699 [equine], NCBI Gene ID: 101080705 [feline]) or an encoded gene product (e.g., UniProt: P14778; NP_001307909.1 [human], XP_038536135.1 [canine], NP_001075263.2 [equine], XP_023107327.2 [feline]), as well as sequence variants, proteins harboring conservative amino acid substitutions, and glycoforms thereof. Canonically, the proteins encoded by the genes listed above are capable of binding all forms of the pro-inflammatory cytokine interleukin 1 (IL1 or IL1) to mediate interleukin-1 -dependent activation of NF-kappa-B, MAPK and other signaling pathways. This intracellular signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAKI or IRAK2 via TIR-TIR interactions with the cytoplasmic domains of receptor / coreceptor subunits. IL1R1 can also bind the Interleukin 1 receptor antagonist (ILIRa or ILIRa or IL1RN), which prevents association with IL 1 RAP to form a signaling-competent complex. In some instances, and merely for the sake of disambiguation, a prefix is added when referring to the protein or gene of a particular species (with h, c, e, and referring to the human, canine, equine, and feline forms, respectively).

[0061] In certain embodiments, any region of an IL1R1 gene (e.g., 5' untranslated region [UTR], exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, exon 11, exon 12, exon 13, exon 14, exon 15, exon 16, exon 17, exon 18, exon 19, exon 20, exon 21, any intervening intronic regions, intron / exon junctions, the 3’ UTR, or polyadenylation signal) is targeted by an RNA-guided nuclease to alter the gene. In some embodiments, the IL1R1 gene targeted by an RNA-guided nuclease is from a mammal. In some embodiments, the IL1R1 gene targeted by an RNA-guided nuclease is from a human (hILlRl). In some embodiments, the IL1R1 gene targeted by an RNA-guided nuclease is from a dog (cILlRl). In some embodiments, the IL1R1 gene targeted by an RNA-guided nuclease is from a horse(elLlRl). In some embodiments, the IL1R1 gene targeted by an RNA-guided nuclease is from a cat (fILlRl).

[0062] The terms “Interleukin 1 Receptor Accessory Protein,” “IL1RAP,” or “IL1RAP” refer to the genes (NCBI Gene ID: 3556 [human], NCBI Gene ID: 488126 [canine], NCBI Gene ID: 100068726 [equine], NCBI Gene ID: 101094125 [feline]) or an encoded gene product (e.g., UniProt: Q9NPH3; NP_002173.1 [human], XP_038318680.1 [canine], XP_001498597.2 [equine], XP_044893081.1 [feline]), as well as sequence variants, proteins harboring conservative amino acid substitutions, and glycoforms thereof. Canonically, the proteins encoded by the genes listed above are capable of associating with IL1R1 bound to IL1 to form the high affinity interleukin- 1 receptor complex that mediates interleukin- 1- dependent activation of NF-kappa-B and other signaling pathways through the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAKI or IRAK2 via TIR-TIR interactions with the cytoplasmic domains of receptor / coreceptor subunits. In some instances, and merely for the sake of disambiguation, a prefix is added when referring to the protein or gene of a particular species (with h, c, e, and f, referring to the human, canine, equine, and feline forms, respectively).

[0063] In certain embodiments, any region of an IL1RAP gene (e.g., 5' untranslated region [UTR], exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, exon 11, exon 12, exon 13, exon 14, exon 15, exon 16, exon 17, any intervening intronic regions, intron / exon junctions, the 3’ UTR, or polyadenylation signal) is targeted by an RNA-guided nuclease to alter the gene (see, e.g., Fig. 2A). In some embodiments, the IL1RAP gene targeted by an RNA-guided nuclease is from a mammal. In some embodiments, the IL1RAP gene targeted by an RNA-guided nuclease is from a human (hILlRAP). In some embodiments, the IL1RAP gene targeted by an RNA-guided nuclease is from a dog (cILlRAP). In some embodiments, the IL1RAP gene targeted by an RNA-guided nuclease is from a horse (elLlRAP). In some embodiments, the IL1RAP gene targeted by an RNA- guided nuclease is from a cat (fILlRAP).

[0064] The term “interleukin- 1 receptor complex” or “IL1R complex” refers to any number of the protein receptors that comprises the family of transmembrane protein receptors responsible for transmitting or modulating intracellular signaling via binding of the pro- inflammatory cytokine interleukin 1 (IL1). These members include IL1R1, IL1R2, which primarily functions as a decoy receptor, IL 1 RAP, and IL1RL1, which can complex with other family members in the IL33 or IL36 signaling system.

[0065] The terms “Transforming Growth Factor Beta Receptor 1” or “TGFBR1” refer to the genes (NCBI Gene ID: 7046 [human], NCBI Gene ID: 481628 [canine], NCBI Gene ID: 100034117 [equine], NCBI Gene ID: 101094057 [feline]) or an encoded gene product (e.g., UniProt: P36897; NP_004603.1 [human], XP 038538191.1 [canine], XP_023485510.1 [equine], XP_023098269.1 [feline]), as well as sequence variants, proteins harboring conservative amino acid substitutions, and glycoforms thereof. Canonically, the proteins encoded by the genes listed above are transmembrane serine / threonine kinases forming, with TGFBR2, the native receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. When bound to its ligand, TGFBR1 is phosphorylated by TGFBR2, activating intracellular signaling regulating multiple physiological and pathological processes through release of SMAD2, which can then translocate to the nucleus or activation of other cytoplasmic signaling mediators. In some instances, and merely for the sake of disambiguation, a prefix is added when referring to the protein or gene of a particular species (with h, c, e, and f, referring to the human, canine, equine, and feline forms, respectively).

[0066] In certain embodiments, any region of an TGFBR1 gene (e.g., 5' untranslated region [UTR], exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, exon 11, exon 12, any intervening intronic regions, intron / exon junctions, the 3’ UTR, or polyadenylation signal) is targeted by an RNA-guided nuclease to alter the gene. In some embodiments, the TGFBR1 gene targeted by an RNA-guided nuclease is from a mammal. In some embodiments, the TGFBR1 gene targeted by an RNA-guided nuclease is from a human (hTGFBRl). In some embodiments, the TGFBR1 gene targeted by an RNA-guided nuclease is from a dog (cTGFBRl). In some embodiments, the TGFBR1 gene targeted by an RNA- guided nuclease is from a horse (eTGFBRl). In some embodiments, the TGFBR1 gene targeted by an RNA-guided nuclease is from a cat (fTGFBRl).

[0067] The terms “Transforming Growth Factor Beta Receptor 2” or “TGFBR2” refer to the genes (NCBI Gene ID: 7048 [human], NCBI Gene ID: 477039 [canine], NCBI Gene ID: 100033860 [equine], NCBI Gene ID: 101091725 [feline]) or an encoded gene product (e.g., UniProt: P37173; NP_003233.4 [human], XP_038288013.1 [canine], XP_023475502.1 [equine], XP_023116415.1 [feline]), as well as sequence variants, proteins harboring conservative amino acid substitutions, and glycoforms thereof Canonically, the proteins encoded by the genes listed above are transmembrane serine / threonine kinases forming, with TGFBR2, the native receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. When bound to its ligand, TGFBR1 is phosphorylated by TGFBR2, activating intracellularsignaling regulating multiple physiological and pathological processes through release of SMAD2, which can then translocate to the nucleus or activation of other cytoplasmic signaling mediators. In some instances, and merely for the sake of disambiguation, a prefix is added when referring to the protein or gene of a particular species (with h, c, e, and f, referring to the human, canine, equine, and feline forms, respectively).

[0068] In certain embodiments, any region of an TGFBR2 gene (e.g., 5' untranslated region [UTR], exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, any intervening intronic regions, intron / exon junctions, the 3’ UTR, or polyadenylation signal) is targeted by an RNA-guided nuclease to alter the gene. In some embodiments, the TGFBR2 gene targeted by an RNA-guided nuclease is from a mammal. In some embodiments, the TGFBR2 gene targeted by an RNA-guided nuclease is from a human (hTGFBR2). In some embodiments, the TGFBR2 gene targeted by an RNA-guided nuclease is from a dog (cTGFBR2). In some embodiments, the TGFBR2 gene targeted by an RNA-guided nuclease is from a horse (eTGFBR2). In some embodiments, the TGFBR2 gene targeted by an RNA- guided nuclease is from a cat (1TGFBR2).

[0069] The terms “Interleukin-6 Receptor” or “IL6R” refer to the genes (NCBI Gene ID: 3560 [human], NCBI Gene ID: 612271 [canine], NCBI Gene ID: 102148787 [equine], NCBI Gene ID: 101085689 [feline]) or an encoded gene product (e.g., UniProt: P08887;CAA41231.1 [human], XP_038527979.1 [canine], XP_023496854.1 [equine], XP_023103841.2 [feline]), as well as sequence variants, proteins harboring conservative amino acid substitutions, and glycoforms thereof. Canonically, the proteins encoded by the genes listed above are transmembrane proteins capable of binding to interleukin-6, its native ligand. This binding event triggers intracellular signaling events that result in pro- inflammatory responses. See generally, Wolf, J., et al. (2014). Cytokine, 70(1), 11-20. In some instances, and merely for the sake of disambiguation, a prefix is added when referring to the protein or gene of a particular species (with h, c, e, and referring to the human, canine, equine, and feline forms, respectively).

[0070] In certain embodiments, any region of an IL6R gene (e.g., 5' untranslated region [UTR], exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, exon 11, exon 12, exon 13, exon 14, exon 15, any intervening intronic regions, intron / exon junctions, the 3’ UTR, or polyadenylation signal) is targeted by an RNA-guided nuclease to alter the gene. In some embodiments, the IL6R gene targeted by an RNA-guided nuclease is from a mammal. In some embodiments, the IL6R gene targeted by an RNA-guided nucleaseis from a human (hIL6R). In some embodiments, the IL6R gene targeted by an RNA-guided nuclease is from a dog (cIL6R). In some embodiments, the IL6R gene targeted by an RNA- guided nuclease is from a horse (eIL6R). In some embodiments, the IL6R gene targeted by an RNA-guided nuclease is from a cat (fIL6R).

[0071] The terms “Interleukin-6 Cytokine Family Signal Transducer,” “GP130,” or “IL6ST” refer to the genes (NCBI Gene ID: 3572 [human], NCBI Gene ID: 403545 [canine], NCBI Gene ID: 100051700 [equine], NCBI Gene ID: 101089832 [feline]) or an encoded gene product (e.g., UniProt: P40189; NP_001177910.1 [human], NP_001273950.1 [canine], XP_023481030.1 [equine], XP_011281205.1 [feline]), as well as sequence variants, proteins harboring conservative amino acid substitutions, and glycoforms thereof. Canonically, the proteins encoded by the genes listed above are signal transducers shared by many cytokines, including interleukin 6 (IL6), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and oncostatin M (OSM) and function as a part of the cytokine receptor complex. Activation of this protein is dependent upon the binding of cytokines to their receptors (e.g., IL6 to IL6R). Knockout studies in mice suggest that this gene plays a critical role in regulating myocyte apoptosis. See generally, Martinez-Perez, C., et al. (2021). Journal of Personalized Medicine , 11(7), 618. In some instances, and merely for the sake of disambiguation, a prefix is added when referring to the protein or gene of a particular species (with h, c, e, and referring to the human, canine, equine, and feline forms, respectively

[0072] In certain embodiments, any region of an IL6ST gene (e.g., 5' untranslated region [UTR], exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, exon 11, exon 12, exon 13, exon 14, exon 15, exon 16, exon 17, exon 18, exon 19, exon 20, any intervening intronic regions, intron / exon junctions, the 3’ UTR, or polyadenylation signal) is targeted by an RNA-guided nuclease to alter the gene. In some embodiments, the IL6ST gene targeted by an RNA-guided nuclease is from a mammal. In some embodiments, the IL6ST gene targeted by an RNA-guided nuclease is from a human (hIL6ST). In some embodiments, the IL6ST gene targeted by an RNA-guided nuclease is from a dog (cIL6ST). In some embodiments, the IL6ST gene targeted by an RNA-guided nuclease is from a horse (eIL6ST). In some embodiments, the IL6ST gene targeted by an RNA-guided nuclease is from a cat (AL6ST).

[0073] The terms “Tumor Necrosis Factor Receptor 1” or “TNFRSF1A” refer to the genes (NCBI Gene ID: 7132 [human], NCBI Gene ID: 403634 [canine], NCBI Gene ID: 100059548 [equine], NCBI Gene ID: 493957 [feline]) or an encoded gene product (e.g.,UniProt: P 19438; NP_001056.1 [human], XP_038295153.1 [canine], XP_023498787.1 [equine], NP 001009361.1 [feline]), as well as sequence variants, proteins harboring conservative amino acid substitutions, and glycoforms thereof. Canonically, the proteins encoded by the genes listed above are transmembrane receptor proteins capable of binding Tumor Necrosis Factor Alpha (TNFA) or lymphotoxin alpha (LT A), its principal ligand. Upon binding to TNFA, the receptor trimerizes and is activated, transmitting intracellular signaling cascades with role in various processes, including apoptosis and inflammation. See generally, Ward-Kavanagh, L. K., et al. (2016). Immunity, 44(5), 1005-1019. In some instances, and merely for the sake of disambiguation, a prefix is added when referring to the protein or gene of a particular species (with h, c, e, and / referring to the human, canine, equine, and feline forms, respectively).

[0074] In certain embodiments, any region of an TNFRSF1A gene (e.g., 5' untranslated region [UTR], exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, exon 11, any intervening intronic regions, intron / exon junctions, the 3’ UTR, or polyadenylation signal) is targeted by an RNA-guided nuclease to alter the gene. In some embodiments, the TNFRSF1A gene targeted by an RNA-guided nuclease is from a mammal. In some embodiments, the TNFRSF1A gene targeted by an RNA-guided nuclease is from a human (hTNFRSFlA). In some embodiments, the TNFRSF1 A gene targeted by an RNA- guided nuclease is from a dog (cTNFRSFlA). In some embodiments, the TNFRSF1A gene targeted by an RNA-guided nuclease is from a horse (eTNFRSFlA). In some embodiments, the TNFRSF1A gene targeted by an RNA-guided nuclease is from a cat (fTNFRSFlA).

[0075] The terms “Tumor Necrosis Factor Receptor 2” or “TNFRSF1B” refer to the genes (NCBI Gene ID: 7133 [human], NCBI Gene ID: 487437 [canine], NCBI Gene ID: 100055840 [equine], NCBI Gene ID: 101080392 [feline]) or an encoded gene product (e.g., UniProt: P20333; XP_011540362.1 [human], XP_038387905.1 [canine], XP_023491528.1 [equine], XP_023113905.2 [feline]), as well as sequence variants, proteins harboring conservative amino acid substitutions, and glycoforms thereof. Canonically, the proteins encoded by the genes listed above are transmembrane receptor proteins capable of binding TNFA or LTA and are implicated in pro-survival pathways through downstream activation of NFkB pathway. See generally, Ward-Kavanagh, L. K., et al. (2016). Immunity, 44(5), 1005- 1019. In some instances, and merely for the sake of disambiguation, a prefix is added when referring to the protein or gene of a particular species (with h, c, e, and / referring to the human, canine, equine, and feline forms, respectively).

[0076] In certain embodiments, any region of an TNFRSF1B gene (e.g., 5' untranslated region [UTR], exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, exon 11, exon 13, any intervening intronic regions, intron / exon junctions, the 3’ UTR, or polyadenylation signal) is targeted by an RNA-guided nuclease to alter the gene. In some embodiments, the TNFRSF1B gene targeted by an RNA-guided nuclease is from a mammal. In some embodiments, the TNFRSF1B gene targeted by an RNA-guided nuclease is from a human (hTNFRSFIB). In some embodiments, the TNFRSF1B gene targeted by an RNA- guided nuclease is from a dog (cTNFRSFIB). In some embodiments, the TNFRSF1B gene targeted by an RNA-guided nuclease is from a horse (eTNFRSFIB). In some embodiments, the TNFRSF1B gene targeted by an RNA-guided nuclease is from a cat (fTNFRSFlB).

[0077] The terms “Lymphotoxin Beta Receptor” or “TNFRSF3” refer to the genes (NCBI Gene ID: 4055 [human], NCBI Gene ID: 486728 [canine], NCBI Gene ID: 100059650 [equine], NCBI Gene ID: 101081146 [feline]) or an encoded gene product (e.g., UniProt: P36941; NP 001257916.1 [human], XP_038295148.1 [canine], XP_001492220.3 [equine], XP_003988366.4 [feline]), as well as sequence variants, proteins harboring conservative amino acid substitutions, and glycoforms thereof. Canonically, the proteins encoded by the genes listed above play a role in signaling during the development of lymphoid and other organs, lipid metabolism, immune response, and programmed cell death. Major ligands of this receptor include lymphotoxin alpha / beta and tumor necrosis factor ligand superfamily member 14 (TNFSF14). Activity of this receptor has also been linked to carcinogenesis. See generally, Seymour, R., et al. (2006). Veterinary Pathology, 43(4), 401-423. In some instances, and merely for the sake of disambiguation, a prefix is added when referring to the protein or gene of a particular species (with h, c, e, and referring to the human, canine, equine, and feline forms, respectively).

[0078] In certain embodiments, any region of an TNFRSF3 gene (e.g., 5' untranslated region [UTR], exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, exon 11, exon 12, any intervening intronic regions, intron / exon junctions, the 3’ UTR, or polyadenylation signal) is targeted by an RNA-guided nuclease to alter the gene. In some embodiments, the TNFRSF3 gene targeted by an RNA-guided nuclease is from a mammal. In some embodiments, the TNFRSF3 gene targeted by an RNA-guided nuclease is from a human (hTNFRSF3). In some embodiments, the TNFRSF3 gene targeted by an RNA-guided nuclease is from a dog (cTNFRSF3). In some embodiments, the TNFRSF3 gene targeted byan RNA-guided nuclease is from a horse (eTNFRSF3). In some embodiments, the TNFRSF3 gene targeted by an RNA-guided nuclease is from a cat (fFNFRSF3).

[0079] The terms “0X40 Receptor,” “0X40,” “CD 134,” or “TNFRSF4” refer to the genes (NCBI Gene ID: 7293 [human], NCBI Gene ID: 489600 [canine], NCBI Gene ID: 100066167 [equine], NCBI Gene ID: 493665 [feline]) or an encoded gene product (e.g., UniProt: P43489; XP_011540377.1 [human], XP_038520220.1 [canine], XP_001503612.3 [equine], NP_001009200.1 [feline]), as well as sequence variants, proteins harboring conservative amino acid substitutions, and glycoforms thereof. Canonically, the proteins encoded by the genes listed above specifically bind to 0X40 ligand (OX40L) and are predominantly expressed on lymphocytes. The result of this binding is transient downstream intracellular signaling mediated via TRAF2 and other effector proteins that often occurs in response to the presence of antigen. See generally, Ward-Kavanagh, L. K., et al. (2016). Immunity, 44(5), 1005-1019. In some instances, and merely for the sake of disambiguation, a prefix is added when referring to the protein or gene of a particular species (with h, c, e, and f, referring to the human, canine, equine, and feline forms, respectively).

[0080] In certain embodiments, any region of an TNFRSF4 gene (e.g., 5' untranslated region [UTR], exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, any intervening intronic regions, intron / exon junctions, the 3’ UTR, or polyadenylation signal) is targeted by an RNA-guided nuclease to alter the gene. In some embodiments, the TNFRSF4 gene targeted by an RNA-guided nuclease is from a mammal. In some embodiments, the TNFRSF4 gene targeted by an RNA-guided nuclease is from a human (hTNFRSF4). In some embodiments, the TNFRSF4 gene targeted by an RNA-guided nuclease is from a dog (cTNFRSF4). In some embodiments, the TNFRSF4 gene targeted by an RNA-guided nuclease is from a horse (eTNFRSF4). In some embodiments, the TNFRSF4 gene targeted by an RNA-guided nuclease is from a cat (ITNFRSF4).

[0081] The terms “TNF Receptor Superfamily Member 11 A” or “TNFRSF11A” refer to the genes (NCBI Gene ID: 8792 [human], NCBI Gene ID: 483957 [canine], NCBI Gene ID: 100056617 [equine], NCBI Gene ID: 101090651 [feline]) or an encoded gene product (e.g., UniProt: Q9Y6Q6; NP_001257878.1 [human], XP_038509502.1 [canine], XP_023503703.1 [equine], XP_023096972.1 [feline]), as well as sequence variants, proteins harboring conservative amino acid substitutions, and glycoforms thereof. Canonically, the proteins encoded by the genes listed above are transmembrane proteins capable of interacting with n various TRAF family proteins, through which the receptors induce the activation of NF-kappa B and MAPK8 / JNK pathways. This receptor, with its ligand, is an important regulator of the interaction between T cells and dendritic cells and is also an essential mediator for bone metabolism and development. See generally, Xue, J. Y., et al. (2021). Journal of Bone and Mineral Metabolism, 39(1), 45-53. In some instances, and merely for the sake of disambiguation, a prefix is added when referring to the protein or gene of a particular species (with h, c, e, and referring to the human, canine, equine, and feline forms, respectively).

[0082] In certain embodiments, any region of an TNFRSF11 A gene (e.g., 5' untranslated region [UTR], exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, exon 11, exon 12, any intervening intronic regions, intron / exon junctions, the 3’ UTR, or polyadenylation signal) is targeted by an RNA-guided nuclease to alter the gene. In some embodiments, the TNFRSF11 A gene targeted by an RNA-guided nuclease is from a mammal. In some embodiments, the TNFRSF11 A gene targeted by an RNA-guided nuclease is from a human (hTNFRSFl 1A). In some embodiments, the TNFRSF11A gene targeted by an RNA-guided nuclease is from a dog (cTNFRSFl 1 A). In some embodiments, the TNFRSF11 A gene targeted by an RNA-guided nuclease is from a horse (eTNFRSFl 1 A). In some embodiments, the TNFRSF11 A gene targeted by an RNA-guided nuclease is from a cat (fTNFRSFUA).

[0083] The term “treatment” refers to obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. For example, a composition, method, or system of the present disclosure may be administered as a prophylactic treatment to a subject that has a predisposition for a given condition (e.g., arthritis). “Treatment”, as used herein, covers any treatment of a disease in a mammal, particularly in a human, canine, feline, or equine, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development or progression; and (c) relieving the disease, i.e., causing regression of the disease and / or relieving one or more disease symptoms.

[0084] “Treatment” is also meant to encompass delivery of an agent in order to provide for a pharmacologic effect, even in the absence of a disease or condition. For example, “treatment” encompasses delivery of a composition that can elicit an immune response or confer immunity in the absence of a disease condition, e.g., in the case of a vaccine. It isunderstood that compositions and methods of the present disclosure are applicable to treat all mammals, including, but not limited to human, canine, feline, equine, and bovine subjects.

[0085] The term “therapeutically effective” refers to the amount of a composition or combination of compositions as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, or the manner of administration. The term also applies to a dose that will induce a particular response in target cells (e.g, the reduction of platelet adhesion and / or cell migration). The specific dose will vary depending on the particular composition(s) chosen, the dosing regimen to be followed, whether the composition is administered in combination with other compositions or compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the composition is carried.

[0086] The term “joint disease” is defined as measurable abnormalities in the cells or tissues of the joint that could lead to illness, for example, metabolic and molecular derangements triggering anatomical and / or physiological changes in the joint. Including, but not limited to, radiographic detection of joint space narrowing, subchondral sclerosis, subchondral cysts, and osteophyte formation.

[0087] “Joint illness” is defined in human subjects as symptoms that drive the subject to seek medical intervention, for example, subject reported pain, stiffness, swelling, or immobility. For non-human mammals, “joint illness” is defined, for example, as lameness, observable changes in gait, weight bearing, allodynia, or exploratory behavior.

[0088] A “back or spine condition or disorder” includes, but is not limited to, low back pain, neck pain, discogenic disorders, adolescent idiopathic scoliosis, adult degenerative scoliosis, cervical degenerative disc disease, cervical disc herniation, cervical myelopathy, cervical stenosis, compression fractures, degenerative spondylolisthesis, isthmic spondylolisthesis, low back sprains and strains, lumbar degenerative disc disease, lumbar disc herniation, lumbar stenosis, neck sprain (whiplash) and strain, neck strain, osteoporosis, and whiplash. Generally, such disorders or conditions contribute to or cause localized nociception, inflammation, or morphological changes (e.g., fibrosis, degeneration, osteolysis, osteogenesis) at the cervical, thoracic, lumbar or sacral spine, or surrounding tissues.

[0089] “Low back pain” is defined as measurable or discernible pain or discomfort (either chronic or sporadic) in a given subject, encompassing at least the lumbar-spinal region of a mammal. The pain may present as being localized to the lower back (e.g., muscle ache) or as shooting, burning, stinging, and / or radiating sensations throughout the subject’s back and / or extremities. The pain may be idiopathic or may be associated with one or more (diagnosed or undiagnosed) underlying conditions including, but not limited to, chronic inflammation, arthritis, osteoporosis, trauma (e.g., post-surgical), neuropathies, musculo-skeletal abnormalities (e.g., slipped discs or spinal stenosis), herniated nucleus pulposus (HNP), annular ligament tears, facet joint arthritis, radicular nerve compression, and / or degenerative disorders.

[0090] “Neck pain” is defined as measurable or discernable pain or discomfort associated with the cervical spine or adjacent ligaments, muscles, and / or tendons. The pain may manifest as localized pain in the neck or shooting, stinging, burning, and / or radiating sensations throughout the back or extremities, including, but not limited to, the subject’s head, shoulders, arms, legs, and / or back. Neck pain may be idiopathic or associated with one or more (diagnosed or undiagnosed) underlying conditions, including, but not limited to, rheumatoid arthritis, osteoporosis, fibromyalgia, chronic inflammation, herniated disc, spondylosis, spinal stenosis, whiplash, and / or degenerative disorders.

[0091] The terms “polynucleotide,” “nucleotide,” and “nucleic acid” are used interchangeably herein to refer to all forms of nucleic acid, oligonucleotides, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Polynucleotides include genomic DNA, cDNA and antisense DNA, and spliced or unspliced mRNA, rRNA, tRNA, IncRNA, RNA antagomirs, and inhibitory DNA or RNA (RNAi, e.g., small or short hairpin (sh)RNA, microRNA (miRNA), aptamers, small or short interfering (si)RNA, trans-splicing RNA, or antisense RNA). Polynucleotides also include non-coding RNA, which include for example, but are not limited to, RNAi, miRNAs, IncRNAs, RNA antagomirs, aptamers, and any other non-coding RNAs known to those of skill in the art. Polynucleotides include naturally occurring, synthetic, and intentionally altered or modified polynucleotides as well as analogues and derivatives. The term “polynucleotide” also refers to a polymeric form of nucleotides of any length, including deoxyribonucleotides or ribonucleotides, or analogs thereof, and is synonymous with nucleic acid sequence. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs, and may be interrupted by non-nucleotide components. If present, modifications to the nucleotidestructure may be imparted before or after assembly of the polymer. The term polynucleotide, as used herein, refers interchangeably to double- and single-stranded molecules. Unless otherwise specified or required, any embodiment as described herein encompassing a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form. Polynucleotides can be single, double, or triplex, linear or circular, and can be of any length. In discussing polynucleotides, a sequence or structure of a particular polynucleotide may be described herein according to the convention of providing the sequence in the 5’ to 3’ direction.

[0092] The term “gene” or “nucleotide sequence encoding a polypeptide” refers to the segment of DNA involved in producing a polypeptide chain. The DNA segment may include regions preceding and following the coding region (leader and trailer) involved in the transcription / translation of the gene product and the regulation of the transcription / translation, as well as intervening sequences (introns) between individual coding segments (exons). For example, a gene includes a polynucleotide containing at least one open reading frame capable of encoding a particular protein or polypeptide after being transcribed and translated.

[0093] The terms “extracellular domain” and “ectodomain” may be used interchangeably and, when referring to transmembrane cellular receptors, is defined as the portion of the protein that is exposed to the extracellular environment and is able to engage with and / or bind a ligand.

[0094] The terms “cytoplasmic domain” and “intracellular domain” may be used interchangeably and, when referring to transmembrane receptors, define the portion of the protein that is exposed to the cytoplasm. In many instances, these portions of the proteins comprise signaling domains to recruit and associate with various intracellular factors. Following engagement with a ligand via the extracellular domain, the interaction effects changes that may result in new association, dissociation or recruitment of various cytoplasmic factors that aid in transducing a signal.

[0095] The term “transmembrane domain,” which may be abbreviated as “TM,” as it refers to transmembrane receptors, is defined as the portion of the protein is embedded within the plasma membrane (i.e., not exposed to either the extracellular environment or the cytosol). Transmembrane domains are generally of a more hydrophobic character than either theextracellular or cytoplasmic portions and often adopt higher order helical structures. Though its primary role is an anchor, ligand-induced conformational changes to particular receptors have been shown to impact the transmembrane domain such that it is integral to the subsequent intracellular signaling.

[0096] The term “receptor” refers to a protein capable of binding another cognate protein (i.e., its ligand) with high affinity. This receptor-ligand interaction may be 1:1, or result in multimerization, wherein numerous proteins aggregate to bind one or more ligands. Receptors are generally present at the cell surface, such that they may most efficiently encounter a ligand and initiate intracellular signaling.

[0097] The term “intracellular signaling” refers to cellular changes that result due to events occurring at the cell surface. Typically, a soluble ligand binds its receptor at the cell surface, which can induce changes in the receptor, such that associated intracellular factors are also affected. These factors may then impact others within the cell, and this cascade continues until, in many cases, a particular factor is able to alter gene expression in the nucleus in response to the stimulus at the surface.

[0098] The term “RNA-guided nuclease” refers to an enzyme capable of breaking the backbone of, for example, a DNA molecule. The activity of RNA-guided nucleases is directed by a nucleic acid molecule (i.e., guide RNA). Once properly oriented to form a functional ribonucleoprotein complex, the enzyme locates a specific position within a target nucleic acid (e.g., a gene or locus) via sequence complementarity with a portion of the guide RNA. Non-exhaustive examples of RNA-guided nucleases include Cas9, Casl2 and Casl2a (previously known as Cpfl).

[0099] The term “Cas9” refers to an RNA-guided, double-stranded DNA-binding nuclease protein or nickase protein, or a variant thereof and may be used to refer to either naturally- occurring or recombinant Cas9 nucleases variants (e.g., ES-Cas9, HF-Cas9, PE-Cas9, and AR-Cas9). The wildtype Cas9 nuclease has two functional domains, e.g., RuvC and HNH, that simultaneously cut both strands of double stranded DNA, resulting in a double-strand break. Cas9 enzymes described herein may comprise a HNH or HNH-like nuclease domain and / or a RuvC or RuvC-like nuclease domain without impacts on the ability to induce double-strand breaks in genomic DNA (e.g., at a target locus) when both functional domains are active. The Cas9 enzyme may comprise one or more catalytic domains of a Cas9 protein derived from bacteria belonging to the group consisting of Corynebacter , Sutter ella,Legionella, Treponema, Filifactor, Eubacterium, Streptococcus, Lactobacillus, Mycoplasma, Bacteroides, Flaviivola, Flavobacterium, Sphaerochaeta, Azospirillum, Gluconacetobacter , Neisseria, Roseburia, Parvibaculum, Staphylococcus, Nitratifractor , and Campylobacter. In some embodiments, the two catalytic domains are derived from different bacteria species.

[0100] As used herein, “PAM” refers to a Protospacer Adjacent Motif and is necessary for an RNA-guided nuclease to bind a target nucleic acid. In many instances, the PAM directly abuts the complementary sequence in the target. Naturally -occurring Cas9, for example, molecules recognize specific PAM sequences (see, e.g., Table 1). In some embodiments, a Cas9 molecule has the same PAM specificities as a naturally occurring Cas9 molecule. In other embodiments, a Cas9 molecule has a PAM specificity not associated with a naturally occurring Cas9 molecule. In other embodiments, a Cas9 molecule’s PAM specificity is not associated with the naturally occurring Cas9 molecule to which it has the closest sequence homology. For example, a naturally occurring Cas9 molecule can be altered such that the PAM sequence recognition is altered to decrease off target sites, improve specificity, or eliminate a PAM recognition requirement. In an embodiment, a Cas9 molecule may be altered (e.g., to lengthen a PAM recognition sequence, improve Cas9 specificity to high level of identity, to decrease off target sites, and / or increase specificity). In an embodiment, the length of the PAM recognition sequence is at least 4, 5, 6, 7, 8, 9, 10 or 15 amino acids in length. In some embodiments, a Cas9 molecule may be altered to ablate PAM recognition.

[0101] The terms “guide RNA,” “gRNA” or “sgRNA” may be used interchangeably and refer to an RNA molecule, preferably a synthetic RNA molecule, composed of a targeting (crRNA) sequence and scaffold. These molecules, once loaded onto a functional RNA- guided nuclease can direct sequence-specific cleavage of a target nucleic acid.

[0102] An sgRNA can be administered or formulated, e.g., as a synthetic RNA, or as a nucleic acid comprising a sequence encoding the gRNA, which is then expressed in the target cells. As would be evident to one of ordinary skill in the art, various tools may be used in the design and / or optimization of an sgRNA in order to, for example, increase specificity and / or precision of genomic editing at a particular site.

[0103] In general, candidate sgRNAs may be designed and identified by first locating suitable PAMs within a genomic sequence. Then additional calculations may be utilized to predict on-target and off-target efficiencies. Available web-based tools to aid in the initial design and modeling of candidate sgRNAs include, without limitation, CRISPRseek,CRISPR Design Tool, Cas-OFFinder, E-CRISP, ChopChop, CasOT, CRISPR direct, CRISPOR, BREAKING-CAS, CrispRGold, and CCTop. See, e g., Safari, F. et al. (2017). Current Pharmaceutical Biotechnology, 18(13): 1038-54, which is incorporated by reference herein in its entirety for all purposes. Such tools are also described, for example, in PCT Publication No. W02014093701A1 and Liu, G. et al. (2020). Computational approaches for effective CRISPR guide RNA design and evaluation. Computational and Structural Biotechnology Journal, 18: 35-44, each of which is incorporated by reference herein in its entirety for all purposes. Candidate sgRNAs may be further assessed by experimental screening or other methodologies.

[0104] The terms “CRISPR RNA” or “crRNA” refer to the portion of an sgRNA molecule with complementarity to the target nucleic acid.

[0105] The phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0106] The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the disclosure is contemplated. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the described compositions and methods.

[0107] The term “pharmaceutically acceptable excipient” is intended to include vehicles and carriers capable of being co-administered with a compound to facilitate the performance of its intended function. The use of such media for pharmaceutically active substances is well known in the art. Examples of such vehicles and carriers include solutions, solvents, dispersion media, delay agents, emulsions and the like. Any other conventional carriersuitable for use with the multi-binding compounds also falls within the scope of the present disclosure.

[0108] As used herein, the term “a”, “an”, or “the” generally is construed to cover both the singular and the plural forms.

[0109] The terms “about” and “approximately” mean within a statistically meaningful range of a value. Such a range can be within an order of magnitude, preferably within 50%, more preferably within 20%, more preferably still within 10%, and even more preferably within 5% of a given value or range. The allowable variation encompassed by the terms “about” or “approximately” depends on the particular system under study, and can be readily appreciated by one of ordinary skill in the art. Moreover, as used herein, the terms “about” and “approximately” mean that compositions, amounts, formulations, parameters, shapes and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, a dimension, size, formulation, parameter, shape or other quantity or characteristic is “about” or “approximate,” whether or not expressly stated to be such. It is noted that embodiments of very different sizes, shapes and dimensions may employ the described arrangements.

[0110] The term “substantially” as used herein can refer to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.

[0111] The transitional terms “comprising,” “consisting essentially of,” and “consisting of,” when used in the appended claims, in original and amended form, define the claim scope with respect to what unrecited additional claim elements or steps, if any, are excluded from the scope of the claim(s). The term “comprising” is intended to be inclusive or open-ended and does not exclude any additional, unrecited element, method, step or material. The term “consisting of’ excludes any element, step or material other than those specified in the claim and, in the latter instance, impurities ordinary associated with the specified material(s). The term “consisting essentially of’ limits the scope of a claim to the specified elements, steps or material(s) and those that do not materially affect the basic and novel characteristic(s) of the claimed methods and compositions. All compositions, methods, and kits described herein that embody the present disclosure can, in alternate embodiments, be more specificallydefined by any of the transitional terms “comprising,” “consisting essentially of,” and “consisting of.”III. MethodsA. CRISPR

[0112] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0113] In one aspect, the present disclosure encompasses compositions relating to clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated RNA- guided nucleases and associated methods, components, and compositions (hereafter, CRISPR / Cas systems). Such systems minimally require at least one isolated or non- naturally-occurring RNA-guided nuclease (e.g., a Cas9 protein) and at least one isolated or non-naturally-occurring guide RNA (e.g., an sgRNA) to effectuate augmentation of a nucleic acid sequence (e.g., genomic DNA).

[0114] In some embodiments, a CRISPR / Cas system effectuates the alteration of a targeted gene or locus in a eukaryotic cell by effecting an alteration of the sequence at a target position (e.g., by creating an insertion or deletion (collectively, an indel) resulting in loss-of- function of (i.e., knocking out) the affected gene or allele; e.g., a nucleotide substitution resulting in a truncation, nonsense mutation, or other type of loss-of-function of an encoded product of, for example, one or more IL1R1, IL1RAP, TGFBR1, TGFBR2, IL6R, IL6ST, TNFRSF1A, TNFRSF1B, TNFRSF3, TNFRSF4, or TNFRSF11A gene (i.e., mRNA or protein); a deletion of one or more nucleotides resulting in a truncation, nonsense mutation, or other type of loss-of-function of an encoded product of, for example, one or more IL1R1, IL1RAP, TGFBR1, TGFBR2, IL6R, IL6ST, TNFRSF1A, TNFRSF1B, TNFRSF3, TNFRSF4, or TNFRSF11A gene; e.g., loss-of-function of the encoded mRNA or protein by a single nucleotide, double nucleotide, or other frame-shifting deletion, or a deletion resulting in a premature stop codon; or an insertion resulting in a truncation, nonsense mutation, or other type of loss-of-function of an encoded gene product, such as an encoded gene productof, for example, one or more IL1R1, IL1RAP, TGFBR1, TGFBR2, IL6R, IL6ST, TNFRSF1A, TNFRSF1B, TNFRSF3, TNFRSF4, or TNFRSF11A gene (i.e., mRNA or protein); e.g., a single nucleotide, double nucleotide, or other frame-shifting insertions, or an insertion resulting in a premature stop codon. In some embodiments, a CRISPR / Cas system of the present disclosure provides for the alteration of a gene and / or encoded product of a gene, such that the altered product has a resultant loss-of-function and becomes a dominant negative or decoy (e.g., a transmembrane receptor incapable of initiating intracellular signaling or a soluble receptor).

[0115] In one aspect, CRISPR / Cas systems effectuate changes to the sequence of a nucleic acid through nuclease activity. For example, in the case of genomic DNA, the RNA-guided- nuclease locates a target position within a targeted gene or locus by sequence complementarity with the target genomic sequence (e.g., CRISPR RNA (crRNA) or a complementary component of a synthetic single guide RNA (sgRNA)) and cleaves the genomic DNA upon recognition of a particular, nuclease-specific motif called the protospacer adjacent motif (PAM). See generally, Collias, D., & Beisel, C. L. (2021). Nature Communications, 12(1), 1-12.

[0116] Nuclease activity (i.e., cleavage) induces a double-strand break (DSB) in the case of genomic DNA. Endogenous cellular mechanisms of DSB repair, namely non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous recombination, result in erroneous repair at a given target position with some calculable frequency as a result of interference from said components of the CRISPR / Cas system, thereby introducing substitutions or indels into the genomic DNA. See generally Scully, R., et al. (2019). Nature Reviews Molecular Cell Biology, 20(11), 698-714. At some frequency, these indels and / or substitutions may result in frameshifts, nonsense mutations (i.e., early stop codons) or truncations that impact the availability of gene products, such as mRNA and / or protein. In certain embodiments, the CRISPR / Cas system may induce a homology-directed repair (HDR) mechanism leading to insertions of non-random sequences at a target position through the use of templates (e.g., an HDR template) provided to the cell as part of the system along with the nuclease and gRNA. See Bloh, K., & Rivera-Torres, N. (2021). International Journal of Molecular Sciences, 22(8), 3834.

[0117] In general, the minimum requirements of the CRISPR / Cas system will be dependent upon the nuclease (i.e., Cas protein) provided therewith. To this extent, these bacterially-derived nucleases have been functionally divided into Types I, III, and V, which all fall into Class 1 and Types II, IV, and VI that are grouped into Class 2.

[0118] Class 1 CRISPR / Cas systems:

[0119] The exact components, compositions, and methods for effectuating a change in a targeted nucleic acid sequence using a Class 1 CRISPR / Cas system will vary, but should minimally include: a nuclease (selected from at least Types I, and III), at least one guide RNA selected from 1) sgRNA or 2) a combination of crRNA and tracrRNA. These CRISPR / Cas systems have been categorized together as Class 1 CRISPR / Cas systems due to their similarities in requirements and mode of action within a eukaryotic cell. To this end, compositions, components, and methods among Class 1 constituents may be considered functionally interchangeable, and the following details, provided merely for exemplary purposes, do not represent an exhaustive list of class members:

[0120] Cas3 (see Table 1) is the prototypical Type I DNA nuclease that functions as the effector protein as part of a larger complex (the Cascade complex comprising Csel, Cse2,), that is capable of genome editing. See generally He, L., et al. (2020). Genes, 11(2), 208. Unlike other CRISPR / Cas systems, Type I systems localize to the DNA target without the Cas3 nuclease via the Cascade complex, which then recruits Cas3 to cleave DNA upon binding and locating the 3’ PAM. The Cascade complex is also responsible for processing crRNAs such that they can be used to guide it to the target position. Because of this functionality, Cascade has the ability to process multiple arrayed crRNAs from a single molecule. See . Luo, M. (2015). Nucleic Acids Research, 43(1), 674-681. As such, Type I system may be used to edit multiple targeted genes or loci from a single molecule.

[0121] Because the natural Cas3 substrate is ssDNA, its function in genomic editing is thought to be as a nickase; however, when targeted in tandem, the resulting edit is a result of blunt end cuts to opposing strands to approximate a blunt-cutting endonuclease, such as Cas9. See Pickar-Oliver, A., & Gersbach, C. A. (2019). Nature Reviews Molecular Cell Biology, 20(8), 490-507.

[0122] Like Type I nucleases, the Type III system relies upon a complex of proteins to effect nucleic acid cleavage. Particularly, Casio possesses the nuclease activity to cleave ssDNA in prokaryotes. See Tamulaitis, G. Trends in Microbiology, 25(1), 49-61 (2017). Interestingly, this CRISPR / Cas system, native to archaea, exhibits dual specificity and targets both ssDNA and ssRNA. Aside from this change, the system functions much like Type I inthat the crRNA targets an effector complex (similar to Cascade) in a sequence-dependent manner. Similarly, the effector complex processes crRNAs prior to association. The dual nature of this nuclease makes its applications to genomic editing potentially more powerful, as both genomic DNA and, in some cases, mRNAs with the same sequence may be targeted to silence particular targeted genes.

[0123] Class 2 CRISPR / Cas systems:

[0124] The exact components, compositions, and methods for effectuating a change in a targeted nucleic acid sequence using a Class 2 CRISPR / Cas system will vary but should minimally include: a nuclease (selected from at least Types II, and V), at least one guide RNA selected from 1) sgRNA or 2) a combination of crRNA and tracrRNA. These CRISPR / Cas systems have been categorized together as Class 2 CRISPR / Cas systems due to their similarities in requirements and mode of action within a eukaryotic cell. To this end, compositions, components, and methods among Class 2 constituents may be considered functionally interchangeable, and the following details, provided merely for exemplary purposes, do not represent an exhaustive list of class members:

[0125] Type II nucleases are the best-characterized CRISPR / Cas systems, particularly the canonical genomic editing nuclease Cas9 (see Table 1). Multiple Cas9 proteins, derived from various bacterial species, have been isolated. The primary distinction between these nucleases is the PAM, a required recognition site within the targeted dsDNA. After association with a gRNA molecule, the crRNA (or targeting domain of a sgRNA) orients the nuclease at the proper position, but the protein’s recognition of the PAM is what induces a cleavage event near that site, resulting in a blunt DSB.

[0126] In addition to the naturally-derived Cas9 proteins, several engineered variants have similarly been reported. These range from Cas9 with enhanced specific (i.e., less off-target activity), such as espCas9. Others have been catalytically modified via point mutations in the RuvC (e.g., D10A) and HNH (e.g., H840A) domains such that they induce only single-strand breaks (i.e., Cas9 nickases). See Frock, R. et al. (2015). Nature Biotechnology, 33(2), 179- 186. These have also been shown to be less error-prone in editing. Such mitigation of off- target effects becomes paramount when selecting for a desired insertion (i.e., a knock in mutation, in which a desired nucleotide sequence is introduced into a target nucleic acid molecule) rather than a deletion. Indeed, less off-target effects may aid in the preferred DNArepair mechanism (HDR, in most instances for knock in mutations). See generally Naeem, M., et al. (2020). Cells, 9(7), 1608.

[0127] Additional exemplary further engineered variants of canonical Cas proteins (e.g., mutants, chimeras, and include the following (each of which are hereby incorporated by reference in their entireties for all purposes): WO2015035162A2, WO2019126716A1, WO2019126774A1, WO2014093694A1, WO2014150624A1, US20190225955 Al, US Pat. No. 11427818, US Pat. No. 11242542, US Pat. No. 11098297, US Pat. No. 10876100, US Pat. No. 10767193, US Pat. No. 10494621, and US Pat. No. 10100291.

[0128] For the avoidance of doubt, SpCas9 collectively refers to any one of the group consisting of espCas9 (also referred to herein as ES-Cas9 or esCas9), HF-Cas9, PE-Cas9, ARCas9 (also referred to as AR-Cas9).

[0129] Like the canonical Cas9 systems, Type V nucleases only require a synthetic sgRNA with a targeting domain complementary to a genomic sequence to carry out genomic editing. These nucleases contain a RuvC domain but lack the HNH domain of Type II nucleases. Further, Casl2, for example, leaves a staggered cut in the dsDNA substrate distal to the PAM, as compared to Cas9’s blunt cut next to the PAM. Both Casl2a, also known as Cpfl, and Casl2b, also known as C2cl (see Table 1), act as part of larger complex of two gRNA- associated nucleases that acts on dsDNA as a quaternary structure, nicking each strand simultaneously. See Zetsche, B. et al. (2015). Cell, 163(3):759-771; see also Liu, L. et al. (2017). Molecular Cell, 65(2):310-322. Additionally, Casl2b (C2cl) is a highly accurate nuclease with little tolerance for mismatches. See Yang, H. et al. (2016). Cell, 167(7): 1814- 1828. el2.

[0130] Table 1. Exemplary list of Cas nucleases and their requirements

[0131] See generally Wang, J., Zhang, C., & Feng, B. (2020). Journal of Cellular and Molecular Medicine, 24(6), 3256-3270, where N=any nucleotide; R=any purine (A or G); Y=any pyrimidine (C or T); W=A or T ; V=A, C or G.

[0132] In one aspect, the CRISPR / Cas system of the present disclosure comprises at least one RNA-guided nuclease (e.g. a Cas protein) derived from one or more of the following selected bacterial genera: Corynebacterium, Sutterella, Legionella, Treponema, Filifactor, Eubacterium, Streptococcus, Lactobacillus, Mycoplasma, Bacteroides, Flavobacterium, Spirochaeta, Azospirillum, Gluconacetobacter, Neisseria, Roseburia, Parvibaculum, Nitratifr actor, Campylobacter, Pseudomonas, Streptomyces, Staphylococcus, Francisella, Acidaminococcus, Lachnospiraceae, Leptotrichia, and Prevotella. In some embodiments, the Cas protein is derived from Deltaproteobacteria or Planctomycetes bacterial species.

[0133] Some aspects of the present disclosure provide strategies, methods, compositions, and treatment modalities for altering a targeted sequence within a gene locus (e.g., altering the sequence of wild type and / or of a mutant sequence within a cell or within a mammal) by insertion or deletion of one or more nucleotides mediated by an RNA-guided nuclease and one or more guide RNAs (gRNAs), resulting in loss of function of the targeted gene product. In some embodiments, the loss of function results in “knocking out” the gene of interest (i.e., generation of a “knock out”) by ablating gene expression. In some embodiments, the loss function results in anon-functional gene product (i.e., a gene product without all functionality of the wildtype gene product). In some embodiments, the loss of function results in expression of gene product with different characteristics (e.g., different binding affinity or different cellular localization).

[0134] In certain embodiments, the targeted gene is selected from IL1R1, IL 1 RAP, TGFBR1, TGFBR2, IL6R, IL6ST, TNFRSF1A, TNFRSF1B, TNFRSF3, TNFRSF4, TNFRSF11 A, and combinations thereof. In some embodiments, any region of the targeted gene (e.g., a promoter region, a 5’ untranslated region, a 3' untranslated region, an exon, an intron, or an exon / intron border) is targeted by an RNA-guided nuclease to alter the gene. Insome embodiments, a non-coding region of the targeted gene (e.g., an enhancer region, a promoter region, an intron, 5' UTR, 3' UTR, polyadenylation signal) is targeted to alter the gene.

[0135] CRISPR guide RNAs:

[0136] In one aspect, the CRISPR / Cas system of the present disclosure further provides a gRNA molecule (e.g., an isolated or non-naturally occurring RNA molecule) that interacts with the RNA-guided nuclease. In certain embodiments, the gRNA is an sgRNA comprising a crRNA sequence comprising a nucleotide sequence which is complementary to a sequence in a target nucleic acid. In some embodiments, the sgRNA further comprises an RNA scaffolding portion (i.e. tracrRNA) that interacts with the RNA-guided nuclease, such that the crRNA is positioned to scan a target nucleic acid for complementarity. In some embodiments, the system is further, optionally, comprised of an oligonucleotide — an HDR template with homology to either side of the target position. See Bloh, K., & Rivera-Torres, N. (2021). International Journal of Molecular Sciences, 22(8):3834.

[0137] In an embodiment, the RNA-guided nuclease and sgRNA are configured to orient an associated nuclease such that a cleavage event, (e.g., a double strand break or a single strand break) occurs sufficiently close to a complementary sequence in the targeted nucleic acid, thereby facilitating an alteration in the nucleic acid sequence. In some embodiments, the crRNA is 20 nucleotides in length. In some embodiments, the crRNA is 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length.

[0138] In some embodiments, the crRNA orients the RNA-guided nuclease such that a cleavage event occurs within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, or 200 nucleotides away from the complementary sequence in the targeted nucleic acid. The double- or single-strand break may be positioned upstream or downstream of the complementary sequence in the targeted nucleic acid. In some embodiments, the cleavage event occurs within a targeted gene. In some embodiments, the cleavage event occurs upstream of a targeted gene.

[0139] In certain embodiments, a second gRNA molecule, comprising a second crRNA orients a second RNA-guided nuclease, such that a cleavage event occurs sufficiently close to a complementary sequence in the targeted nucleic acid, thereby facilitating an alteration in the nucleic acid sequence. In some embodiments, the first gRNA and the second gRNA promote a cleavage event within a single targeted gene. In some embodiments, the firstgRNA and the second gRNA promote a cleavage event within different targeted genes. In some embodiments, the second crRNA is 20 nucleotides in length. In some embodiments, the second crRNA is 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length.

[0140] In some embodiments, the second crRNA orients the RNA-guided nuclease such that a cleavage event occurs within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, or 200 nucleotides away from the complementary sequence in the targeted nucleic acid. The double- or single-strand break may be positioned upstream or downstream of the complementary sequence in the targeted nucleic acid. In some embodiments, the cleavage event occurs within a targeted gene. In some embodiments, the cleavage event occurs upstream of a targeted gene.

[0141] In some embodiments, the targeting domains of the first gRNA and the second gRNA are configured such that a cleavage event is positioned, independently for each of the gRNA molecules, within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, or 200 nucleotides of the others cleavage event. In some embodiments, the first gRNA and the second gRNA molecules alter the targeted nucleic acid sequences simultaneously. In some embodiments, the first gRNA and the second gRNA molecules alter the targeted nucleic acid sequences sequentially.

[0142] In some embodiments, a single-strand break is accompanied by a second singlestrand break, positioned by the crRNA of a first gRNA and a second gRNA, respectively. For example, the crRNA may orient the associated RNA-guided nucleases such that a cleavage event, (e.g., the two single-strand breaks), are positioned within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, or 200 nucleotides of one another. In some embodiments, a first crRNA and a second crRNA are configured to orient associated RNA-guided nucleases such that, for example, two single-strand breaks occurs at the same position, or within 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 nucleotides of one another, on opposing strands of genomic DNA, thereby essentially approximating a double strand break.

[0143] In some embodiments, the nucleic acid encoding one or more crRNAs is selected from any of SEQ ID NOs: 680-1039. In some embodiments, the nucleic acid encoding one or more crRNAs target hILlRl and is selected from any of SEQ ID NOs: 680-824. In some embodiments, the nucleic acid encoding one or more crRNAs target cILlRl and is selectedfrom any of SEQ ID NOs: 825-892 and SEQ ID NOs: 3336-3420. In some embodiments, the nucleic acid encoding one or more crRNAs target elLlRl and is selected from any of SEQ ID NOs: 893-967. In some embodiments, the nucleic acid encoding one or more crRNAs target fILlRl and is selected from any of SEQ ID NOs: 968-1039.

[0144] In some embodiments, the nucleic acid encoding one or more crRNAs is selected from any of SEQ ID NOs: 1040-1424. In some embodiments, the nucleic acid encoding one or more crRNAs target hILlRAP and is selected from any of SEQ ID NOs: 1040-1203. In some embodiments, the nucleic acid encoding one or more crRNAs target cILlRAP and is selected from any of SEQ ID NOs: 1204-1271 and SEQ ID NOs: 3421-3490. In some embodiments, the nucleic acid encoding one or more crRNAs target elLlRAP and is selected from any of SEQ ID NOs: 1272-1348. In some embodiments, the nucleic acid encoding one or more crRNAs target fILlRAP and is selected from any of SEQ ID NOs: 1349-1424.

[0145] In some embodiments, the nucleic acid encoding one or more crRNAs is selected from any of SEQ ID NOs: 1425-1546. In some embodiments, the nucleic acid encoding one or more crRNAs target hTGFBRl and is selected from any of SEQ ID NOs: 1425-1546.

[0146] In some embodiments, the nucleic acid encoding one or more crRNAs is selected from any of SEQ ID NOs: 1547-1745. In some embodiments, the nucleic acid encoding one or more crRNAs target hTGFBR2 and is selected from any of SEQ ID NOs: 1547-1745.

[0147] In some embodiments, the nucleic acid encoding one or more crRNAs is selected from any of SEQ ID NOs: 1746-1968. In some embodiments, the nucleic acid encoding one or more crRNAs target hIL6R and is selected from any of SEQ ID NOs: 1746-1968.

[0148] In some embodiments, the nucleic acid encoding one or more crRNAs is selected from any of SEQ ID NOs: 1969-2178. In some embodiments, the nucleic acid encoding one or more crRNAs target hIL6ST and is selected from any of SEQ ID NOs: 1969-2178.

[0149] In some embodiments, the nucleic acid encoding one or more crRNAs is selected from any of SEQ ID NOs: 2179-2395. In some embodiments, the nucleic acid encoding one or more crRNAs target hTNFRSFlA and is selected from any of SEQ ID NOs: 2179-2395.

[0150] n some embodiments, the nucleic acid encoding one or more crRNAs is selected from any of SEQ ID NOs: 2396-2642. In some embodiments, the nucleic acid encoding one or more crRNAs target hTNFRSFIB and is selected from any of SEQ ID NOs: 2396-2642.

[0151] n some embodiments, the nucleic acid encoding one or more crRNAs is selected from any of SEQ ID NOs: 2643-2866. In some embodiments, the nucleic acid encoding one or more crRNAs target hTNFRSF3 and is selected from any of SEQ ID NOs: 2643-2866.

[0152] n some embodiments, the nucleic acid encoding one or more crRNAs is selected from any of SEQ ID NOs: 2867-3041. In some embodiments, the nucleic acid encoding one or more crRNAs target hTNFRSF4 and is selected from any of SEQ ID NOs: 2867-3041.

[0153] n some embodiments, the nucleic acid encoding one or more crRNAs is selected from any of SEQ ID NOs: 3042-3335. In some embodiments, the nucleic acid encoding one or more crRNAs target hTNFRSFl 1 A and is selected from any of SEQ ID NOs: 3042-3335.

[0154] In some embodiments a nucleic acid encodes a second sgRNA molecule. In some embodiments, a nucleic acid encodes a third sgRNA molecule. In some embodiments, a nucleic acid encodes a fourth sgRNA molecule.

[0155] In certain embodiments, a nucleic acid may comprise (a) a sequence encoding a first sgRNA, comprising a crRNA that is complementary with a sequence in a targeted gene, (b) a sequence encoding a second sgRNA, comprising a crRNA that is complementary with a sequence in a second targeted gene, and (c) a sequence encoding an RNA-guided nuclease(e.g., Cas9). Optionally, (d) and (e) are sequences encoding a third sgRNA and a fourth sgRNA, respectively. In some embodiments, the second targeted gene is the same as the first targeted gene. In other embodiments, the second targeted gene is different from the first targeted gene. In some embodiments, (a), (b), and (c) are encoded within the same nucleic acid molecule (e.g., the same vector). In some embodiments, (a) and (b) are encoded within the same nucleic acid molecule. In some embodiments, (a), (b) and (d) are encoded within the same nucleic acid molecule. In some embodiments, (a), (b) and (e) are encoded within the same nucleic acid molecule. In some embodiments, (a), (b), (d) and (e) are encoded within the same nucleic acid molecule. In some embodiments, (a), (b), and (c) are encoded within separate nucleic acid molecules. When more than two sgRNAs are used, any combination of (a), (b), (c), (d) and (e) may be encoded within a single or separate nucleic acid molecules.

[0156] In one aspect, the nucleic acid molecules (i.e. , those encoding (a), (b), (c), (d) or (e)) are delivered to a target cell (i.e., any combination of the encoded RNA-guided nuclease of (c) and at least one encoded gRNA molecule of (a), (b), (d), or (e) contact a target cell). In some embodiments, said nucleic acid molecules are delivered to a target cell in vivo. In otherembodiments, said nucleic acid molecules are delivered to a target cell ex vivo. In some embodiments, said nucleic acid molecules are delivered to a target cell in vitro. In certain embodiments, said nucleic acid molecules are delivered to a target cell as DNA. In other embodiments, said nucleic acid molecules are delivered to a target cell as RNA (e.g., mRNA). In some embodiments, the products of said nucleic acid molecules are delivered as an assembled ribonucleoprotein (RNP).

[0157] In some embodiments, contacting a target cell comprises delivering said RNA- guided nuclease of (c), as a protein with at least one said nucleic acid molecules selected from (a), (b), (d), and (e). In some embodiments, contacting a target cell comprises delivering said encoded RNA-guided nuclease of (c), as DNA with at least one said nucleic acid molecules selected from (a), (b), (d), and (e). In some embodiments, contacting a target cell comprises delivering said encoded RNA-guided nuclease of (c), as mRNA with at least one said nucleic acid molecules selected from (a), (b), (d), and (e).

[0158] In certain embodiments, CRISPR components are delivered to a target cell via nanoparticles. Exemplary nanoparticles that may be used with all CRISPR / Cas systems disclosed herein include, at least, lipid nanoparticles or liposomes, hydrogel nanoparticles, metalorganic nanoparticles, gold nanoparticles, magnetic nanoparticles and virus-like particles. See generally Xu, C. F. et al. (2021). Advanced Drug Delivery Reviews, 168:3-29.B. TALEN

[0159] In one aspect, the present disclosure contemplates use of methods, components, and compositions relating to Transcription Activator-Like Effector Nucleases (TALENs) to effectuate augmentation of a 'nucleic acid sequence (e.g., a targeted gene.

[0160] TALE stands for “Transcription Activator-Like Effector” proteins, which include TALENs (“Transcription Activator-Like Effector Nucleases”). A method of using a TALE system for gene editing may also be referred to herein as a TALE method. TALEs are naturally occurring proteins from the plant pathogenic bacteria genus Xanthomonas, and contain DNA-binding domains composed of a series of 33-35-amino-acid repeat domains that each recognizes a single base pair. TALE specificity is determined by two hypervariable amino acids that are known as the repeat-variable di-residues (RVDs). Modular TALE repeats are linked together to recognize contiguous DNA sequences. A specific RVD in the DNA-binding domain recognizes a base in the target locus, providing a structural feature to assemble predictable DNA-binding domains. The DNA binding domains of a TALE arefused to the catalytic domain of a type IIS FokI endonuclease to make a targetable TALE nuclease. To induce site-specific mutation, two individual TALEN arms, separated by a 14- 20 base pair spacer region, bring FokI monomers in close proximity to dimerize and produce a targeted double-strand break.

[0161] Several large, systematic studies utilizing various assembly methods have indicated that TALE repeats can be combined to recognize virtually any user-defined sequence. Custom-designed TALE arrays are also commercially available through Cellectis Bioresearch (Paris, France), Transposagen Biopharmaceuticals (Lexington, KY, USA), and Life Technologies (Grand Island, NY, USA). TALE and TALEN methods suitable for use in the present disclosure are described in U.S. Patent Application Publication Nos. US 2011 / 0201118 Al; US 2013 / 0117869 Al; US 2013 / 0315884 Al; US 2015 / 0203871 Al and US 2016 / 0120906 Al, the disclosures of which are incorporated by reference herein.

[0162] Non-limiting examples of genes that may be silenced or inhibited by permanently gene-editing via a TALE method include IL1R1, IL1RAP, TGFBR1, TGFBR2, IL6R, IL6ST, TNFRSF1A, TNFRSF1B, TNFRSF3, TNFRSF4, TNFRSF11A, and combinations thereof. Non-limiting examples of genes that may be augmented such that their resultant products function as decoys or dominant negatives by permanently gene-editing via a TALE method include IL1R1, IL 1 RAP, TGFBR1, TGFBR2, IL6R, IL6ST, TNFRSF1A, TNFRSF1B, TNFRSF3, TNFRSF4, TNFRSF11A, and combinations thereof. Non-limiting examples of genes that may be enhanced by permanently gene-editing via a TALE method include IL1R1, IL1RAP, TGFBR1, TGFBR2, IL6R, IL6ST, TNFRSF1A, TNFRSF1B, TNFRSF3, TNFRSF4, TNFRSF11A, and combinations thereof. In an aspect, the disclosure provides compositions for up-regulation of protein receptors (including wildtype or genetically edited), including those that bind to anti-inflammatory cytokines via a TALE method.

[0163] Examples of systems, methods, and compositions for altering the expression of a target gene sequence by a TALE method, and which may be used in accordance with embodiments of the present disclosure, are described in U.S. Patent No. 8,586,526, which is incorporated by reference herein.C. Zinc-finger nucleases (ZFN)In one aspect, the present disclosure contemplates use of methods, components, and compositions relating to zinc-finger nucleases (ZFNs) to effectuate augmentation of a 'nucleic acid sequence (e.g., a targeted gene).

[0164] An individual zinc finger contains approximately 30 amino acids in a conserved PPa configuration. Several amino acids on the surface of the a-helix typically contact 3 bp in the major groove of DNA, with varying levels of selectivity. Zinc fingers have two protein domains. The first domain is the DNA binding domain, which includes eukaryotic transcription factors and contain the zinc finger. The second domain is the nuclease domain, which includes the FokI restriction enzyme and is responsible for the catalytic cleavage of DNA.

[0165] The DNA-binding domains of individual ZFNs typically contain between three and six individual zinc finger repeats and can each recognize between 9 and 18 base pairs. If the zinc finger domains are specific for their intended target site then even a pair of 3 -finger ZFNs that recognize a total of 18 base pairs can, in theory, target a single locus in a mammalian genome. One method to generate new zinc-finger arrays is to combine smaller zinc-finger “modules” of known specificity. The most common modular assembly process involves combining three separate zinc fingers that can each recognize a 3 base pair DNA sequence to generate a 3-finger array that can recognize a 9 base pair target site. Alternatively, selection-based approaches, such as oligomerized pool engineering (OPEN) can be used to select for new zinc-finger arrays from randomized libraries that take into consideration context-dependent interactions between neighboring fingers. Engineered zinc fingers are available commercially; Sangamo Biosciences (Richmond, CA, USA) has developed a propriety platform (CompoZr®) for zinc-finger construction in partnership with Sigma- Aldrich (St. Louis, MO, USA).

[0166] Non-limiting examples of genes that may be silenced or inhibited by permanently gene-editing via a zinc finger method include IL1R1, IL1RAP, TGFBR1, TGFBR2, IL6R, IL6ST, TNFRSF1A, TNFRSF1B, TNFRSF3, TNFRSF4, TNFRSF11A, and combinations thereof. Non-limiting examples of genes that may be augmented such that their resultant products function as decoys or dominant negatives by permanently gene-editing via a zinc finger method include IL1R1, IL1RAP, TGFBR1, TGFBR2, IL6R, IL6ST, TNFRSF1A, TNFRSF1B, TNFRSF3, TNFRSF4, TNFRSF11A, and combinations thereof. Non-limiting examples of genes that may be enhanced by permanently gene-editing via a zinc finger method include IL1R1, IL1RAP, TGFBR1, TGFBR2, IL6R, IL6ST, TNFRSF1A, TNFRSF1B, TNFRSF3, TNFRSF4, TNFRSF11A, and combinations thereof. In an aspect, the disclosure provides compositions for up-regulation of protein receptors (including wildtype or genetically edited), including those that bind to anti-inflammatory cytokines via a zinc finger method.

[0167] Examples of systems, methods, and compositions for altering the expression of a target gene sequence by a zinc finger method, which may be used in accordance with embodiments of the present disclosure, are described in U.S. Patent Nos. 6,534,261, 6,607,882, 6,746,838, 6,794,136, 6,824,978, 6,866,997, 6,933,113, 6,979,539, 7,013,219, 7,030,215, 7,220,719, 7,241,573, 7,241,574, 7,585,849, 7,595,376, 6,903,185, and 6,479,626, which are incorporated by reference herein.

[0168] Other examples of systems, methods, and compositions for altering the expression of a target gene sequence by a zinc finger method, which may be used in accordance with embodiments of the present disclosure, are described in Beane, et al., Mol. Therapy, 2015, 23 1380-1390, the disclosure of which is incorporated by reference herein.IV. Joint Disease or IllnessA. Introduction

[0169] As described herein, embodiments of the present disclosure provide compositions and methods for improving joint function and treating joint disease. In particular embodiments, compositions and methods are provided to gene-edit synovial fibroblasts, synoviocytes, chondrocytes, tissue (resident) macrophages, or other cells to reduce pro- inflammatory signaling mediated by the binding of inflammatory cytokines — including, but not limited to, ILla, ILip, TNFa, IL6, IL8, IL18, IL33, matrix metalloproteinases (MMPs), TGFpi, TGFP2, and combinations thereof — to their cognate receptor(s). Some embodiments are used for treating various forms of arthritis and other inflammatory joint diseases. Some embodiments are further useful for treating canine lameness due to osteoarthritis. Some embodiments are further useful for treating equine lameness due to joint disease. Some embodiments are further useful for treating feline lameness due to joint disease. Some embodiments are also useful for treating post-traumatic arthritis, gout, pseudogout, psoriatic arthritis, and other inflammation-mediated or immune-mediated joint diseases.

[0170] Treatment of osteoarthritis, degenerative joint disease, and other joint dysfunctions is complex, and few long-term options exist for either symptomatic relief or restoring joint function. Osteoarthritis (OA) is the leading cause of disability due to pain. See, Neogi, T. (2013). Osteoarthritis Cartilage, 21(9): 1145-53. OA and similar diseases impact all mammal species, including working animals, domestic pets, and their owners. The common mechanistic thread among joint diseases is the presence of acute of chronic inflammation, which is driven by increased levels of pro-inflammatory cytokine signaling. Joint diseasestend to take a progressive course that encompasses discomfort, pain, and — especially in the case of OA — disability, depending on the degree of disease progression.

[0171] Psoriatic arthritis (PsA) is another chronic inflammatory joint disease, in which the joint symptoms are accompanied by skin lesions, such as those commonly associated with psoriasis. See, Boehncke, W. et al. (2014). British Journal of Dermatology, 170(4):772-786. Like other forms of arthritis, such as OA, PsA is caused by pro-inflammatory signaling of a host of cytokines, including ILL Indeed, PsA morbidity has been shown to correlate with single nucleotide polymorphisms (SNPs) that impact the activity of the IL1 gene locus. See, Rahman, P. et al. (2006). Arthritis and Rheumatism, 54(7):2321-2325. These studies also implicate inflammatory cytokine signaling, in general, and IL1 more specifically, in disease progression.

[0172] Gout is a chronic inflammatory condition that affects joints. The underlying cause is monosodium urate (MSU) crystal deposition and the resultant host response, particularly in joint structures (as well as subcutaneous tissues and other sites). See, Dalbeth, N., & Stamp, L. (2014). Annals of the Rheumatic Diseases, 73(9): 1598-1600. The clinical manifestations include recurrent acute flares of severe inflammatory arthritis and tendinobursitis. IL1 and other pro-inflammotory mediators are a major contributor to this host response. See, Dinarello, C. A. (2014). Molecular Medicine, 20(l):S43-S58. To this end, effective blockade of these signaling pathways may provide relief to gout patients.

[0173] The current standard of care for many joint disease patients includes antiinflammatory medications (e.g., NSAIDs) or anti-rheumatics (e.g., methotrexate [inhibitor of AICAR] or adalimumab [anti-TNF alpha monoclonal antibody]). See, Friedman, B., & Cronstein, B. (2019). Joint Bone Spine, 86(3):301-307. All of these treatments require repeated dosing for continued effectiveness, which may lead to toxicity issues or tolerance over time. As such, new methods and compositions to treat joint disease and illness are acutely needed to treat these chronic conditions.

[0174] In one aspect, the compositions and methods herein described are directed to treat joint disease or illness in a mammal in need thereof. In some embodiments, the joint disease or illness is osteoarthritis. In some embodiments, the joint disease or illness is psoriatic arthritis. In some embodiments, the joint disease or illness is gout.

[0175] Among the advantages of the present disclosure over treatments currently available for mammals afflicted with one or more joint disease or illness include the period of relieffrom symptoms. Upon genetic editing of a cell within a joint, pro-inflammatory signaling is silenced through the targeted gene for the life of that cell and any mitotic progeny. By contrast, biologic treatments require periodic dosing, which may magnify the impact of the host of potentially severe side effects. Among various genetic approaches, the present disclosure is also superior due to, among other reasons, a resistance to leakiness by virtue of modifying a protein receptor, rather than ablating expression of a ligand, which may result in compensatory effects (e.g., buildup of other factors due to lack of negative feedback).

[0176] In some embodiments, the present disclosure includes a method for the treatment or prevention of a joint disease or condition in a subject in need thereof, the method comprising administering, to a joint of the subject, a pharmaceutical composition comprising a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising (i) a CRISPR Associated (Cas) protein; and (ii) at least one guide RNA targeting an IL1R1 gene, IL1RAP gene, TGFBR1 gene, TGFBR2 gene, IL6R gene, IL6ST gene, TNFRSF1 A gene, TNFRSF1B gene, TNFRSF3 gene, TNFRSF4 gene, or TNFRSF11 A gene or a combination thereof. In some embodiments, the joint disease or condition is osteoarthritis. In some embodiments, the joint disease or condition is psoriatic arthritis. In some embodiments, the joint disease or condition is gout.

[0177] In some embodiments, the present disclosure includes a method for the treatment or prevention of an arthritis. Non-limiting examples of arthritis the can be treated using the compositions and methods described herein include post-tramatic arthritis, osteoarthritis (a degenerative condition that affects the joints, most commonly the hips, knees, and hands), rheumatoid arthritis (an autoimmune disorder that causes inflammation in the joints and surrounding tissue), psoriatic arthritis (a type of arthritis that occurs in people with psoriasis, a skin condition characterized by scaly red patches), gout (a type of arthritis caused by the buildup of uric acid crystals in the joints), lupus (a chronic autoimmune disorder that can cause inflammation and damage to the joints, as well as other organs), ankylosing spondylitis (a type of arthritis that primarily affects the spine, causing inflammation and stiffness), reactive arthritis (a type of arthritis that occurs as a reaction to an infection in the body), septic arthritis (a type of arthritis caused by an infection in the joint), juvenile idiopathic arthritis (a form of arthritis that affects children under the age of 16), and fibromyalgia (a chronic pain disorder that can cause widespread pain and stiffness, including in the joints).

[0178] In some embodiments, the present disclosure includes a method for the treatment or prevention of pseudogout, Crystal arthropathies (caused by the formation of crystals in the joints, such as gout and pseudogout), or CPPD disease (calcium pyrophosphate deposition disease) also called chondroclacinosis.

[0179] In some embodiments, the present disclosure includes a method for the treatment or prevention of rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, multiple sclerosis, Alzheimer's disease, Type 2 diabetes, cardiovascular disease, or cancer. In some embodiments, these disorders are treated by administering a CRISPR composition, as described herein, targeting an IL1 receptor, e.g., IL1R1 or IL1AP.B. Osteoarthritis

[0180] In one aspect, the present disclosure encompasses treatments for osteoarthritis (OA). In some embodiments, OA treatment comprises a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) a CRISPR Associated (Cas) protein; and (ii) at least one guide RNA targeting IL1R1. In some embodiments, the OA treatment comprises a CRISPR geneediting system targeting hILlRl. In some embodiments, the OA treatment comprises a CRISPR gene-editing system targeting cILlRl. In some embodiments, the OA treatment comprises a CRISP gene-editing system R targeting elLlRl. In some embodiments, the OA treatment comprises a CRISPR gene-editing system targeting fILlRl.

[0181] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of hILlRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OAcomprises one or more sgRNAs targeting exon 8 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of hILlRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 14 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 15 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 16 of hILlRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 17 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 18 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 19 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 20 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 21 of hILlRl.

[0182] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of cILlRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 7 ofcILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of cILlRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 14 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 15 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 16 of cILlRl.

[0183] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of elLlRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of elLlRl. In some embodiments, the CRISPR gene-editingsystem for the treatment of OA comprises one or more sgRNAs targeting exon 12 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of elLlRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 14 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 15 of elLlRl.

[0184] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of ULI Rl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of fILlRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of fILlRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 14 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 15 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 16 of ULI Rl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 17 of fILlRl. In someembodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 18 of fILlRl.

[0185] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting IL 1 RAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting fILlRAP.

[0186] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of hILlRAP. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of hILlRAP. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 14 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 15 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 16 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 17 of hILlRAP.

[0187] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 14 of cILlRAP. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 15 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 16 of cILlRAP.

[0188] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of elLlRAP. In some embodiments, theCRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of elLlRAP.

[0189] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of ULI RAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of HL 1 RAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAstargeting exon 9 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of fILlRAP. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of HL 1 RAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 14 of fILlRAP.

[0190] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting TGFBR1. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting e TGFBR1. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting fTGFBRl.

[0191] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of hTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of hTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 10 ofhTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of hTGFBRl.

[0192] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of cTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of cTGFBRl.

[0193] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of eTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of eTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 10 ofeTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of eTGFBRl.

[0194] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of fTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of fTGFBRl . In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of fTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of fTGFBRl . In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of fTGFBRl.

[0195] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting TGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting fTGFBR2.

[0196] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAstargeting exon 2 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of hTGFBR2. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of hTGFBR2.

[0197] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of cTGFBR2. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of CTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of cTGFBR2.

[0198] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of eTGFBR2. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 ofeTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of eTGFBR2. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of eTGFBR2.

[0199] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of ITGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of ITGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of ITGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of ITGFBR2. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of ITGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of ITGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of ITGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of ITGFBR2.

[0200] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting IL6R. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting fIL6R.

[0201] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAstargeting exon 2 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of hIL6R. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of hIL6R In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of hIL6R. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 14 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 15 of hIL6R.

[0202] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of cIL6R. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OAcomprises one or more sgRNAs targeting exon 8 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of cIL6R.

[0203] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of eIL6R. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of eIL6R.

[0204] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one ormore sgRNAs targeting exon 4 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of fIL6R.

[0205] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting IL6ST. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting fIL6ST.

[0206] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of hIL6ST. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of hIL6ST. In some embodiments, the CRISPR gene-editing system for thetreatment of OA comprises one or more sgRNAs targeting exon 10 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 14 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 15 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 16 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 17 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 18 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 19 of hIL6ST.

[0207] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of cIL6ST. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of cIL6ST In some embodiments, the CRISPR gene-editingsystem for the treatment of OA comprises one or more sgRNAs targeting exon 12 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of cIL6ST. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 14 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 15 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 16 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 17 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 18 of cIL6ST.

[0208] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of eIL6ST. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of eIL6ST In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of eIL6ST. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 14 ofeIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 15 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 16 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 17 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 18 of eIL6ST.

[0209] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of fIL6ST. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of fIL6ST In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of fIL6ST. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 14 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 15 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 16 of fIL6ST. In some embodiments, the CRISPR gene-editing system for thetreatment of OA comprises one or more sgRNAs targeting exon 17 of HL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 18 of HL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 19 of HL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 20 of HL6ST.

[0210] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting TNFRSF1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting hTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting cTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting eTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting fTNFRSFlA.

[0211] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of hTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of hTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of hTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of hTNFRSFl A. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of hTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of hTNFRSFlA. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of hTNFRSFl A. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of hTNFRSFlA.

[0212] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of cTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of cTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of cTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of cTNFRSFlA. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of cTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of cTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of cTNFRSFlA. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of cTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of cTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of cTNFRSFlA. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of cTNFRSFlA.

[0213] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of eTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of eTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of eTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of eTNFRSFlA. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of eTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of eTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of eTNFRSFlA. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of eTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment ofOA comprises one or more sgRNAs targeting exon 9 of eTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of eTNFRSFlA.

[0214] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of ITNFRSF1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of fTNFRSFl A. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of fTNFRSFl A. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of fTNFRSFl A.

[0215] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting TNFRSF1B. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting fTNFRSFIB.

[0216] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of hTNFRSFIB. Insome embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of hTNFRSFIB. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of hTNFRSFIB. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of hTNFRSFIB. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of hTNFRSFIB In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 13 of hTNFRSFIB.

[0217] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of cTNFRSFIB. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of cTNFRSFIB. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one ormore sgRNAs targeting exon 10 of cTNFRSFIB. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of cTNFRSFIB.

[0218] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of eTNFRSFIB. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of eTNFRSFIB. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of eTNFRSFIB. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of eTNFRSFIB.

[0219] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of fTNFRSFlB. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAstargeting exon 7 of fTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of fTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of fTNFRSFIB. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of fTNFRSFIB.

[0220] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting TNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting fTNFRSF3.

[0221] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of hTNFRSF3. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of hTNFRSF3. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of hTNFRSF3. In some embodiments,the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of hTNFRSF3.

[0222] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of cTNFRSF3. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of CTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of cTNFRSF3. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of CTNFRSF3.

[0223] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of eTNFRSF3. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises oneor more sgRNAs targeting exon 9 of eTNFRSF3. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of eTNFRSF3.

[0224] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of fTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of ITNFRSF3. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of ITNFRSF3. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of fFNFRSF3.

[0225] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting TNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting hTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting ITNFRSF4.

[0226] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of hTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of hTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of hTNFRSF4. Insome embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of hTNFRSF4. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of hTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of hTNFRSF4.

[0227] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of cTNFRSF4. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of CTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of cTNFRSF4.

[0228] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of eTNFRSF4. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of eTNFRSF4.

[0229] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of ITNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of ITNFRSF4. In some embodiments, the CRISPR gene-editing system forthe treatment of OA comprises one or more sgRNAs targeting exon 3 of fTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of fFNFRSF4. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of ITNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of ITNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of ITNFRSF4.

[0230] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting TNFRSF11A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting eTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting fTNFRSFUA.

[0231] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of hTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of hTNFRSFl 1A. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of hTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of hTNFRSFl 1A. In some embodiments, the CRISPRgene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of hTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 12 of hTNFRSFl 1 A.

[0232] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of cTNFRSFUA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of cTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of cTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of cTNFRSFl 1 A. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of cTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of cTNFRSFl 1 A. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of cTNFRSFl 1 A.

[0233] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of eTNFRSFUA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of eTNFRSFUA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of eTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of eTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of eTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of eTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one ormore sgRNAs targeting exon 7 of eTNFRSFl 1 A. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of eTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of eTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of eTNFRSFl 1 A.

[0234] In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 1 of fTNFRSFUA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 2 of fTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 3 of fTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 4 of fTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 5 of fTNFRSFUA. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 6 of fTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 7 of fTNFRSFl 1A. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 8 of fTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 9 of fTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of OA comprises one or more sgRNAs targeting exon 10 of fTNFRSFUA. In some embodiments, the CRISPR geneediting system for the treatment of OA comprises one or more sgRNAs targeting exon 11 of fTNFRSFUA.C. Psoriatic arthritis

[0235] In one aspect, the present disclosure encompasses treatments for psoriatic arthritis (PsA). In some embodiments, the psoriatic arthritis treatment comprises a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) a CRISPR Associated (Cas) protein; and (ii) at least one guide RNA targeting IL1R1. In some embodiments, the psoriatic arthritis treatment comprises a CRISPR gene-editing system targeting hILlRl . In someembodiments, the psoriatic arthritis treatment comprises a CRISPR gene-editing system targeting cILlRl. In some embodiments, the psoriatic arthritis treatment comprises a CRISP gene-editing system R targeting elLlRl . In some embodiments, the psoriatic arthritis treatment comprises a CRISPR gene-editing system targeting fILlRl.

[0236] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 15 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 16 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment ofpsoriatic arthritis comprises one or more sgRNAs targeting exon 17 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 18 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 19 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 20 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 21 of hILlRl.

[0237] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of cILlRl. In some embodiments, theCRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 15 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 16 of cILlRl.

[0238] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 15 of elLlRl.

[0239] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of fILlRl. In someembodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 15 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 16 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 17 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 18 of fILlRl.

[0240] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting IL1RAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one ormore sgRNAs targeting hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting fILlRAP.

[0241] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 15 of hILlRAP. In some embodiments, the CRISPR gene-editingsystem for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 16 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 17 of hILlRAP.

[0242] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 15 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 16 of cILlRAP.

[0243] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of elLlRAP.

[0244] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of HL 1 RAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritiscomprises one or more sgRNAs targeting exon 6 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of HL 1 RAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of HL 1 RAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of HL 1 RAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of HL 1 RAP. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of fILlRAP.

[0245] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting TGFBR1. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting e TGFBR1. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting fTGFBRl.

[0246] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of hTGFBRl. In someembodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of hTGFBRl . In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of hTGFBRl.

[0247] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of cTGFBRl.

[0248] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of eTGFBRl. In some embodiments, the CRISPR gene-editingsystem for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of eTGFBRl.

[0249] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of fTGFBRl . In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritiscomprises one or more sgRNAs targeting exon 10 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of fTGFBRl .

[0250] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting TGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting fTGFBR2.

[0251] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of hTGFBR2.

[0252] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or moresgRNAs targeting exon 3 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of cTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of CTGFBR2.

[0253] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of eTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of eTGFBR2.

[0254] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of ITGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of ITGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or moresgRNAs targeting exon 3 of fTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of fTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of ITGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of ITGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of ITGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 offFGFBR2.

[0255] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting IL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting eIL6R. In some embodiments, the CRISPR geneediting system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting fIL6R.

[0256] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of hIL6R. In someembodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of hIL6R In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of hIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 15 of hIL6R.

[0257] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment ofpsoriatic arthritis comprises one or more sgRNAs targeting exon 12 of cIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of cIL6R.

[0258] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of eIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of eIL6R.

[0259] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one ormore sgRNAs targeting exon 6 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of fIL6R. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of fIL6R.

[0260] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting IL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting eIL6ST. In some embodiments, the CRISPR geneediting system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting fIL6ST.

[0261] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of hIL6ST. In someembodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 15 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 16 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 17 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 18 of hIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 19 of hIL6ST.

[0262] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment ofpsoriatic arthritis comprises one or more sgRNAs targeting exon 9 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of cIL6ST In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 15 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 16 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 17 of cIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 18 of cIL6ST.

[0263] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of eIL6ST. In someembodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of eIL6ST In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 15 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 16 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 17 of eIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 18 of eIL6ST.

[0264] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of IIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of IIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of IIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of IIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of IIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of IIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of IIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritiscomprises one or more sgRNAs targeting exon 10 of HL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of HL6ST In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of HL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 14 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 15 of IIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 16 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 17 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 18 of fIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 19 of IIL6ST. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 20 offIL6ST.

[0265] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting TNFRSF1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting cTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting eTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting fTNFRSFl A.

[0266] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or moresgRNAs targeting exon 3 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of hTNFRSFlA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of hTNFRSFlA.

[0267] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of cTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of cTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of cTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of cTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of cTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of cTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of cTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of cTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of cTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of cTNFRSFl A. In some embodiments,the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of cTNFRSFlA.

[0268] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of eTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of eTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of eTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of eTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of eTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of eTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of eTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of eTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of eTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of eTNFRSFlA.

[0269] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of ITNFRSF1A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of fTNFRSFlA. In some embodiments, the CRISPR gene-editingsystem for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of fTNFRSFl A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of fTNFRSFlA.

[0270] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting TNFRSF1B. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting ITNFRSF1B.

[0271] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one ormore sgRNAs targeting exon 11 of hTNFRSFIB In some embodiments, the CRISPR geneediting system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of hTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 13 of hTNFRSFIB.

[0272] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of cTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of cTNFRSFIB.

[0273] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment ofpsoriatic arthritis comprises one or more sgRNAs targeting exon 5 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of eTNFRSFIB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of eTNFRSFIB.

[0274] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of ITNFRSF1B. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of fTNFRSFlB. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of fTNFRSFlB.

[0275] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting TNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritiscomprises one or more sgRNAs targeting hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting ITNFRSF3.

[0276] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of hTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of hTNFRSF3.

[0277] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or moresgRNAs targeting exon 3 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of cTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of cTNFRSF3.

[0278] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of eTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of eTNFRSF3.

[0279] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of ITNFRSF3. In someembodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of fTNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of ITNFRSF3. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of ITNFRSF3.

[0280] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting TNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting hTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting ITNFRSF4.

[0281] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of hTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of hTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of hTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of hTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment ofpsoriatic arthritis comprises one or more sgRNAs targeting exon 5 of hTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of hTNFRSF4.

[0282] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of cTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of cTNFRSF4.

[0283] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of eTNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of eTNFRSF4.

[0284] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of ITNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of ITNFRSF4. In some embodiments, theCRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of 1TNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of fFNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of ITNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of ITNFRSF4. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of ITNFRSF4.

[0285] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting TNFRSF11 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting eTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting fTNFRSFl 1 A.

[0286] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of hTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of hTNFRSFl 1A. In some embodiments, the CRISPR geneediting system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of hTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of hTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 ofhTNFRSFUA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 12 of hTNFRSFl 1 A.

[0287] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of cTNFRSFl 1 A. In some embodiments, the CRISPR geneediting system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of cTNFRSFUA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of cTNFRSFl 1 A. In some embodiments, the CRISPR geneediting system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of cTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of cTNFRSFl 1 A.

[0288] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of eTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of eTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of eTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of eTNFRSFUA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of eTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of eTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of eTNFRSFUA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of eTNFRSFl 1 A. In some embodiments, the CRISPR geneediting system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of eTNFRSFUA. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of eTNFRSFUA.

[0289] In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 1 of fTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 2 of fTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 3 of fTNFRSFl 1A. In some embodiments, the CRISPR geneediting system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 4 of fTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 5 of fTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 6 of fTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 7 of fTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 8 of fTNFRSFl 1A. In some embodiments, the CRISPR geneediting system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 9 of fTNFRSFl 1 A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 10 of fTNFRSFl 1A. In some embodiments, the CRISPR gene-editing system for the treatment of psoriatic arthritis comprises one or more sgRNAs targeting exon 11 of fTNFRSFl 1 A.D. Gout

[0290] In one aspect, the present disclosure encompasses treatments for gout and other crystallopathies affecting the joint, e.g., octacalcium phosphate and calcium pyrophosphate dihydrate in horses. In some embodiments, the gout treatment comprises a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) a CRISPR Associated (Cas) protein; and (ii) at least one guide RNA targeting IL1R1. In some embodiments, the gout treatment comprises a CRISPR gene-editing system targeting hILlRl. In some embodiments, the gout treatment comprises a CRISPR gene-editing system targeting cILlRl. In some embodiments, the gout treatment comprises a CRISP gene-editing system R targeting elLlRl. In some embodiments, the gout treatment comprises a CRISPR gene-editing system targeting fILlRl.

[0291] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 2 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of hILlRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 10 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 11 of hILlRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 12 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 13 of hILlRl. In some embodiments, theCRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 14 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 15 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 16 of hILlRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 17 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 18 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 19 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 20 of hILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 21 of hILlRl.

[0292] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 2 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of cILlRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 10 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 11 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 12 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of goutcomprises one or more sgRNAs targeting exon 13 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 14 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 15 of cILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 16 of cILlRl.

[0293] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 2 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of elLlRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 10 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 11 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 12 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 13 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 14 of elLlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 15 of elLlRl.

[0294] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAstargeting exon 2 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of ULI Rl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of fILlRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 10 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 11 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 12 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 13 of fILlRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 14 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 15 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 16 of ULI Rl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 17 of fILlRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 18 of fILlRl.

[0295] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting IL 1 RAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targetingelLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting fILlRAP.

[0296] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 2 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of hILlRAP. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of hILlRAP. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 10 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 11 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 12 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 13 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 14 of hILlRAP. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 15 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 16 of hILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 17 of hILlRAP.

[0297] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAstargeting exon 2 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 10 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 11 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 12 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 13 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 14 of cILlRAP. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 15 of cILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 16 of cILlRAP.

[0298] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 2 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of elLlRAP. In some embodiments, theCRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 10 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 11 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 12 of elLlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 13 of elLlRAP.

[0299] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 2 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of ULI RAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of ULI RAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of ULI RAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 10 of ULI RAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 11 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 12 of fILlRAP. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 13 of fILlRAP. Insome embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 14 of fILlRAP.

[0300] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting TGFBR1. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting e TGFBR1. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting fTGFBRl.

[0301] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 2 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of hTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of hTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 10 of hTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 11 of hTGFBRl.

[0302] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 2 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of cTGFBRl. In someIl lembodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of cTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of cTGFBRl . In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of cTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of cTGFBRl.

[0303] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 2 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of eTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of eTGFBRl . In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of eTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 10 of eTGFBRl . In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 11 of eTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 12 of eTGFBRl.

[0304] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 1 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAstargeting exon 2 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 3 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 4 of fTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 5 of fTGFBRl . In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 6 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 7 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 8 of fTGFBRl. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 9 of fTGFBRl. In some embodiments, the CRISPR geneediting system for the treatment of gout comprises one or more sgRNAs targeting exon 10 of fTGFBRl . In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting exon 11 of fTGFBRl.

[0305] In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting TGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting hTGFBR2. In some embodiments, the CRISPR gene-editing system for the treatment of gout comprises one or more sgRNAs targeting cTGFBR2. In some embodim...

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition for treating a disorder having a symptom caused, at least in part, by intercellular signaling mediated through a transmembrane receptor, the composition comprising:(i) an RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease; and(ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

2. The pharmaceutical composition of claim 1, wherein the disorder is a musculoskeletal disorder.

3. The pharmaceutical composition of claim 2, wherein the musculoskeletal disorder is selected from the group consisting of Rheumatoid Arthritis, Gout, Osteoarthritis, Osteoporosis, Intervertebral disc disease (IVDD), Psoriatic arthritis (PsA), Arthritis, Polymyositis, Proliferative synovitis, Malignant bone neoplasm, Sarcoid Myopathy, Cortex Bone Disorders, Idiopathic Scoliosis, Tendinopathy, Myofibrillar Myopathy, Enthesis- Related Arthritis, Ankylosing spondylitis, Degenerative, polyarthritis, Arthropathy, Osteitis Deformans, Prolapsed Lumbar Disc, Polymyositis Ossificans, Idiopathic Polymyositis, Luft Disease, Adult-onset Still's Disease, Osteoarthrosis Deformans, and Bachet’s Disease.

4. The pharmaceutical composition of claim 2, wherein the musculoskeletal disorder is selected from the group consisting of Rheumatoid arthritis, Idiopathic osteoporosis, Postmenopausal osteoporosis, Paget's disease, Osteoarthritis, Juvenile idiopathic arthritis (JIA), Still's disease, Ankylosing spondylitis, Polymyalgia rheumatica, Arthritis, Secondary malignant neoplasm of bone, Type II, Mucolipidosis, Sjogren's Syndrome, Psoriatic arthritis, Rheumatism, Castleman’s disease, Degenerative Polyarthritis, Arthropathy, Bone neoplasm, Osteoporosis, Massive osteolysis, Bone fracture healing, Systemic sclerosis, Systemic Juvenile Idiopathic, Arthritis, and Synovitis.

5. The pharmaceutical composition of claim 2, wherein the musculoskeletal disorder is selected from the group consisting of Arthritis, Infectious Intermittent joint effusion, Ankylosing spondylitis, Arthritis, Osteoarthritis, Spondylarthritis, Plantar fasciitis, Degenerative polyarthritis, Hemophilic arthropathy, Inflammatory myopathy with abundantmacrophages, Polymyositis, Tendinosis, Malignant Bone Neoplasm, Osteoporosis, Psoriatic arthritis, Rheumatism, Rheumatoid arthritis, Adult Still's disease, Juvenile arthritis, Early rheumatoid arthritis, Palindromic rheumatism, Gout, Infectious Arthritis, Myotonic dystrophy, Dermatomyositis, Hemophilic arthropathy, Osteopenia, Sjogren's syndrome, Juvenile Idiopathic Arthritis, Myasthenia gravis, Osteolysis, Inflammation, Degenerative polyarthritis, Osteitis deformans, Pigmented villonodular synovitis, or Hyperphosphatasemia with bone disease.

6. The pharmaceutical composition of claim 2, wherein the musculoskeletal disorder is selected from the group consisting of Loeys-Dietz Syndrome, Osteoarthrosis, Marfan Syndrome, Aortic aneurysm (familial thoracic 3), and a Craniofacial abnormality.

7. The pharmaceutical composition of claim 1, wherein the disorder is a neoplasia.

8. The pharmaceutical composition of claim 7, wherein the neoplasia is selected from the group consisting of Osteosarcoma, Colon Cancer, Metastasis (General), Lung Cancer, Multiple Myeloma. Breast Cancer, Solid Tumors, Lymphoma, Pancreatic Cancer, Stomach Cancer, Epithelial Ovarian Cancer, Mammary Neoplasms, Oropharyngeal Carcinoma, Renal Cell Carcinoma, Chondrosarcoma, Esophageal Neoplasms, B-Cell Lymphoma, Cutaneous Lymphoma T-Cell, Leukemia, Thyroid Carcinoma, Skin carcinogenesis, Cholectoral Cancer, Glioma, Liver Cancer, Melanoma, Neuroblastoma, Polycystic Ovary Syndrome, Glioblastoma, Prostate Cancer, Cervical Cancer, Ovarian Cancer, Bladder Cancer, Squamous cell carcinoma, Kaposi Sarcoma, Oral Cavity Cancer, Leiomyosarcoma, Malignant Peripheral Nerve Sheath Tumor, and Ewing's Sarcoma.

9. The pharmaceutical composition of claim 7, wherein the neoplasia is selected from the group consisting of Multiple myeloma, Lung Cancer, Stomach Cancer, Breast Cancer, Kidney Cancer, Neoplasm Metastasis, Colorectal Neoplasms, Ovarian cancer, Osteosarcoma, Cholangiocarcinoma, Leukemia, Prostate cancer, Plasmacytoma, Pancreatic cancer, Cervical cancer, Lymphoma, Liver neoplasms, Neuroblastoma, Melanoma, Mastocytosis, Endometrial cancer, Bladder Cancer, Squamous cell carcinoma, Gallbladder carcinoma, Adenocarcinoma, Thyroid Cancer, prostate neoplasms, stomach cancer, liver carcinoma, pituitary neoplasms, hepatoblastoma, multiple myeloma, hepatocellular adenoma, breast carcinoma, carcinogenesis, leukemia, colon carcinoma, melanoma, metastasis (general), lung cancer,pancreatic cancer, Kaposi sarcoma, medulloblastoma, carcinoma of bladder, squamous cell carcinoma, mast cell neoplasm, glioma, mastocytoma, brain neoplasms, ovarian neoplasms, bone neoplasm, rhabdomyosarcoma, solid tumors, metastatic kidney cancer, and metastatic renal cell carcinoma10. The pharmaceutical composition of claim 7, wherein the neoplasia is selected from the group consisting of a Neoplasm, Glioblastoma, Astrocytoma, Adenocarcinoma, Osteosarcoma, Squamous cell carcinoma, Metastasis, Ameloblastoma, Cholangiocarcinoma, Choriocarcinoma, Ovarian cancer, Prostate cancer, Lung Cancer, Larynx Cancer, Breast Cancer, Lip and Oral Cavity Carcinoma, Squamous intraepithelial lesion, Neuroblastoma, Non-Hodgkin lymphomas, Malignant Neoplasms, Skin Neoplasms, Neuroblastoma, Neoplasm Metastasis, Colorectal Cancer, Fibrosarcoma, Myeloid Leukemia, Myelofibrosis, Hodgkin Lymphomas, Non-Small Cell Lung Carcinoma, Cervical Cancer, Liver cancer, Extrapulmonary small cell carcinoma, Basal cell carcinoma, Kidney cancer, Pancreatic carcinoma, Mesothelioma, Gastric cancer, Polycystic Ovary Syndrome, Chordoma, Cholangiocarcinoma, Malignant ascites, Nasopharyngeal carcinoma, Head and Neck Carcinoma, Cancer metastasis, Prostate carcinoma, Fibrosarcoma, Liver carcinoma, Carcinoma of bladder, T-Cell Lymphoblastic Leukemia, Bladder Neoplasm, melanoma, Leukemia, acute myeloid leukemia, Hepatocellular carcinoma, Colorectal cancer, a Lymphoma, Mycosis fungoides, and Sezary syndrome.

11. The pharmaceutical composition of claim 7, wherein the neoplasia is selected from the group consisting of Pancreatic cancer, Multiple self-healing squamous epithelioma (Ferguson-Smith disease), Pancreatic cancer, Gastrointestinal Stromal Tumors (GIST), Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome), Metastasis, Colorectal Carcinoma, Bone neoplasms, Anaplastic carcinoma, Spindle-Cell carcinoma, Malignant Bone Neoplasm, Lung neoplasms, and Malignant brain neoplasm.

12. The pharmaceutical composition of claim 1, wherein the disorder is a neurological disorder.

13. The pharmaceutical composition of claim 12, wherein the neurological disorder is selected from the group consisting of Acute Thrombotic Stroke, Epilepsy, Multiple Sclerosis, and Alzheimer's Disease.

14. The pharmaceutical composition of claim 1, wherein the disorder is a cardiac disorder.

15. The pharmaceutical composition of claim 14, wherein the cardiac disorder is selected from the group consisting of Acute Myocardial Infarction, refractory heart failure, arrhythmias, pericarditis, myocarditis, sepsis-induced cardiomyopathy, Acute Decompensated Heart Failure, Refractory Idiopathic Pericarditis, Atherosclerosis, coronary artery disease, myocardial infarction, and cardiac remodeling.

16. The pharmaceutical composition of claim 14, wherein the cardiac disorder is atherosclerosis or abdominal aortic aneurism.

17. The pharmaceutical composition of claim 1, wherein the disorder is an inflammatory disorder.

18. The pharmaceutical composition of claim 17, wherein the inflammatory disorder is selected from the group consisting of Autoinflammatory Disease (AID), Cryopyrin Associated Periodic syndrome (CAPS), Familial Mediterranean Fever (FMF), TNF-Receptor Associated Periodic Syndrome (TRAPS), Hyper-IgD Syndrome (HIDS), Systemic Lupus Erythematosus (SLE), and Fibrosis.

19. The pharmaceutical composition of claim 17, wherein the inflammatory disorder is selected from the group consisting of a cytokine storm, acute local inflammation, inflammatory bowel disease, Crohn's disease, sepsis, Experimental sepsis, and Castleman’s disease20. The pharmaceutical composition of claim 1, wherein the disorder is a digestive disorder.

21. The pharmaceutical composition of claim 20, wherein the digestive disorder is selected from the group consisting of Inflammatory Bowel Disease (IBD), Gastroesophageal reflux disease (GERD), and Non-HP-associated Peptic Ulcer Disease.

22. The pharmaceutical composition of claim 1, wherein the disorder is a respiratory disorder.

23. The pharmaceutical composition of claim 22, wherein the respiratory disorder is Asthma or Pulmonary Fibrosis.

24. The pharmaceutical composition of claim 1, wherein the disorder is a renal, metabolic, or ophthalmic disorder.

25. The pharmaceutical composition of claim 24, wherein the renal, metabolic, or ophthalmic disorder is selected from the group consisting of Chronic Kidney Disease, Type 2 Diabetes, an Eye Disease, Uveitis, Scleritis, Sjogren asthenia, and dry eye.

26. The pharmaceutical composition of claim 1, wherein the disorder is an autoimmune disorder.

27. The pharmaceutical composition of claim 26, wherein the autoimmune disorder is Systemic Lupus Erythematosus.

28. The pharmaceutical composition of claim 1, wherein the disorder is acute synovitis, chronic synovitis, inflammatory arthritis, or immune-mediated arthritides.

29. The pharmaceutical composition of claim 1, wherein the disorder is an autoimmune or inflammatory disorder.

30. The pharmaceutical composition of claim 28, wherein the autoimmune or inflammatory disorder is selected from the group consisting of an Allergy, Asthma, Multiple sclerosis, Psoriasis, Inflammatory bowel disease, Autoimmune experimental uveitis, Colitis, Hypersensitivity reaction disease, Diabetes, Crohn's disease, Systemic lupus erythematosus, Pulmonary sarcoidosis, Leishmaniasis, Experimental autoimmune encephalomyelitis, HTLV- 1 -associated myelopathy, Tropical spastic paraparesis, Scleroderma, an Idiopathic inflammatory myopathy, polymyositis, and dermatomyositis.

31. The pharmaceutical composition of any one of claims 1-30, wherein the transmembrane receptor is an interleukin- 1 receptor.

32. The pharmaceutical composition of claim 31, wherein the at least one guide RNA targets a gene selected from the group consisting of IL1R1, IL1RAP, IL1R5, IL1R6, IL1R7, and IL1R9.

33. The pharmaceutical composition of claim 31, wherein the at least one guide RNA targets an IL1R1 gene.

34. The pharmaceutical composition of claim 33, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS : 680-811.

35. The pharmaceutical composition of claim 33, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 825-892 and 3336-3405.

36. The pharmaceutical composition of claim 33, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 893-967.

37. The pharmaceutical composition of claim 33, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 968-1039.

38. The pharmaceutical composition of claim 33, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3491- 3513.

39. The pharmaceutical composition of claim 31, wherein the at least one guide RNA targets an IL 1 RAP gene.

40. The pharmaceutical composition of claim 39, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1040- 1194.

41. The pharmaceutical composition of claim 39, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1204-1271 and 3421-3490.

42. The pharmaceutical composition of claim 39, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1272- 1348.

43. The pharmaceutical composition of claim 39, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1349- 1424.

44. The pharmaceutical composition of claim 39, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3514- 3543.

45. The pharmaceutical composition of any one of claims 1-30, wherein the transmembrane receptor is an interleukin-6 receptor.

46. The pharmaceutical composition of claim 45, wherein the at least one guide RNA targets an IL6R gene.

47. The pharmaceutical composition of claim 46, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1746- 1920.

48. The pharmaceutical composition of claim 46, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3544- 3566.

49. The pharmaceutical composition of claim 45, wherein the at least one guide RNA targets an IL6ST gene.

50. The pharmaceutical composition of claim 49, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1969- 2176.

51. The pharmaceutical composition of claim 49, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3567- 3606.

52. The pharmaceutical composition of any one of claims 1-30, wherein the transmembrane receptor is a tumor necrosis factor receptor.

53. The pharmaceutical composition of claim 52, wherein the at least one guide RNA targets a TNFRSF1 A gene.

54. The pharmaceutical composition of claim 53, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2179- 2383.

55. The pharmaceutical composition of claim 53, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3607- 3647.

56. The pharmaceutical composition of claim 52, wherein the at least one guide RNA targets a TNFRSF1B gene.

57. The pharmaceutical composition of claim 56, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2396- 2622.

58. The pharmaceutical composition of claim 56, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3648- 3692.

59. The pharmaceutical composition of claim 52, wherein the at least one guide RNA targets a TNFRSF3 gene.

60. The pharmaceutical composition of claim 59, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2643-61. The pharmaceutical composition of claim 59, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3693- 3713.

62. The pharmaceutical composition of claim 52, wherein the at least one guide RNA targets a TNFRSF4 gene.

63. The pharmaceutical composition of claim 62, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2867- 3035.

64. The pharmaceutical composition of claim 62, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3714- 3740.

65. The pharmaceutical composition of claim 52, wherein the at least one guide RNA targets a TNFRSF11A gene.

66. The pharmaceutical composition of claim 65, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3042- 3331.

67. The pharmaceutical composition of claim 65, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3741- 3788.

68. The pharmaceutical composition of any one of claims 1-30, wherein the transmembrane receptor is a transforming growth factor beta receptor.

69. The pharmaceutical composition of claim 68, wherein the at least one guide RNA targets a TGFBR1 gene.

70. The pharmaceutical composition of claim 69, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1425- 1544.

71. The pharmaceutical composition of claim 69, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3789- 3813.

72. The pharmaceutical composition of claim 68, wherein the at least one guide RNA targets a TGFBR2 gene.

73. The pharmaceutical composition of claim 72, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1547- 1734.

74. The pharmaceutical composition of claim 72, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3814- 3865.

75. The pharmaceutical composition of any one of claims 1-73, wherein the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease is the RNA-guided nuclease.

76. The pharmaceutical composition of any one of claims 1-73, wherein the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease is DNA encoding the RNA- guided nuclease.

77. The pharmaceutical composition of any one of claims 1-73, wherein the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease is mRNA encoding the RNA- guided nuclease.

78. The pharmaceutical composition of any one of claims 1-77, wherein the RNA-guided nuclease is a Cas protein.

79. The pharmaceutical composition of claim 78, wherein the Cas protein is a Cas9 protein.

80. The pharmaceutical composition of claim 78, wherein the Cas9 protein is an 5. pyogenes Cas9 polypeptide.

81. The pharmaceutical composition of claim 78, wherein the Cas9 protein is selected from the group consisting of esCas9, hfCas9, peCas9, and ARCas9.

82. The pharmaceutical composition of any one of claims 1-81, wherein the at least one guide RNA or a nucleic acid encoding at least one guide RNA is the at least one guide RNA.

83. The pharmaceutical composition of any one of claims 1-81, wherein the at least one guide RNA or a nucleic acid encoding at least one guide RNA is DNA encoding the at least one guide RNA.

84. The pharmaceutical composition of any one of claims 1-81, comprising a nucleic acid encoding both the RNA-guided nuclease and the at least one guide RNA.

85. The pharmaceutical composition of any one of claims 1-84, wherein the at least one guide RNA is a single guide RNA (sgRNA).

86. The pharmaceutical composition of any one of claims 1-85, wherein the at least one guide RNA targets a human gene.

87. The pharmaceutical composition of any one of claims 1-85, wherein the at least one guide RNA targets a canine gene.

88. The pharmaceutical composition of any one of claims 1-85, wherein the at least one guide RNA targets an equine gene.

89. The pharmaceutical composition of any one of claims 1-85, wherein the at least one guide RNA targets a feline gene.

90. The pharmaceutical composition of any one of claims 1-85, wherein the at least one guide RNA targets a mammalian gene.

91. The pharmaceutical composition of any one of claims 1-90, wherein the composition comprises one or more viral vectors collectively comprising the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

92. The pharmaceutical composition of claim 91, wherein the one of more viral vectors comprise a recombinant virus selected from a retrovirus, an adenovirus, an adeno-associated virus, a lentivirus, and a herpes simplex virus-1.

93. The pharmaceutical composition of claim 91, wherein the one of more viral vectors comprise a recombinant adeno-associated virus (AAV).

94. The pharmaceutical composition of claim 93, wherein the recombinant AAV is of serotype 5 (AAV5).

95. The pharmaceutical composition of claim 93, wherein the recombinant AAV is of serotype 6 (AAV 6).

96. The pharmaceutical composition of any one of claims 1-90, wherein the composition comprises one or more lipid nanoparticles (LNP) collectively comprising the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

97. The pharmaceutical composition of claim 96, wherein the one or more LNP comprises: a first plurality of LNP encapsulating the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease; and a second plurality of LNP encapsulating the at least one guide RNA or a nucleic acid encoding at least one guide RNA.

98. The pharmaceutical composition of claim 96, wherein the one or more LNP comprises a plurality of LNP encapsulating both the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

99. The pharmaceutical composition of any one of claims 96-98, wherein the one or more LNP comprises a component selected from the group consisting of 3-(didodecylamino)-N 1 ,N 1 ,4-tri dodecyl- 1 -piperazineethanamine (KL 10), N 1 - [2-(didodecy lamino)ethy 1] -N 1 ,N4,N4-tridodecyl-l ,4-piperazinedi ethanamine (KL22), 14,25-ditridecyl- 15,18,21 ,24- tetraaza-octatriacontane (KL25), l,2-dilinoleyloxy-N,N-dimethylaminopropane (DLin- DMA), 2,2-dilinoley 1-4-dimethylaminomethyl- [ 1,3] -di oxolane (DLin-K-DMA), heptatriaconta-6,9,28,31-tetraen- 19-yl 4-(dimethylamino)butanoate (DLin-MC3-DMA), 2,2- dilinoleyl-4-(2-dimethylaminoethyl)-[l,3]-dioxolane (DLin-KC2-DMA), 1,2-dioleyloxy- N,N-dimethylaminopropane (DODMA), 2-({8-[(3.beta.)-cholest-5-en-3-yloxy]octyl}oxy)- N,N-dimethyl-3-[(9Z,12Z)- -octadeca-9,12-dien-l-yloxy]propan-l -amine (Octyl-CLinDMA), (2R)-2-({8-[(3.beta.)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z- ,12Z)-octadeca- 9, 12-dien-l-yloxy] propan- 1 -amine (Octyl-CLinDMA (2R)), (2S)-2-({8-[(3.beta.)-cholest-5- en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z- , 12Z)-octadeca-9,l 2-dien-l-yloxy] propan- 1- amine (Octyl-CLinDMA (2S)), a lipid including a cyclic amine group, and a mixture thereof.

100. The pharmaceutical composition of any one of claims 96-99, wherein the LNP comprises a component selected from the group consisting of l,2-dilinoleoyl-sn-glycero-3- phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl- sn-gly cero-3-phosphocholine (DOPC), 1 ,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di- O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), l-oleoyl-2- cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn- glycero-3-phosphocholine (Cl 6 Lyso PC), l,2-dilinolenoyl-sn-glycero-3-phosphocholine,1.2-diarachidonoyl-sn-glycero-3-phosphocholine, l,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, l,2-dioleoyl-sn-glycero-3 -phosphoethanolamine (DOPE), 1 ,2-diphytanoyl- sn-glycero-3-phosphoethanolamine (ME 16.0 PE), l,2-distearoyl-sn-glycero-3- phosphoethanolamine, 1 ,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1 ,2-dilinolenoyl- sn-glycero-3-phosphoethanolamine, l,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine,1.2-didocosahexaenoyl-sn-glycero-3 -phosphoethanolamine, l,2-dioleoyl-sn-glycero-3- phospho-rac-(l -glycerol) sodium salt (DOPG), sphingomyelin (SM), and a mixture thereof.

101. The pharmaceutical composition of any one of claims 96-296, wherein the LNP comprises a component selected from the group consisting of PEG-modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols, and mixtures thereof. For example, a PEG lipid may be PEG-c-DOMG,PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, PEG-DMA, a PEG-DSPE lipid, and a mixture thereof.

102. The pharmaceutical composition of any one of claims 96-100, wherein the LNP comprises a component selected from the group consisting of a cholesterol, fecosterol, stigmasterol, stigmastanol, sitosterol, P-sitosterol, lupeol, betulin, ursolic acid, oleanolic acid, campesterol, fucosterol, brassicasterol, ergosterol, 9, 11 -dehydroergosterol, tomatidine, tomatine, a-tocopherol, and a mixture thereof.

103. The pharmaceutical composition of any one of claims 1-90, wherein the composition comprises one or more liposomes collectively comprising the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

104. The pharmaceutical composition of claim 103, wherein the one or more liposomes comprises: a first plurality of liposomes encapsulating the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease; and a second plurality of liposomes encapsulating the at least one guide RNA or a nucleic acid encoding at least one guide RNA.

105. The pharmaceutical composition of claim 103, wherein the one or more liposomes comprises a plurality of liposomes encapsulating both the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

106. The pharmaceutical composition of any one of claims 1-90, wherein the composition comprises one or more virus-like particles collectively comprising the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

107. The pharmaceutical composition of claim 106, wherein the one or more virus-like particles comprises:a first plurality of virus-like particles encapsulating the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease; and a second plurality of virus-like particles encapsulating the at least one guide RNA or a nucleic acid encoding at least one guide RNA.

108. The pharmaceutical composition of claim 106, wherein the one or more virus-like particles comprises a plurality of virus-like particles encapsulating both the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

109. The pharmaceutical composition of any one of claims 1-108, wherein the composition is formulated for parenteral administration.

110. The pharmaceutical composition of any one of claims 1-108, wherein the composition is formulated for intra-articular injection within a joint of the subject.

111. The pharmaceutical composition of any one of claims 1-108, wherein the composition is formulated for intradiscal injection.

112. The pharmaceutical composition of any one of claims 1-108, wherein the composition is formulated for peri discal injection.

113. The pharmaceutical composition of any one of claims 1-108, wherein the composition is formulated for intravertebral injection.

114. A method for treating a disorder having a symptom caused, at least in part, by intracellular signaling mediated through a transmembrane receptor in a subject in need thereof, comprising: administering a therapeutically effective amount of a composition, wherein the composition comprises:(i) an RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease; and(ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

115. The method of claim 114, wherein the at least one guide RNA targets a gene selected from the group consisting of IL1R1, IL1RAP, IL1R5, IL1R6, IL1R7, and IL1R9.

116. The method of claim 114, wherein the at least one guide RNA targets an IL1R1 gene.

117. The method of claim 116, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 680-758.

118. The method of claim 116, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 825-864.

119. The method of claim 116, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 893-922.

120. The method of claim 116, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 968-997.

121. The method of claim 116, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3491-3503.

122. The method of claim 114, wherein the at least one guide RNA targets an IL1RAP gene.

123. The method of claim 122, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1040-1122.

124. The method of claim 122, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1204-1271 and 3421-3458.

125. The method of claim 122, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1272-1301.

126. The method of claim 122, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1349-1378.

127. The method of claim 122, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3514-3529.

128. The method of claim 114, wherein the transmembrane receptor is an interleukin-6 receptor.

129. The method of claim 128, wherein the at least one guide RNA targets an IL6R gene.

130. The method of claim 129, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1746-1834.

131. The method of claim 129, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3544-3553.

132. The method of claim 128, wherein the at least one guide RNA targets an IL6ST gene.

133. The method of claim 132, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1969-2037.

134. The method of claim 132, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3567-3574.

135. The method of claim 114, wherein the transmembrane receptor is a tumor necrosis factor receptor.

136. The method of claim 135, wherein the at least one guide RNA targets a TNFRSF1 A gene.

137. The method of claim 136, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2179-2247.

138. The method of claim 136, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3607-3621.

139. The method of claim 135, wherein the at least one guide RNA targets a TNFRSF1B gene.

140. The method of claim 139, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2396-2482.

141. The method of claim 139, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3648-3673.

142. The method of claim 135, wherein the at least one guide RNA targets a TNFRSF3 gene.

143. The method of claim 142, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2643-2737.

144. The method of claim 142, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3693-3698.

145. The method of claim 135, wherein the at least one guide RNA targets a TNFRSF4 gene.

146. The method of claim 145, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2867-2950.

147. The method of claim 145, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3714-3734.

148. The method of claim 135, wherein the at least one guide RNA targets a TNFRSF11 A gene.

149. The method of claim 148, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3042-3106.

150. The method of claim 148, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3741-3754.

151. The method of claim 114, wherein the transmembrane receptor is a transforming growth factor beta receptor.

152. The method of claim 151, wherein the at least one guide RNA targets a TGFBR1 gene.

153. The method of claim 152, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1425-1454.

154. The method of claim 152, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3789-3791.

155. The method of claim 151, wherein the at least one guide RNA targets a TGFBR2 gene.

156. The method of claim 155, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1547-1580.

157. The method of claim 155, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3814-3819.

158. The method of claim 114, wherein editing of a genomic copy of the gene for the transmembrane receptor by the RNA-guided nuclease and at least one guide RNA results in a genomic sequence encoding a membrane-bound form of the transmembrane receptor lacking signaling function.

159. The method of claim 158, wherein the at least one guide RNA targets a gene selected from the group consisting of IL1R1, IL1RAP, IL1R5, IL1R6, IL1R7, and IL1R9.

160. The method of claim 158, wherein the at least one guide RNA targets an IL1R1 gene.

161. The method of claim 160, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 759-808.

162. The method of claim 160, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3336-3401.

163. The method of claim 160, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 942-967.

164. The method of claim 160, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1010-1039.

165. The method of claim 160, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3505-3513.

166. The method of claim 158, wherein the at least one guide RNA targets an IL1RAP gene.

167. The method of claim 166, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1123-1180.

168. The method of claim 166, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3459-3485.

169. The method of claim 166, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1323-1348.

170. The method of claim 166, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1397-1424.

171. The method of claim 166, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3533-3543.

172. The method of claim 158, wherein the transmembrane receptor is an interleukin-6 receptor.

173. The method of claim 172, wherein the at least one guide RNA targets an IL6ST gene.

174. The method of claim 173, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2038-2102.

175. The method of claim 173, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3595-3606.

176. The method of claim 158, wherein the transmembrane receptor is a tumor necrosis factor receptor.

177. The method of claim 176, wherein the at least one guide RNA targets a TNFRSF1 A gene.

178. The method of claim 177, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2248-2369.

179. The method of claim 177, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3623-3647.

180. The method of claim 176, wherein the at least one guide RNA targets a TNFRSF1B gene.

181. The method of claim 180, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2483-2574.

182. The method of claim 180, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3681-3692.

183. The method of claim 176, wherein the at least one guide RNA targets a TNFRSF3 gene.

184. The method of claim 183, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2738-2846.

185. The method of claim 183, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3703-3713.

186. The method of claim 176, wherein the at least one guide RNA targets a TNFRSF4 gene.

187. The method of claim 186, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2951-2981.

188. The method of claim 186, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3738-3740.

189. The method of claim 176, wherein the at least one guide RNA targets a TNFRSF11A gene.

190. The method of claim 189, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3107-3322.

191. The method of claim 189, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3757-3788.

192. The method of claim 158, wherein the transmembrane receptor is a transforming growth factor beta receptor.

193. The method of claim 192, wherein the at least one guide RNA targets a TGFBR1 gene.

194. The method of claim 193, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1455-1534.

195. The method of claim 193, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3792-3813.

196. The method of claim 192, wherein the at least one guide RNA targets a TGFBR2 gene.

197. The method of claim 196, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1581-1724.

198. The method of claim 196, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3821-3865.

199. The method of claim 114, wherein editing of a genomic copy of the gene for the transmembrane receptor by the RNA-guided nuclease and at least one guide RNA results in a genomic sequence encoding a soluble form of the transmembrane receptor.

200. The method of claim 199, wherein the at least one guide RNA targets a gene selected from the group consisting of IL1R1, IL1RAP, IL1R5, IL1R6, IL1R7, and IL1R9.

201. The method of claim 200, wherein the at least one guide RNA targets an IL1R1 gene.

202. The method of claim 201, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 809-811.

203. The method of claim 201, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3402-3405.

204. The method of claim 201, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 923-941.

205. The method of claim 201, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 998-1009.

206. The method of claim 201, wherein the at least one guide RNA comprises a crRNA sequence of SEQ ID NO 3504.

207. The method of claim 200, wherein the at least one guide RNA targets an IL 1 RAP gene.

208. The method of claim 207, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1181-1194.

209. The method of claim 207, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3481-3490.

210. The method of claim 207, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1302-1322.

211. The method of claim 207, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1379-1396.

212. The method of claim 207, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3530-3532.

213. The method of claim 199, wherein the transmembrane receptor is an interleukin-6 receptor.

214. The method of claim 213, wherein the at least one guide RNA targets an IL6R gene.

215. The method of claim 214, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1835-1920.

216. The method of claim 214, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3554-3566.

217. The method of claim 213, wherein the at least one guide RNA targets an IL6ST gene.

218. The method of claim 217, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2103-2176.

219. The method of claim 217, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3575-3594.

220. The method of claim 199, wherein the transmembrane receptor is a tumor necrosis factor receptor.

221. The method of claim 220, wherein the at least one guide RNA targets a TNFRSF1 A gene.

222. The method of claim 221, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2370-2383.

223. The method of claim 221, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3621-3622.

224. The method of claim 220, wherein the at least one guide RNA targets a TNFRSF1B gene.

225. The method of claim 224, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2575-2622.

226. The method of claim 224, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3664-3680.

227. The method of claim 220, wherein the at least one guide RNA targets a TNFRSF3 gene.

228. The method of claim 227, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2847-2852.

229. The method of claim 227, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3699-3702.

230. The method of claim 220, wherein the at least one guide RNA targets a TNFRSF4 gene.

231. The method of claim 230, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 2982-3035.

232. The method of claim 230, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3730-3737.

233. The method of claim 220, wherein the at least one guide RNA targets a TNFRSF11 A gene.

234. The method of claim 233, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3323-3331.

235. The method of claim 233, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3749-3756.

236. The method of claim 199, wherein the transmembrane receptor is a transforming growth factor beta receptor.

237. The method of claim 236, wherein the at least one guide RNA targets a TGFBR1 gene.

238. The method of claim 237, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1535-1544.

239. The method of claim 237, wherein the at least one guide RNA comprises a crRNA sequence of 3792.

240. The method of claim 236, wherein the at least one guide RNA targets a TGFBR2 gene.

241. The method of claim 240, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 1725-1734.

242. The method of claim 240, wherein the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOS: 3820-3822.

243. The method of any one of claims 114-242, wherein the disorder is a musculoskeletal disorder.

244. The method of claim 243, wherein the musculoskeletal disorder is selected from the group consisting of Rheumatoid Arthritis, Gout, Osteoarthritis, Osteoporosis, Intervertebral disc disease (IVDD), Psoriatic arthritis (PsA), Arthritis, Polymyositis, Proliferative synovitis, Malignant bone neoplasm, Sarcoid Myopathy, Cortex Bone Disorders, Idiopathic Scoliosis, Tendinopathy, Myofibrillar Myopathy, Enthesis-Related Arthritis, Ankylosing spondylitis,Degenerative, polyarthritis, Arthropathy, Osteitis Deformans, Prolapsed Lumbar Disc, Polymyositis Ossificans, Idiopathic Polymyositis, Luft Disease, Adult-onset Still's Disease, Osteoarthrosis Deformans, and Bachet’s Disease.

245. The method of claim 243, wherein the musculoskeletal disorder is selected from the group consisting of Rheumatoid arthritis, Idiopathic osteoporosis, Post-menopausal osteoporosis, Paget's disease, Osteoarthritis, Juvenile idiopathic arthritis (JIA), Still's disease, Ankylosing spondylitis, Polymyalgia rheumatica, Arthritis, Secondary malignant neoplasm of bone, Type II, Mucolipidosis, Sjogren's Syndrome, Psoriatic arthritis, Rheumatism, Castleman’s disease, Degenerative Polyarthritis, Arthropathy, Bone neoplasm, Osteoporosis, Massive osteolysis, Bone fracture healing, Systemic sclerosis, Systemic Juvenile Idiopathic, Arthritis, and Synovitis.

246. The method of claim 243, wherein the musculoskeletal disorder is selected from the group consisting of Arthritis, Infectious Intermittent joint effusion, Ankylosing spondylitis, Arthritis, Osteoarthritis, Spondylarthritis, Plantar fasciitis, Degenerative polyarthritis, Hemophilic arthropathy, Inflammatory myopathy with abundant macrophages, Polymyositis, Tendinosis, Malignant Bone Neoplasm, Osteoporosis, Psoriatic arthritis, Rheumatism, Rheumatoid arthritis, Adult Still's disease, Juvenile arthritis, Early rheumatoid arthritis, Palindromic rheumatism, Gout, Infectious Arthritis, Myotonic dystrophy, Dermatomyositis, Hemophilic arthropathy, Osteopenia, Sjogren's syndrome, Juvenile Idiopathic Arthritis, Myasthenia gravis, Osteolysis, Inflammation, Degenerative polyarthritis, Osteitis deformans, Pigmented villonodular synovitis, or Hyperphosphatasemia with bone disease.

247. The method of claim 243, wherein the musculoskeletal disorder is selected from the group consisting of Loeys-Dietz Syndrome, Osteoarthrosis, Marfan Syndrome, Aortic aneurysm (familial thoracic 3), and a Craniofacial abnormality.

248. The method of any one of claims 114-242, wherein the disorder is a neoplasia.

249. The method of claim 248, wherein the neoplasia is selected from the group consisting of Osteosarcoma, Colon Cancer, Metastasis (General), Lung Cancer, Multiple Myeloma. Breast Cancer, Solid Tumors, Lymphoma, Pancreatic Cancer, Stomach Cancer, Epithelial Ovarian Cancer, Mammary Neoplasms, Oropharyngeal Carcinoma, Renal Cell Carcinoma,Chondrosarcoma, Esophageal Neoplasms, B-Cell Lymphoma, Cutaneous Lymphoma T-Cell, Leukemia, Thyroid Carcinoma, Skin carcinogenesis, Cholectoral Cancer, Glioma, Liver Cancer, Melanoma, Neuroblastoma, Polycystic Ovary Syndrome, Glioblastoma, Prostate Cancer, Cervical Cancer, Ovarian Cancer, Bladder Cancer, Squamous cell carcinoma, Kaposi Sarcoma, Oral Cavity Cancer, Leiomyosarcoma, Malignant Peripheral Nerve Sheath Tumor, and Ewing's Sarcoma.

250. The method of claim 248, wherein the neoplasia is selected from the group consisting of Multiple myeloma, Lung Cancer, Stomach Cancer, Breast Cancer, Kidney Cancer, Neoplasm Metastasis, Colorectal Neoplasms, Ovarian cancer, Osteosarcoma, Cholangiocarcinoma, Leukemia, Prostate cancer, Plasmacytoma, Pancreatic cancer, Cervical cancer, Lymphoma, Liver neoplasms, Neuroblastoma, Melanoma, Mastocytosis, Endometrial cancer, Bladder Cancer, Squamous cell carcinoma, Gallbladder carcinoma, Adenocarcinoma, Thyroid Cancer, prostate neoplasms, stomach cancer, liver carcinoma, pituitary neoplasms, hepatoblastoma, multiple myeloma, hepatocellular adenoma, breast carcinoma, carcinogenesis, leukemia, colon carcinoma, melanoma, metastasis (general), lung cancer, pancreatic cancer, Kaposi sarcoma, medulloblastoma, carcinoma of bladder, squamous cell carcinoma, mast cell neoplasm, glioma, mastocytoma, brain neoplasms, ovarian neoplasms, bone neoplasm, rhabdomyosarcoma, solid tumors, metastatic kidney cancer, and metastatic renal cell carcinoma251. The method of claim 248, wherein the neoplasia is selected from the group consisting of a Neoplasm, Glioblastoma, Astrocytoma, Adenocarcinoma, Osteosarcoma, Squamous cell carcinoma, Metastasis, Ameloblastoma, Cholangiocarcinoma, Choriocarcinoma, Ovarian cancer, Prostate cancer, Lung Cancer, Larynx Cancer, Breast Cancer, Lip and Oral Cavity Carcinoma, Squamous intraepithelial lesion, Neuroblastoma, Non-Hodgkin lymphomas, Malignant Neoplasms, Skin Neoplasms, Neuroblastoma, Neoplasm Metastasis, Colorectal Cancer, Fibrosarcoma, Myeloid Leukemia, Myelofibrosis, Hodgkin Lymphomas, Non-Small Cell Lung Carcinoma, Cervical Cancer, Liver cancer, Extrapulmonary small cell carcinoma, Basal cell carcinoma, Kidney cancer, Pancreatic carcinoma, Mesothelioma, Gastric cancer, Polycystic Ovary Syndrome, Chordoma, Cholangiocarcinoma, Malignant ascites, Nasopharyngeal carcinoma, Head and Neck Carcinoma, Cancer metastasis, Prostate carcinoma, Fibrosarcoma, Liver carcinoma, Carcinoma of bladder, T-Cell LymphoblasticLeukemia, Bladder Neoplasm, melanoma, Leukemia, acute myeloid leukemia, Hepatocellular carcinoma, Colorectal cancer, a Lymphoma, Mycosis fungoides, and Sezary syndrome.

252. The method of claim 248, wherein the neoplasia is selected from the group consisting of Pancreatic cancer, Multiple self-healing squamous epithelioma (Ferguson-Smith disease), Pancreatic cancer, Gastrointestinal Stromal Tumors (GIST), Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome), Metastasis, Colorectal Carcinoma, Bone neoplasms, Anaplastic carcinoma, Spindle-Cell carcinoma, Malignant Bone Neoplasm, Lung neoplasms, and Malignant brain neoplasm.

253. The method of any one of claims 114-242, wherein the disorder is a neurological disorder.

254. The method of claim 253, wherein the neurological disorder is selected from the group consisting of Acute Thrombotic Stroke, Epilepsy, Multiple Sclerosis, and Alzheimer's Disease.

255. The method of any one of claims 114-242, wherein the disorder is a cardiac disorder.

256. The method of claim 255, wherein the cardiac disorder is selected from the group consisting of Acute Myocardial Infarction, refractory heart failure, arrhythmias, pericarditis, myocarditis, sepsis-induced cardiomyopathy, Acute Decompensated Heart Failure, Refractory Idiopathic Pericarditis, Atherosclerosis, coronary artery disease, myocardial infarction, and cardiac remodeling.

257. The method of claim 255, wherein the cardiac disorder is atherosclerosis or abdominal aortic aneurism.

258. The method of any one of claims 114-242, wherein the disorder is an inflammatory disorder.

259. The method of claim 258, wherein the inflammatory disorder is selected from the group consisting of Autoinfl ammatory Disease (AID), Cryopyrin Associated Periodic syndrome (CAPS), Familial Mediterranean Fever (FMF), TNF-Receptor Associated PeriodicSyndrome (TRAPS), Hyper-IgD Syndrome (HIDS), Systemic Lupus Erythematosus (SLE), and Fibrosis.

260. The method of claim 258, wherein the inflammatory disorder is selected from the group consisting of a cytokine storm, acute local inflammation, inflammatory bowel disease, Crohn's disease, sepsis, Experimental sepsis, and Castleman’s disease261. The method of any one of claims 114-242, wherein the disorder is a digestive disorder.

262. The method of claim 261, wherein the digestive disorder is selected from the group consisting of Inflammatory Bowel Disease (IBD), Gastroesophageal reflux disease (GERD), and Non-HP-associated Peptic Ulcer Disease.

263. The method of any one of claims 114-242, wherein the disorder is a respiratory disorder.

264. The method of claim 263, wherein the respiratory disorder is Asthma or Pulmonary Fibrosis.

265. The method of any one of claims 114-242, wherein the disorder is a renal, metabolic, or ophthalmic disorder.

266. The method of claim 265, wherein the renal, metabolic, or ophthalmic disorder is selected from the group consisting of Chronic Kidney Disease, Type 2 Diabetes, an Eye Disease, Uveitis, Scleritis, Sjogren asthenia, and dry eye.

267. The method of any one of claims 114-242, wherein the disorder is an autoimmune disorder.

268. The method of claim 267, wherein the autoimmune disorder is Systemic Lupus Erythematosus.

269. The method of any one of claims 114-242, wherein the disorder is an autoimmune or inflammatory disorder.

270. The method of claim 269, wherein the autoimmune or inflammatory disorder is selected from the group consisting of an Allergy, Asthma, Multiple sclerosis, Psoriasis, Inflammatory bowel disease, Autoimmune experimental uveitis, Colitis, Hypersensitivity reaction disease, Diabetes, Crohn's disease, Systemic lupus erythematosus, Pulmonary sarcoidosis, Leishmaniasis, Experimental autoimmune encephalomyelitis, HTLV-1- associated myelopathy, Tropical spastic paraparesis, Scleroderma, an Idiopathic inflammatory myopathy, polymyositis, and dermatomyositis.

271. The method of any one of claims 114-270, wherein the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease is the RNA-guided nuclease.

272. The method of any one of claims 114-270, wherein the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease is DNA encoding the RNA-guided nuclease.

273. The method of any one of claims 114-270, wherein the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease is mRNA encoding the RNA-guided nuclease.

274. The method of any one of claims 114-273, wherein the RNA-guided nuclease is a Cas protein.

275. The method of claim 274, wherein the Cas protein is a Cas9 protein.

276. The method of claim 274, wherein the Cas9 protein is an S. pyogenes Cas9 polypeptide.

277. The method of claim 274, wherein the Cas9 protein is selected from the group consisting of esCas9, hfCas9, peCas9, and ARCas9.

278. The method of any one of claims 114-277, wherein the at least one guide RNA or a nucleic acid encoding at least one guide RNA is the at least one guide RNA.

279. The method of any one of claims 114-277, wherein the at least one guide RNA or a nucleic acid encoding at least one guide RNA is DNA encoding the at least one guide RNA.

280. The method of any one of claims 114-277, comprising a nucleic acid encoding both the RNA-guided nuclease and the at least one guide RNA.

281. The method of any one of claims 114-280, wherein the at least one guide RNA is a single guide RNA (sgRNA).

282. The method of any one of claims 114-281, wherein the at least one guide RNA targets a human gene.

283. The method of any one of claims 114-281, wherein the at least one guide RNA targets a canine gene.

284. The method of any one of claims 114-281, wherein the at least one guide RNA targets an equine gene.

285. The method of any one of claims 114-281, wherein the at least one guide RNA targets a feline gene.

286. The method of any one of claims 114-281, wherein the at least one guide RNA targets a mammalian gene.

287. The method of any one of claims 114-286, wherein the composition comprises one or more viral vectors collectively comprising the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

288. The method of claim 287, wherein the one of more viral vectors comprise a recombinant virus selected from a retrovirus, an adenovirus, an adeno-associated virus, a lentivirus, and a herpes simplex virus-1.

289. The method of claim 287, wherein the one of more viral vectors comprise a recombinant adeno-associated virus (AAV).

290. The method of claim 289, wherein the recombinant AAV is of serotype 5 (AAV5).

291. The method of claim 289, wherein the recombinant AAV is of serotype 6 (AAV6).

292. The method of any one of claims 114-286, wherein the composition comprises one or more lipid nanoparticles (LNP) collectively comprising the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

293. The method of claim 292, wherein the one or more LNP comprises: a first plurality of LNP encapsulating the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease; and a second plurality of LNP encapsulating the at least one guide RNA or a nucleic acid encoding at least one guide RNA.

294. The method of claim 292, wherein the one or more LNP comprises a plurality of LNP encapsulating both the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

295. The method of any one of claims 292-294, wherein the one or more LNP comprises a component selected from the group consisting of 3-(didodecylamino)-Nl,Nl,4-tridodecyl-l- piperazineethanamine (KL10), Nl-[2-(didodecylamino)ethyl]-Nl,N4,N4-tridodecyl-l,4- piperazinediethanamine (KL22), 14,25-ditridecyl-15,18,21,24-tetraaza-octatriacontane (KL25), l,2-dilinoleyloxy-N,N-dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4- dimethylaminomethyl-[l,3]-dioxolane (DLin-K-DMA), heptatriaconta-6,9,28,31-tetraen-19- yl 4-(dimethylamino)butanoate (DLin-MC3-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)- [l,3]-dioxolane (DLin-KC2-DMA), l,2-dioleyloxy-N,N-dimethylaminopropane (DODMA), 2-({8-[(3.beta.)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)- -octadeca-9,12- dien-l-yloxy]propan-l -amine (Octyl-CLinDMA), (2R)-2-({8-[(3.beta.)-cholest-5-en-3- y loxy] octyl } oxy)-N,N-dimethyl-3- [(9Z- , 12Z)-octadeca-9, 12-dien- 1 -yloxy ]propan- 1 -amine (Octyl-CLinDMA (2R)), (2S)-2-({8-[(3.beta.)-cholest-5-en-3-yloxy]octyl}oxy)-N,N- dimethyl-3-[(9Z- , 12Z)-octadeca-9,l 2-dien- 1 -yloxy] propan- 1 -amine (Octyl-CLinDMA (2S)), a lipid including a cyclic amine group, and a mixture thereof.

296. The method of any one of claims 292-295, wherein the LNP comprises a component selected from the group consisting of l,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC),1.2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1 ,2-dioleoyl-sn-glycero-3- phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di- O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), l-oleoyl-2- cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn- glycero-3-phosphocholine (Cl 6 Lyso PC), l,2-dilinolenoyl-sn-glycero-3-phosphocholine,1.2-diarachidonoyl-sn-glycero-3-phosphocholine, l,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, l,2-dioleoyl-sn-glycero-3 -phosphoethanolamine (DOPE), 1 ,2-diphytanoyl- sn-glycero-3-phosphoethanolamine (ME 16.0 PE), l,2-distearoyl-sn-glycero-3- phosphoethanolamine, 1 ,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1 ,2-dilinolenoyl- sn-glycero-3-phosphoethanolamine, l,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine,1.2-didocosahexaenoyl-sn-glycero-3 -phosphoethanolamine, l,2-dioleoyl-sn-glycero-3- phospho-rac-(l -glycerol) sodium salt (DOPG), sphingomyelin (SM), and a mixture thereof.

297. The method of any one of claims 292-296, wherein the LNP comprises a component selected from the group consisting of PEG-modified phosphatidylethanolamines, PEG- modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG- modified diacylglycerols, PEG-modified dialkylglycerols, and mixtures thereof. For example, a PEG lipid may be PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG- DPPC, PEG-DMA, a PEG-DSPE lipid, and a mixture thereof.

298. The method of any one of claims 96-100, wherein the LNP comprises a component selected from the group consisting of a cholesterol, fecosterol, stigmasterol, stigmastanol, sitosterol, P-sitosterol, lupeol, betulin, ursolic acid, oleanolic acid, campesterol, fucosterol, brassicasterol, ergosterol, 9, 11 -dehydroergosterol, tomatidine, tomatine, a-tocopherol, and a mixture thereof.

299. The method of any one of claims 114-286, wherein the composition comprises one or more liposomes collectively comprising the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

300. The method of claim 299, wherein the one or more liposomes comprises: a first plurality of liposomes encapsulating the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease; and a second plurality of liposomes encapsulating the at least one guide RNA or a nucleic acid encoding at least one guide RNA.

301. The method of claim 299, wherein the one or more liposomes comprises a plurality of liposomes encapsulating both the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

302. The method of any one of claims 114-286, wherein the composition comprises one or more virus-like particles collectively comprising the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

303. The method of claim 302, wherein the one or more virus-like particles comprises: a first plurality of virus-like particles encapsulating the RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease; and a second plurality of virus-like particles encapsulating the at least one guide RNA or a nucleic acid encoding at least one guide RNA.

304. The method of claim 302, wherein the one or more virus-like particles comprises a plurality of virus-like particles encapsulating both the (i) RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease, and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene encoding the transmembrane receptor.

305. The method of any one of claims 114-304, wherein the composition is formulated for parenteral administration.

306. The method of any one of claims 114-304, wherein the composition is formulated for intra-articular injection within a joint of the subject.

307. The method of any one of claims 114-304, wherein the composition is formulated for intradiscal injection.

308. The method of any one of claims 114-304, wherein the composition is formulated for peri discal injection.

309. The method of any one of claims 114-304, wherein the composition is formulated for intravertebral injection.

310. The method of any one of claims 114-304, wherein the administering comprises parenteral administration.

311. The method of any one of claims 114-304, wherein the administering comprises intraarticular injection within a joint of the subject.

312. The method of any one of claims 114-304, wherein the administering comprises intradiscal injection.

313. The method of any one of claims 114-304, wherein the administering comprises peri discal injection.

314. The method of any one of claims 114-304, wherein the administering comprises intravertebral injection.

315. The method of any one of claims 114-304, wherein the administering comprises intraarticular injection of the pharmaceutical composition into the joint of the subject.

316. The method of any one of claims 114-315, wherein the pharmaceutical composition is administered during surgery.

317. The method of any one of claims 114-316, wherein the pharmaceutical composition is administered after surgery.

318. The method of any one of claims 114-317, wherein the pharmaceutical composition is a controlled release pharmaceutical composition.

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