Mutation repair methods and related compositions

Abstract

Disclosed herein are systems for repairing or causing mutational correction to a mutant allele and uses thereof for treatment of genetic disorders.

Description

[0001] Attorney Docket No.10935-031WO1 MUTATION REPAIR METHODS AND RELATED COMPOSITIONS CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of, U.S. Provisional Application No. 63 / 516,744, filed July 31, 2023, entitled “MUTATION REPAIR METHODS AND RELATED COMPOSITIONS,” which is incorporated by reference herein in its entirety. REFERENCE TO SEQUENCE LISTING The sequence listing submitted on July 31, 2024 as an .XML file entitled “10935- 031WO1_ST26.xml” created on July 31, 2024, and having a file size of 327,616 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5). FIELD The present disclosure relates to allele-specific targeting and methods thereof. BACKGROUND Inherited human diseases are caused by different types of gene mutations, insertions / deletions (indels), genomic structural variations, as well as pathogenic single nucleotide polymorphisms (SNPs). In autosomal dominant disorders, only one allele harboring a mutation can cause disease phenotype. This presents a great challenge for conducting gene-therapies. The treatment strategy for diseases with dominant-negative mutations typically involves the silencing of the pathogenic alleles in an allele-specific manner, without affecting the wild-type ones. CRISPR-mediated targeting of the mutant allele can provide treatment for these diseases by leaving the wild-type allele intact and functional. The CRISPR system enables rapid, effective, and convenient modification of endogenous genes in various cell types. Principally, two components of this system - Cas endonuclease and gRNA - form a complex that binds to dsDNA complementary to the gRNA and initiates a double-strand cut at that complimentary site. This double strand cut drives repair mechanisms of either non-homologous end joining (NHEJ) pathway or homology-directed repair (HDR). The NHEJ pathway dominates in quiescent cells, and this repair typically leads to random indels, which results in frameshift mutations that result in loss of protein function. It has been previously shown that using a specific gRNA design can result in targeting only the mutant allele. However, HDR requires a template providing the correct nucleotide with homology arms to the targeting site. Providing HDR templates such as ssDNA, pDNA or AAV vectors can be expensive and sometimes results in biological changes in the target cells. Attorney Docket No.10935-031WO1 What is needed are new compositions and methods for treating genetic disorders. SUMMARY In one aspect, disclosed herein are systems for repairing or causing mutational correction of a mutant allele of a heterozygous gene, said system comprising a guide RNA (gRNA), wherein: a) the gRNA targets a mutant allele of a heterozygous gene including, but not limited to an incomplete or complete autosomal dominant allele, b) the mutant allele comprises one or more mutations (such as, for example, point mutations, insertions, deletions, or translocations), and c) the gRNA does not target the wild-type allele of the gene, including those systems, wherein the system is free from homology directed repair (HDR) template. In one aspect disclosed herein are systems for repairing or causing mutational correction of a mutant allele of a heterozygous gene of any preceding aspect further comprising an HDR enhancer to enhance intra-homologous recombination. In some aspects, the HDR enhancer.is a DNA-dependent protein kinase (DNA-PK) Inhibitor (such as for example AZD7648, LY294002, Compound 401, PIK-75 HCl, KU-0060648, CC-115, PP121, SF2523, YU238259, LTURM34, Nedisertib (M3814), Samotolisib (LY3023414), Wortmannin, NU7441 (KU-57788), PI-103, T0070907, Torin 2, Alt-R™, SCR7, L755507, EPZ5676, rucaparib, pevonedistat, brefeldin A, Alt- R HDR Enhancer V1, XL413, trichostatin A, CRISPYTMMix, romidepsin, nedisertib, and Alt-R HDR Enhancer V2 and NU7026). Also disclosed herein are system for repairing or causing mutational correction of a mutant allele of a heterozygous gene of any preceding aspect, wherein the mutant allele comprises a target strand and a non-target strand complementary to the target strand. In some aspects, the gRNA is complementary to target strand. In one aspect, disclosed herein are systems for modulating a mutant allele of a gene of any preceding aspect, wherein at least one of the one or more mutations is within 7, 6, 5, 4, 3, 2, or 1 nucleotide upstream the 5’ end or within 7, 6, 5, 4, 3, 2, or 1 nucleotide downstream the 3’ end of a protospacer adjacent motif (PAM) sequence. Also disclosed herein are system for repairing or causing mutational correction of a mutant allele of a heterozygous gene of any preceding aspect, wherein atleast one of the one or more mutations is upstream the 5’ end or downstream of the 3’ end of a protospacer adjacent motif (PAM) sequence (such as, for example, NGG, NNGRR, NNGRRT, or NNNNGATT including, but not limited to AAGAA, TGGGAT, GGG, or TGG). In one aspect disclosed herein are systems for modulating a mutant allele of a gene of any preceding aspect, wherein the gRNA does not target the wild-type allele of the gene. Attorney Docket No.10935-031WO1 Also disclosed herein is a system for modulating a mutant allele of a gene of any preceding aspect, wherein the mutant allele is associated with a genetic disorder (such as, for example, a dominant-negative disorder including, but not limited to inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal dominant hyper- IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, or KCNT1- related developmental and epileptic encephalopathy). In one aspect, disclosed herein is a system for modulating a mutant allele of a gene of any preceding aspect, wherein the mutant allele is of a VCP gene (such as, for example, a VCP gene comprising SEQ ID NO: 10 or a gene for, a STAT3 gene, a FBN1 gene, a APOB gene, a LDLR gene, a PCSK9 gene, a DOCK8 gene, a TBCD gene, or a KCNT1 gene). Also disclosed herein is a system for modulating a mutant allele of a gene of any preceding aspect, wherein the gRNA comprises a sequence selected from the group consisting of SEQ ID NOs: 1-9 or a fragment thereof. In one aspect, disclosed herein is a system for modulating a mutant allele of a gene of any preceding aspect, wherein the mutant allele is an autosomal dominant allele, and wherein the autosomal dominant allele is a pathogenic autosomal dominant allele. In some aspects, the pathogenic autosomal dominant allele expresses in a mammal as a disorder selected from the group consisting of: proliferation disorder, blood disorder, vision disorder, connective tissue disorder, and protein processing disorder said disorder including, but not limited to achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, hereditary elliptocytosis, Ablepharon macrostomia syndrome Acropectoral syndrome, Acute intermittent porphyria Adermatoglyphia, ADNP syndrome, Albright's hereditary osteodystrophy Ankylosing vertebral hyperostosis with tylosis Aphalangy-syndactyly- microcephaly syndrome Arakawa's syndrome II, Aromatase excess syndrome Autosomal dominant cerebellar ataxia, Autosomal dominant Charcot–Marie–Tooth disease type 2 with giant axons Autosomal dominant GTP cyclohydrolase I deficiency, Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Autosomal dominant nocturnal frontal lobe epilepsy, Autosomal dominant partial epilepsy with auditory features Autosomal dominant polycystic kidney disease Axenfeld–Rieger syndrome, Bainbridge–Ropers syndrome Barber–Say syndrome Beck–Fahrner syndrome Benign hereditary chorea Bethlem myopathy, Birt–Hogg– Dubé syndrome, Blepharophimosis, ptosis, epicanthus inversus syndrome Blepharoptosis-myopia- ectopia lentis syndrome Boomerang dysplasia, Bosch-Boonstra-Schaaf optic atrophy syndrome Attorney Docket No.10935-031WO1 Brachydactyly-long thumb syndrome, Branchio-oto-renal syndrome Buschke–Ollendorff syndrome, Calvarial doughnut lesions-bone fragility syndrome Camptodactyly-taurinuria syndrome Camurati–Engelmann disease, CAPOS syndrome Central core disease, Cerebro-costo- mandibular syndrome, Cochleosaccular degeneration with progressive cataracts Cohen-Gibson syndrome, Collagen disease Collagenopathy, types II and XI Collins–Pope syndrome, Coloboma of macula-brachydactyly type B syndrome Congenital distal spinal muscular atrophy, Congenital stromal corneal dystrophy Costello syndrome, Craniofacial dysostosis-diaphyseal hyperplasia syndrome Currarino syndrome, Cyprus facial neuromusculoskeletal syndrome Czech dysplasia, metatarsal type, Darier's disease GLUT1 deficiency, Dentatorubral–pallidoluysian atrophy Dermatopathia pigmentosa reticularis DiGeorge syndrome Dysfibrinogenemia, Emberger syndrome, Familial amyloid polyneuropathy Familial atrial fibrillation, Familial cutaneous collagenoma, Familial disseminated comedones without dyskeratosis Familial hypercholesterolemia, Familial male-limited precocious puberty Feingold syndrome, Felty's syndrome, Fibular aplasia-ectrodactyly syndrome Flynn–Aird syndrome, Gardner's syndrome GATA2 deficiency, GATAD2B-associated neurodevelopmental disorder Gillespie syndrome, Gray platelet syndrome, Greig cephalopolysyndactyly syndrome, Hagemoser–Weinstein– Bresnick syndrome Hajdu–Cheney syndrome Haploinsufficiency of A20, Hawkinsinuria Hay– Wells syndrome, Heart-hand syndrome, Spanish type Hemochromatosis type 4, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome Hereditary elliptocytosis, Hereditary hemorrhagic telangiectasia Hereditary mucoepithelial dysplasia Hereditary neurocutaneous angioma Hereditary spherocytosis, Holt–Oram syndrome Huntington's disease, Huntington's disease-like syndrome Hyperinsulinism-hyperammonemia syndrome Hypertrophic cardiomyopathy Hypoalphalipoproteinemia Hypochondroplasia, Hypodysfibrinogenemia, IVIC syndrome, Jackson–Weiss syndrome Jordan's Syndrome, Juberg-Hayward syndrome Juvenile- onset dystonia, Keratoendotheliitis fugax hereditaria Keratolytic winter erythema, Kniest dysplasia, Langer–Giedion syndrome Larsen syndrome, Leucine-sensitive hypoglycemia of infancy Liddle's syndrome, Marfan syndrome Marshall syndrome Marsili syndrome, Medullary cystic kidney disease Menke-Hennekam syndrome Metachondromatosis Miller–Dieker syndrome, MOMO syndrome Monilethrix MonoMAC, Multiple endocrine neoplasia Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2B, Muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome Myelokathexis, Myotonic dystrophy, Nablus mask-like facial syndrome, Naegeli–Franceschetti–Jadassohn syndrome Nail–patella syndrome, Noonan syndrome, Oculopharyngeal muscular dystrophy Otofaciocervical syndrome, Pachyonychia congenita Pallister–Hall syndrome, Palmoplantar Attorney Docket No.10935-031WO1 keratoderma with deafness PAPA syndrome, Papillorenal syndrome Parastremmatic dwarfism Pashayan syndrome Pelger–Huët anomaly Peutz–Jeghers syndrome Piebaldism, Platyspondylic lethal skeletal dysplasia, Torrance type Polydactyly, Polymerase proofreading-associated polyposis Popliteal pterygium syndrome, Porphyria cutanea tarda Pseudoachondroplasia, RASopathy, Reis–Bucklers corneal dystrophy Romano–Ward syndrome Rosselli–Gulienetti syndrome Roussy–Lévy syndrome Rubinstein–Taybi syndrome, Saethre–Chotzen syndrome, Scalp defects-postaxial polydactyly syndrome Schmitt Gillenwater Kelly syndrome, Severe congenital neutropenia, Severe intellectual disability-progressive spastic diplegia syndrome Short QT syndrome, Singleton Merten syndrome, Spastic paraplegia 6 Spastic paraplegia 31, Spinal muscular atrophy with lower extremity predominance 1 Spinal muscular atrophy with lower extremity predominance 2A Spinal muscular atrophy with lower extremity predominance 2B Spinocerebellar ataxia, Spinocerebellar ataxia type 1 Spinocerebellar ataxia type 6, Split hand split foot-nystagmus syndrome Spondyloepimetaphyseal dysplasia, Strudwick type Spondyloepiphyseal dysplasia congenita Spondyloperipheral dysplasia, St. Helena familial genu valgum Stickler syndrome, Syndactyly-nystagmus syndrome due to 2q31.1 microduplication SYNGAP1-related intellectual disability, SYT1-associated neurodevelopmental disorder, Thumb stiffness-brachydactyly-intellectual disability syndrome Tietz syndrome, Timothy syndrome Treacher Collins syndrome, Tricho–dento–osseous syndrome, TRPM3-related neurodevelopmental disorders Tuberous sclerosis, Upington disease, Variegate porphyria, Ventricular extrasystoles with syncopal episodes-perodactyly-Robin sequence syndrome Verloes Van Maldergem Marneffe syndrome, Vitelliform macular dystrophy Von Hippel–Lindau disease Von Willebrand disease, Wallis–Zieff–Goldblatt syndrome WHIM syndrome, and White sponge nevus. In some aspects, the autosomal dominant mutation is associated with a cancer, such as, for example, alveolar soft part sarcoma, pre-B acute lymphocytic leukemia, acute myeloid leukemia, dermatofibrosarcoma protuberans, gastrointestinal stromal tumor, giant cell fibroblastoma, granulocytic sarcoma, Kaposi’s sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, meningeal hemangiopericytoma, cutaneous fibrous histiocytoma, angiosarcoma, meningiomas, neurofibromas, schwannomas, or papillary thyroid carcinoma. In one aspect, disclosed herein is a system for modulating a mutant allele of a gene of any preceding aspect, wherein the mutant allele is expressed in a cell that is heterozygous for the allele. In one aspect, the cell expresses CD34 on its membrane. Also disclosed herein are methods of treating, reducing, decreasing, inhibiting, ameliorating, and / or preventing a genetic disorder (such as, for example inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal Attorney Docket No.10935-031WO1 dominant hyper-IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, KCNT1-related developmental and epileptic encephalopathy, or genetic disorders associated with a mutant allele of a VCP gene, a STAT3 gene, a FBN1 gene, a APOB gene, a LDLR gene, a PCSK9 gene, a DOCK8 gene, a TBCD gene, or a KCNT1 gene) in a subject, comprising administering to the subject the system of preceding aspect. For example, disclosed herein are methods of treating, reducing, decreasing, inhibiting, ameliorating, and / or preventing a genetic disorder (such as, for example inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal dominant hyper-IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, KCNT1-related developmental and epileptic encephalopathy, or genetic disorders associated with a mutant allele of a VCP gene, a STAT3 gene, a DOCK8 gene, a TBCD gene, or a KCNT1 gene) in a subject, comprising administering to the subject a system for repairing or causing mutational correction of a mutant allele of a heterozygous gene, said system comprising a guide RNA (gRNA), wherein: a) the gRNA targets a mutant allele of a heterozygous VCP gene, a STAT3 gene, a FBN1 gene, a APOB gene, a LDLR gene, a PCSK9 gene, a DOCK8 gene, a TBCD gene, or a KCNT1 gene gene, b) the mutant allele comprises one or more mutations (such as, for example, point mutations, insertions, deletions, or translocations), and c) the gRNA does not target the wild-type allele of the gene, including those systems, wherein the system is free from homology directed repair (HDR) template. For example, disclosed herein are methods of treating a genetic disorder (such as, for example inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal dominant hyper-IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, KCNT1-related developmental and epileptic encephalopathy, or genetic disorders associated with a mutant allele of a VCP gene, a STAT3 gene, a FBN1 gene, a APOB gene, a LDLR gene, a PCSK9 gene, a DOCK8 gene, a TBCD gene, or a KCNT1 gene). In one aspect disclosed herein are methods of treating, reducing, decreasing, inhibiting, ameliorating, and / or preventing a genetic disorder of any preceding aspect, wherein the system further comprises an HDR enhancer to enhance intra-homologous recombination. In some aspects, the HDR enhancer.is a DNA-dependent protein kinase (DNA-PK) Inhibitor (such as for example AZD7648, LY294002, Compound 401, PIK-75 HCl, KU-0060648, CC-115, PP121, SF2523, YU238259, LTURM34, Nedisertib (M3814), Samotolisib (LY3023414), Wortmannin, NU7441 (KU-57788), PI-103, T0070907, Torin 2, Alt-R™, SCR7, L755507, EPZ5676, rucaparib, pevonedistat, brefeldin A, Alt-R HDR Enhancer V1, XL413, trichostatin A, CRISPYTMMix, romidepsin, nedisertib, and Alt-R HDR Enhancer V2 and NU7026). Attorney Docket No.10935-031WO1 Also disclosed herein are methods of treating, reducing, decreasing, inhibiting, ameliorating, and / or preventing a genetic disorder of any preceding aspect, wherein the mutant allele can comprise an autosomal dominant allele including, but not limited to an incomplete or complete autosomal dominant allele. In some aspects, the mutant allele comprises a target strand and a non-target strand complementary to the target strand. In some aspects, the gRNA is complementary to target strand. In one aspect, disclosed herein are methods of treating, reducing, decreasing, inhibiting, ameliorating, and / or preventing a genetic disorder of any preceding aspect, wherein the gRNA does not target the wild-type allele of the gene. In some aspects, the gRNA comprises a sequence selected from the group consisting of SEQ ID NOs: 1-9 or a fragment thereof. Also disclosed herein are methods of treating, reducing, decreasing, inhibiting, ameliorating, and / or preventing a genetic disorder of any preceding aspect, wherein the genetic disorder is an autosomal dominant genetic disorder (such as for example, a proliferation disorder, blood disorder, vision disorder, connective tissue disorder, and protein processing disorder including, but not limited to achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, hereditary elliptocytosis, and Ablepharon macrostomia syndrome Acropectoral syndrome, Acute intermittent porphyria Adermatoglyphia, ADNP syndrome, Albright's hereditary osteodystrophy Ankylosing vertebral hyperostosis with tylosis Aphalangy-syndactyly-microcephaly syndrome Arakawa's syndrome II, Aromatase excess syndrome Autosomal dominant cerebellar ataxia, Autosomal dominant Charcot–Marie–Tooth disease type 2 with giant axons Autosomal dominant GTP cyclohydrolase I deficiency, Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Autosomal dominant nocturnal frontal lobe epilepsy, Autosomal dominant partial epilepsy with auditory features Autosomal dominant polycystic kidney disease Axenfeld–Rieger syndrome, Bainbridge– Ropers syndrome Barber–Say syndrome Beck–Fahrner syndrome Benign hereditary chorea Bethlem myopathy, Birt–Hogg–Dubé syndrome, Blepharophimosis, ptosis, epicanthus inversus syndrome Blepharoptosis-myopia-ectopia lentis syndrome Boomerang dysplasia, Bosch- Boonstra-Schaaf optic atrophy syndrome Brachydactyly-long thumb syndrome, Branchio-oto- renal syndrome Buschke–Ollendorff syndrome, Calvarial doughnut lesions-bone fragility syndrome Camptodactyly-taurinuria syndrome Camurati–Engelmann disease, CAPOS syndrome Central core disease, Cerebro-costo-mandibular syndrome, Cochleosaccular degeneration with progressive cataracts Cohen-Gibson syndrome, Collagen disease Collagenopathy, types II and XI Attorney Docket No.10935-031WO1 Collins–Pope syndrome, Coloboma of macula-brachydactyly type B syndrome Congenital distal spinal muscular atrophy, Congenital stromal corneal dystrophy Costello syndrome, Craniofacial dysostosis-diaphyseal hyperplasia syndrome Currarino syndrome, Cyprus facial neuromusculoskeletal syndrome Czech dysplasia, metatarsal type, Darier's disease GLUT1 deficiency, Dentatorubral–pallidoluysian atrophy Dermatopathia pigmentosa reticularis DiGeorge syndrome Dysfibrinogenemia, Emberger syndrome, Familial amyloid polyneuropathy Familial atrial fibrillation, Familial cutaneous collagenoma, Familial disseminated comedones without dyskeratosis Familial hypercholesterolemia, Familial male-limited precocious puberty Feingold syndrome, Felty's syndrome, Fibular aplasia-ectrodactyly syndrome Flynn–Aird syndrome, Gardner's syndrome GATA2 deficiency, GATAD2B-associated neurodevelopmental disorder Gillespie syndrome, Gray platelet syndrome, Greig cephalopolysyndactyly syndrome, Hagemoser–Weinstein–Bresnick syndrome Hajdu–Cheney syndrome Haploinsufficiency of A20, Hawkinsinuria Hay–Wells syndrome, Heart-hand syndrome, Spanish type Hemochromatosis type 4, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome Hereditary elliptocytosis, Hereditary hemorrhagic telangiectasia Hereditary mucoepithelial dysplasia Hereditary neurocutaneous angioma Hereditary spherocytosis, Holt–Oram syndrome Huntington's disease, Huntington's disease-like syndrome Hyperinsulinism-hyperammonemia syndrome Hypertrophic cardiomyopathy Hypoalphalipoproteinemia Hypochondroplasia, Hypodysfibrinogenemia, IVIC syndrome, Jackson–Weiss syndrome Jordan's Syndrome, Juberg- Hayward syndrome Juvenile-onset dystonia, Keratoendotheliitis fugax hereditaria Keratolytic winter erythema, Kniest dysplasia, Langer–Giedion syndrome Larsen syndrome, Leucine- sensitive hypoglycemia of infancy Liddle's syndrome, Marfan syndrome Marshall syndrome Marsili syndrome, Medullary cystic kidney disease Menke-Hennekam syndrome Metachondromatosis Miller–Dieker syndrome, MOMO syndrome Monilethrix MonoMAC, Multiple endocrine neoplasia Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2B, Muscular atrophy-ataxia-retinitis pigmentosa- diabetes mellitus syndrome Myelokathexis, Myotonic dystrophy, Nablus mask-like facial syndrome, Naegeli–Franceschetti–Jadassohn syndrome Nail–patella syndrome, Noonan syndrome, Oculopharyngeal muscular dystrophy Otofaciocervical syndrome, Pachyonychia congenita Pallister–Hall syndrome, Palmoplantar keratoderma with deafness PAPA syndrome, Papillorenal syndrome Parastremmatic dwarfism Pashayan syndrome Pelger–Huët anomaly Peutz–Jeghers syndrome Piebaldism, Platyspondylic lethal skeletal dysplasia, Torrance type Polydactyly, Polymerase proofreading-associated polyposis Popliteal pterygium syndrome, Porphyria cutanea tarda Pseudoachondroplasia, RASopathy, Reis–Bucklers corneal dystrophy Attorney Docket No.10935-031WO1 Romano–Ward syndrome Rosselli–Gulienetti syndrome Roussy–Lévy syndrome Rubinstein– Taybi syndrome, Saethre–Chotzen syndrome, Scalp defects-postaxial polydactyly syndrome Schmitt Gillenwater Kelly syndrome, Severe congenital neutropenia, Severe intellectual disability- progressive spastic diplegia syndrome Short QT syndrome, Singleton Merten syndrome, Spastic paraplegia 6 Spastic paraplegia 31, Spinal muscular atrophy with lower extremity predominance 1 Spinal muscular atrophy with lower extremity predominance 2A Spinal muscular atrophy with lower extremity predominance 2B Spinocerebellar ataxia, Spinocerebellar ataxia type 1 Spinocerebellar ataxia type 6, Split hand split foot-nystagmus syndrome Spondyloepimetaphyseal dysplasia, Strudwick type Spondyloepiphyseal dysplasia congenita Spondyloperipheral dysplasia, St. Helena familial genu valgum Stickler syndrome, Syndactyly-nystagmus syndrome due to 2q31.1 microduplication SYNGAP1-related intellectual disability, SYT1-associated neurodevelopmental disorder, Thumb stiffness-brachydactyly-intellectual disability syndrome Tietz syndrome, Timothy syndrome Treacher Collins syndrome, Tricho–dento–osseous syndrome, TRPM3-related neurodevelopmental disorders Tuberous sclerosis, Upington disease, Variegate porphyria, Ventricular extrasystoles with syncopal episodes-perodactyly-Robin sequence syndrome Verloes Van Maldergem Marneffe syndrome, Vitelliform macular dystrophy Von Hippel–Lindau disease Von Willebrand disease, Wallis–Zieff–Goldblatt syndrome WHIM syndrome,or White sponge nevus) comprising administering to the subject the system of any of the preceding aspects. For example, disclosed herein are methods of treating a genetic disorder (such as for example, a proliferation disorder, blood disorder, vision disorder, connective tissue disorder, and protein processing disorder associated with an autosomal dominant mutation including, but not limited to achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, hereditary elliptocytosis, and Ablepharon macrostomia syndrome Acropectoral syndrome, Acute intermittent porphyria Adermatoglyphia, ADNP syndrome, Albright's hereditary osteodystrophy Ankylosing vertebral hyperostosis with tylosis Aphalangy-syndactyly-microcephaly syndrome Arakawa's syndrome II, Aromatase excess syndrome Autosomal dominant cerebellar ataxia, Autosomal dominant Charcot–Marie–Tooth disease type 2 with giant axons Autosomal dominant GTP cyclohydrolase I deficiency, Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Autosomal dominant nocturnal frontal lobe epilepsy, Autosomal dominant partial epilepsy with auditory features Autosomal dominant polycystic kidney disease Axenfeld–Rieger syndrome, Bainbridge– Ropers syndrome Barber–Say syndrome Beck–Fahrner syndrome Benign hereditary chorea Attorney Docket No.10935-031WO1 Bethlem myopathy, Birt–Hogg–Dubé syndrome, Blepharophimosis, ptosis, epicanthus inversus syndrome Blepharoptosis-myopia-ectopia lentis syndrome Boomerang dysplasia, Bosch- Boonstra-Schaaf optic atrophy syndrome Brachydactyly-long thumb syndrome, Branchio-oto- renal syndrome Buschke–Ollendorff syndrome, Calvarial doughnut lesions-bone fragility syndrome Camptodactyly-taurinuria syndrome Camurati–Engelmann disease, CAPOS syndrome Central core disease, Cerebro-costo-mandibular syndrome, Cochleosaccular degeneration with progressive cataracts Cohen-Gibson syndrome, Collagen disease Collagenopathy, types II and XI Collins–Pope syndrome, Coloboma of macula-brachydactyly type B syndrome Congenital distal spinal muscular atrophy, Congenital stromal corneal dystrophy Costello syndrome, Craniofacial dysostosis-diaphyseal hyperplasia syndrome Currarino syndrome, Cyprus facial neuromusculoskeletal syndrome Czech dysplasia, metatarsal type, Darier's disease GLUT1 deficiency, Dentatorubral–pallidoluysian atrophy Dermatopathia pigmentosa reticularis DiGeorge syndrome Dysfibrinogenemia, Emberger syndrome, Familial amyloid polyneuropathy Familial atrial fibrillation, Familial cutaneous collagenoma, Familial disseminated comedones without dyskeratosis Familial hypercholesterolemia, Familial male-limited precocious puberty Feingold syndrome, Felty's syndrome, Fibular aplasia-ectrodactyly syndrome Flynn–Aird syndrome, Gardner's syndrome GATA2 deficiency, GATAD2B-associated neurodevelopmental disorder Gillespie syndrome, Gray platelet syndrome, Greig cephalopolysyndactyly syndrome, Hagemoser–Weinstein–Bresnick syndrome Hajdu–Cheney syndrome Haploinsufficiency of A20, Hawkinsinuria Hay–Wells syndrome, Heart-hand syndrome, Spanish type Hemochromatosis type 4, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome Hereditary elliptocytosis, Hereditary hemorrhagic telangiectasia Hereditary mucoepithelial dysplasia Hereditary neurocutaneous angioma Hereditary spherocytosis, Holt–Oram syndrome Huntington's disease, Huntington's disease-like syndrome Hyperinsulinism-hyperammonemia syndrome Hypertrophic cardiomyopathy Hypoalphalipoproteinemia Hypochondroplasia, Hypodysfibrinogenemia, IVIC syndrome, Jackson–Weiss syndrome Jordan's Syndrome, Juberg- Hayward syndrome Juvenile-onset dystonia, Keratoendotheliitis fugax hereditaria Keratolytic winter erythema, Kniest dysplasia, Langer–Giedion syndrome Larsen syndrome, Leucine- sensitive hypoglycemia of infancy Liddle's syndrome, Marfan syndrome Marshall syndrome Marsili syndrome, Medullary cystic kidney disease Menke-Hennekam syndrome Metachondromatosis Miller–Dieker syndrome, MOMO syndrome Monilethrix MonoMAC, Multiple endocrine neoplasia Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2B, Muscular atrophy-ataxia-retinitis pigmentosa- diabetes mellitus syndrome Myelokathexis, Myotonic dystrophy, Nablus mask-like facial Attorney Docket No.10935-031WO1 syndrome, Naegeli–Franceschetti–Jadassohn syndrome Nail–patella syndrome, Noonan syndrome, Oculopharyngeal muscular dystrophy Otofaciocervical syndrome, Pachyonychia congenita Pallister–Hall syndrome, Palmoplantar keratoderma with deafness PAPA syndrome, Papillorenal syndrome Parastremmatic dwarfism Pashayan syndrome Pelger–Huët anomaly Peutz–Jeghers syndrome Piebaldism, Platyspondylic lethal skeletal dysplasia, Torrance type Polydactyly, Polymerase proofreading-associated polyposis Popliteal pterygium syndrome, Porphyria cutanea tarda Pseudoachondroplasia, RASopathy, Reis–Bucklers corneal dystrophy Romano–Ward syndrome Rosselli–Gulienetti syndrome Roussy–Lévy syndrome Rubinstein– Taybi syndrome, Saethre–Chotzen syndrome, Scalp defects-postaxial polydactyly syndrome Schmitt Gillenwater Kelly syndrome, Severe congenital neutropenia, Severe intellectual disability- progressive spastic diplegia syndrome Short QT syndrome, Singleton Merten syndrome, Spastic paraplegia 6 Spastic paraplegia 31, Spinal muscular atrophy with lower extremity predominance 1 Spinal muscular atrophy with lower extremity predominance 2A Spinal muscular atrophy with lower extremity predominance 2B Spinocerebellar ataxia, Spinocerebellar ataxia type 1 Spinocerebellar ataxia type 6, Split hand split foot-nystagmus syndrome Spondyloepimetaphyseal dysplasia, Strudwick type Spondyloepiphyseal dysplasia congenita Spondyloperipheral dysplasia, St. Helena familial genu valgum Stickler syndrome, Syndactyly-nystagmus syndrome due to 2q31.1 microduplication SYNGAP1-related intellectual disability, SYT1-associated neurodevelopmental disorder, Thumb stiffness-brachydactyly-intellectual disability syndrome Tietz syndrome, Timothy syndrome Treacher Collins syndrome, Tricho–dento–osseous syndrome, TRPM3-related neurodevelopmental disorders Tuberous sclerosis, Upington disease, Variegate porphyria, Ventricular extrasystoles with syncopal episodes-perodactyly-Robin sequence syndrome Verloes Van Maldergem Marneffe syndrome, Vitelliform macular dystrophy Von Hippel–Lindau disease Von Willebrand disease, Wallis–Zieff–Goldblatt syndrome WHIM syndrome,or White sponge nevus) in a subject comprising administering to the subject a system for modulating a mutant allele of a gene, said system comprising a guide RNA (gRNA) sequence targeting the mutant allele of the gene comprising one or more mutations (including, but not limited to point mutations, insertions, deletions, or translocations), wherein at least one of the one or more mutations is upstream the 5’ end or downstream of the 3’ end of a protospacer adjacent motif (PAM) sequence (such as, for example, NGG, NNGRR, NNGRRT, or NNNNGATT including, but not limited to AAGAA, TGGGAT, GGG, or TGG). In some instances, the one or more mutations are within 7, 6, 5, 4, 3, 2, 1, nucleotides of the PAM sequence. In one aspect, disclosed herein are methods of repairing or causing the mutational correction of an autosomal dominant mutation (such as, for example, a mutation associated with Attorney Docket No.10935-031WO1 achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, hereditary elliptocytosis, and Ablepharon macrostomia syndrome Acropectoral syndrome, Acute intermittent porphyria Adermatoglyphia, ADNP syndrome, Albright's hereditary osteodystrophy Ankylosing vertebral hyperostosis with tylosis Aphalangy-syndactyly-microcephaly syndrome Arakawa's syndrome II, Aromatase excess syndrome Autosomal dominant cerebellar ataxia, Autosomal dominant Charcot–Marie–Tooth disease type 2 with giant axons Autosomal dominant GTP cyclohydrolase I deficiency, Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Autosomal dominant nocturnal frontal lobe epilepsy, Autosomal dominant partial epilepsy with auditory features Autosomal dominant polycystic kidney disease Axenfeld–Rieger syndrome, Bainbridge– Ropers syndrome Barber–Say syndrome Beck–Fahrner syndrome Benign hereditary chorea Bethlem myopathy, Birt–Hogg–Dubé syndrome, Blepharophimosis, ptosis, epicanthus inversus syndrome Blepharoptosis-myopia-ectopia lentis syndrome Boomerang dysplasia, Bosch- Boonstra-Schaaf optic atrophy syndrome Brachydactyly-long thumb syndrome, Branchio-oto- renal syndrome Buschke–Ollendorff syndrome, Calvarial doughnut lesions-bone fragility syndrome Camptodactyly-taurinuria syndrome Camurati–Engelmann disease, CAPOS syndrome Central core disease, Cerebro-costo-mandibular syndrome, Cochleosaccular degeneration with progressive cataracts Cohen-Gibson syndrome, Collagen disease Collagenopathy, types II and XI Collins–Pope syndrome, Coloboma of macula-brachydactyly type B syndrome Congenital distal spinal muscular atrophy, Congenital stromal corneal dystrophy Costello syndrome, Craniofacial dysostosis-diaphyseal hyperplasia syndrome Currarino syndrome, Cyprus facial neuromusculoskeletal syndrome Czech dysplasia, metatarsal type, Darier's disease GLUT1 deficiency, Dentatorubral–pallidoluysian atrophy Dermatopathia pigmentosa reticularis DiGeorge syndrome Dysfibrinogenemia, Emberger syndrome, Familial amyloid polyneuropathy Familial atrial fibrillation, Familial cutaneous collagenoma, Familial disseminated comedones without dyskeratosis Familial hypercholesterolemia, Familial male-limited precocious puberty Feingold syndrome, Felty's syndrome, Fibular aplasia-ectrodactyly syndrome Flynn–Aird syndrome, Gardner's syndrome GATA2 deficiency, GATAD2B-associated neurodevelopmental disorder Gillespie syndrome, Gray platelet syndrome, Greig cephalopolysyndactyly syndrome, Hagemoser–Weinstein–Bresnick syndrome Hajdu–Cheney syndrome Haploinsufficiency of A20, Hawkinsinuria Hay–Wells syndrome, Heart-hand syndrome, Spanish type Hemochromatosis type 4, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome Hereditary Attorney Docket No.10935-031WO1 elliptocytosis, Hereditary hemorrhagic telangiectasia Hereditary mucoepithelial dysplasia Hereditary neurocutaneous angioma Hereditary spherocytosis, Holt–Oram syndrome Huntington's disease, Huntington's disease-like syndrome Hyperinsulinism-hyperammonemia syndrome Hypertrophic cardiomyopathy Hypoalphalipoproteinemia Hypochondroplasia, Hypodysfibrinogenemia, IVIC syndrome, Jackson–Weiss syndrome Jordan's Syndrome, Juberg- Hayward syndrome Juvenile-onset dystonia, Keratoendotheliitis fugax hereditaria Keratolytic winter erythema, Kniest dysplasia, Langer–Giedion syndrome Larsen syndrome, Leucine- sensitive hypoglycemia of infancy Liddle's syndrome, Marfan syndrome Marshall syndrome Marsili syndrome, Medullary cystic kidney disease Menke-Hennekam syndrome Metachondromatosis Miller–Dieker syndrome, MOMO syndrome Monilethrix MonoMAC, Multiple endocrine neoplasia Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2B, Muscular atrophy-ataxia-retinitis pigmentosa- diabetes mellitus syndrome Myelokathexis, Myotonic dystrophy, Nablus mask-like facial syndrome, Naegeli–Franceschetti–Jadassohn syndrome Nail–patella syndrome, Noonan syndrome, Oculopharyngeal muscular dystrophy Otofaciocervical syndrome, Pachyonychia congenita Pallister–Hall syndrome, Palmoplantar keratoderma with deafness PAPA syndrome, Papillorenal syndrome Parastremmatic dwarfism Pashayan syndrome Pelger–Huët anomaly Peutz–Jeghers syndrome Piebaldism, Platyspondylic lethal skeletal dysplasia, Torrance type Polydactyly, Polymerase proofreading-associated polyposis Popliteal pterygium syndrome, Porphyria cutanea tarda Pseudoachondroplasia, RASopathy, Reis–Bucklers corneal dystrophy Romano–Ward syndrome Rosselli–Gulienetti syndrome Roussy–Lévy syndrome Rubinstein– Taybi syndrome, Saethre–Chotzen syndrome, Scalp defects-postaxial polydactyly syndrome Schmitt Gillenwater Kelly syndrome, Severe congenital neutropenia, Severe intellectual disability- progressive spastic diplegia syndrome Short QT syndrome, Singleton Merten syndrome, Spastic paraplegia 6 Spastic paraplegia 31, Spinal muscular atrophy with lower extremity predominance 1 Spinal muscular atrophy with lower extremity predominance 2A Spinal muscular atrophy with lower extremity predominance 2B Spinocerebellar ataxia, Spinocerebellar ataxia type 1 Spinocerebellar ataxia type 6, Split hand split foot-nystagmus syndrome Spondyloepimetaphyseal dysplasia, Strudwick type Spondyloepiphyseal dysplasia congenita Spondyloperipheral dysplasia, St. Helena familial genu valgum Stickler syndrome, Syndactyly-nystagmus syndrome due to 2q31.1 microduplication SYNGAP1-related intellectual disability, SYT1-associated neurodevelopmental disorder, Thumb stiffness-brachydactyly-intellectual disability syndrome Tietz syndrome, Timothy syndrome Treacher Collins syndrome, Tricho–dento–osseous syndrome, TRPM3-related neurodevelopmental disorders Tuberous sclerosis, Upington disease, Variegate Attorney Docket No.10935-031WO1 porphyria, Ventricular extrasystoles with syncopal episodes-perodactyly-Robin sequence syndrome Verloes Van Maldergem Marneffe syndrome, Vitelliform macular dystrophy Von Hippel–Lindau disease Von Willebrand disease, Wallis–Zieff–Goldblatt syndrome WHIM syndrome,or White sponge nevus) in a subject comprising administering to the subject the system of any of the preceding aspect. For example, disclosed herein are methods of repairing or causing the mutational correction of an autosomal dominant mutation in a subject comprising administering to the subject a system for repairing or causing mutational correction of a mutant allele of a heterozygous gene, said system comprising a Cas endonuclease and a guide RNA (gRNA), wherein: a) the gRNA targets a mutant allele of a heterozygous gene, b) the mutant allele comprises one or more mutations (such as, for example, point mutations, insertions, deletions, or translocations), and c) the gRNA does not target the wild-type allele of the gene, including those systems, wherein the system is free from homology directed repair (HDR) template. Also disclosed herein are methods of repairing or causing the mutational correction of an autosomal dominant mutation of any preceding aspect, wherein the guide RNA (gRNA) sequence targeting the mutant allele of the gene comprising one or more mutations (including, but not limited to point mutations, insertions, deletions, or translocations), wherein at least one of the one or more mutations is upstream the 5’ end or downstream of the 3’ end of a protospacer adjacent motif (PAM) sequence (such as, for example, NGG, NNGRR, NNGRRT, or NNNNGATT including, but not limited to AAGAA, TGGGAT, GGG, or TGG). In some instances, the one or more mutations are within 7, 6, 5, 4, 3, 2, 1, nucleotides of the PAM sequence. In one aspect, the method does not use a homology directed repair (HDR) template. In one aspect the system further comprises an HDR enhancer to enhance intra-homologous recombination. In some aspects, the HDR enhancer.is a DNA-dependent protein kinase (DNA-PK) Inhibitor (such as for example AZD7648, LY294002, Compound 401, PIK-75 HCl, KU-0060648, CC-115, PP121, SF2523, YU238259, LTURM34, Nedisertib (M3814), Samotolisib (LY3023414), Wortmannin, NU7441 (KU-57788), PI-103, T0070907, Torin 2, Alt-R™, SCR7, L755507, EPZ5676, rucaparib, pevonedistat, brefeldin A, Alt-R HDR Enhancer V1, XL413, trichostatin A, CRISPYTMMix, romidepsin, nedisertib, and Alt-R HDR Enhancer V2 and NU7026). In some aspects, the mutant allele can comprise an autosomal dominant allele including, but not limited to an incomplete or complete autosomal dominant allele. In some aspects, the mutant allele comprises a target strand and a non-target strand complementary to the target strand. In some aspects, the gRNA is complementary to target strand. In some instances the system is used to modulate a mutant allele of a gene of any preceding aspect, wherein the gRNA does not target the wild-type allele of the gene and wherein the mutant allele is associated with a genetic disorder (such as, for example, a Attorney Docket No.10935-031WO1 dominant-negative disorder including, but not limited to inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal dominant hyper- IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, or KCNT1- related developmental and epileptic encephalopathy). In one aspect, disclosed herein is a system for modulating a heterozygous mutant allele of a gene of any preceding aspect, wherein the mutant allele is of a VCP gene (such as, for example, a VCP gene comprising SEQ ID NO: 10 or a gene for, a STAT3 gene, a FBN1 gene, a APOB gene, a LDLR gene, a PCSK9 gene, a DOCK8 gene, a TBCD gene, or a KCNT1 gene. Also disclosed herein is a system for modulating a mutant allele of a gene of any preceding aspect, wherein the gRNA comprises a sequence selected from the group consisting of SEQ ID NOs: 1-9 or a fragment thereof. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain examples of the present disclosure and together with the description, serve to explain, without limitation, the principles of the disclosure. Like numbers represent the same elements throughout the figures. Figure.1 shows design of gRNAs for targeting mutant allele in IBMPFD patients. Figure 1 shows the sequence of: SaCas9 gRNA1 comprising SEQ ID NO: 1, SaCas9 gRNA2 comprising SEQ ID NO: 2, SpCas9 gRNA1 comprising SEQ ID NO: 3, SpCas9 gRNA2 comprising SEQ ID NO: 4 and SpCas9 gRNA3 comprising SEQ ID NO: 5. SaCas9 gRNA1 PAM sequence comprises SEQ ID NO: 16 (NNGRR) or SEQ ID NO: 17 (AAGAA). SaCas9 gRNA2 PAM sequence comprises SEQ ID NO: 14 (NNGRRT) or SEQ ID NO: 18 (TGGGAT). Figure 1 shows the nucleotide sequence (SEQ ID NO: 20 (top) and SEQ ID NO: 21 (bottom)) and amino acid sequence (SEQ ID NO: 22) of VCP. Figure. 2 shows analysis results of human SpCas9 gRNAs in wildtype and mutant allele. Figure 2 shows the SpCas9 gRNA1 guide target comprising SEQ ID NO: 23. Figure 2 shows that for forward sequencing using the gRNA1, the Normalized Indel Sequence (0) comprises SEQ ID NO: 24, Normalized Indel Sequence (+1) comprises SEQ ID NO: 25, Edited Sample 137 to 202 bp comprises SEQ ID NO: 26 and Control Sample 141 to 206 bp comprises SEQ ID NO: 27. Figure 2 continued further shows that for reverse sequencing using gRNA1, the Normalized Indel Sequence (0) comprises SEQ ID NO: 28, Normalized Indel Sequence (+1) comprises SEQ ID NO: 29, and Edited Sample 131 to 196 bp comprises SEQ ID NO: 30. Figure 2 further shows that SpCas9 gRNA2 guide target comprises SEQ ID NO: 31. Figure 2 continued further shows that for forward sequencing using gRNA2, the Normalized Indel Sequence (0) comprises SEQ ID NO: 32 Attorney Docket No.10935-031WO1 (top) or SEQ ID NO: 33 (bottom). Figure 2 continued also shows that SpCas9 gRNA3 guide target comprises SEQ ID NO: 19 and that for forward sequencing using the gRNA3, the Normalized Indel Sequence (0) comprises SEQ ID NO: 34, Normalized Indel Sequence (+1) comprises SEQ ID NO: 35, Normalized Indel Sequence (-1, 5%) comprises SEQ ID NO: 36, Normalized Indel Sequence (-1, 4%) comprises SEQ ID NO: 37, Normalized Indel Sequence (-6) comprises SEQ ID NO: 38, Normalized Indel Sequence (-4) comprises SEQ ID NO: 39, Normalized Indel Sequence (-2) comprises SEQ ID NO: 40, Edited Sample 136 to 204 bp comprises SEQ ID NO: 41 and Control Sample 137 to 202 bp comprises SEQ ID NO: 42. Figure 2 shows that SpCas9 gRNA3 guide target comprises SEQ ID NO: 43. Figure 2 shows that for reverse sequencing using the gRNA3, the Normalized Indel Sequence (0) comprises SEQ ID NO: 44, Normalized Indel Sequence (+1) comprises SEQ ID NO: 45, Edited Sample 133 to 198 bp comprises SEQ ID NO: 46 and Control Sample 136 to 201 bp comprises SEQ ID NO: 47. Figure 2 shows that the Normalized Indel Sequence (0) with shows no targeting in Jurkat cells and comprises SEQ ID NO: 48 when the guide target sequence is ACATTTTTCTTGTCCGTGGT (SEQ ID NO: 23). The Normalized Indel Sequence (0) comprising SEQ ID NO: 49 shows no targeting in Jurkat cells when guide target sequence is GACATTTTTCTTGTCCGTGG (SEQ ID NO: 31). The Normalized Indel Sequence (0) comprising SEQ ID NO: 50 shows no targeting in Jurkat cells when guide target sequence is GGAGACATTTTTCTTGTCCG (SEQ ID NO: 19). The Normalized Indel Sequence (0) showing no targeting by SaCas9 gRNA2 in Jurkat cells comprises SEQ ID NO: 51. The Normalized Indel Sequence (0) showing no targeting by SaCas9 gRNA1 (SEQ ID NO: 53) in Jurkat cells comprises SEQ ID NO: 52. Figure.3 shows analysis results of SpCas9 gRNAs on mouse myoblast VCP NeoCassette. SpCas9 gRNA1 comprises SEQ ID NO: 6, SpCas9 gRNA2 comprises SEQ ID NO: 7, SpCas9 gRNA3 comprises SEQ ID NO: 8, and SpCas9 gRNA4 comprises SEQ ID NO: 9. Figure 3 shows the nucleotide sequence (SEQ ID NO: 54 (top) and SEQ ID NO: 55 (bottom)) and amino acid sequence (368-20017 Region 5) (SEQ ID NO: 56) of Mouse Neocassette VCP. Figure 3 continued shows that the mouse gRNA2 guide target comprises SEQ ID NO: 57. The Normalized Indel Sequence (0) comprises SEQ ID NO: 58, Normalized Indel Sequence (+2) comprises SEQ ID NO: 59, Edited Sample 305 to 370 bp and Control Sample 305 to 370 bp comprise SEQ ID NO: 60. Figure 3 further continued shows that the mouse gRNA3 guide target comprises SEQ ID NO: 61. The Normalized Indel Sequence (0) comprises SEQ ID NO: 62, Normalized Indel Sequence (+1) comprises SEQ ID NO: 63, Edited Sample 303 to 368 bp comprise SEQ ID NO: 64 and Control Sample 302 to 367 bp comprise SEQ ID NO: 65. Figure 3 continued also shows that the mouse gRNA4 guide target comprises SEQ ID NO: 11. The Normalized Indel Sequence (0) comprises Attorney Docket No.10935-031WO1 SEQ ID NO: 66, Normalized Indel Sequence (+1) comprises SEQ ID NO: 67, Edited Sample 300 to 365 bp comprise SEQ ID NO: 68 and Control Sample 301 to 366 bp comprise SEQ ID NO: 69. Figure.4 shows analysis result of SpCas9 gRNAs on healthy mouse fibroblast. The mouse gRNA1 guide target comprises SEQ ID NO: 70. Normalized Indel Sequence (-1) comprises SEQ ID NO: 71, Normalized Indel Sequence (-2, 19%) comprises SEQ ID NO: 72, Normalized Indel Sequence (+1) comprises SEQ ID NO: 73, Normalized Indel Sequence (-4, 10%) comprises SEQ ID NO: 74, Normalized Indel Sequence (-3) comprises SEQ ID NO: 75, Normalized Indel Sequence (-4, 2%) comprises SEQ ID NO: 76, Normalized Indel Sequence (0) comprises SEQ ID NO: 77, Normalized Indel Sequence (-2, 2%) comprises SEQ ID NO: 78, Edited Sample 214 to 279 bp comprise SEQ ID NO: 79 and Control Sample 217 to 282 bp comprise SEQ ID NO: 80. Normalized Indel Sequence (0) targeted by gRNA2 comprises SEQ ID NO: 81. Edited Sample 205 to 271 bp and Control Sample 211 to 276 bp targeted by gRNA2 comprises SEQ ID NO: 82. Normalized Indel Sequence (0) targeted by gRNA3 comprises SEQ ID NO: 83. Edited Sample 209 to 274 bp and Control Sample 214 to 278 bp targeted by gRNA3 (SEQ ID NO: 61) comprises SEQ ID NO: 84. Normalized Indel Sequence (0) targeted by gRNA3 with guide target comprising SEQ ID NO: 11 comprises SEQ ID NO: 85. Edited Sample 211 to 276 bp and Control Sample 215 to 260 bp targeted by gRNA3 comprise SEQ ID NO: 86. Figure. 5 displays schematic showing targeting autosomal dominant genetic disorders using gRNAs recognizing only the mutant allele. Figure. 6 shows design of gRNA. Amino acid sequence comprising mutation R155H in VCP comprises SEQ ID NO: 87 (top) or SEQ ID NO: 96 (bottom). SEQ ID NO: 94 (top) or SEQ ID NO: 95 (bottom) comprise the nucleotide sequence of VCP comprising mutation R155H. Figure 6 also shows that gRNAs can be designed with the mutated sequence (M) included in the gRNA within 1-5 base pairs of the PAM sequence at the 5’ side. SEQ ID NO: 88 shows when M is adjacent to the PAM. SEQ ID NO: 89 shows when M is 1 base pair away from the PAM sequence. SEQ ID NO: 90 shows when M is 2 base pairs away from the PAM sequence. SEQ ID NO: 91 shows when M is 3 base pairs away from the PAM sequence. SEQ ID NO: 92 shows when M is 4 base pairs away from the PAM sequence. SEQ ID NO: 93 shows when M is 5 base pairs away from the PAM sequence. Figure. 7 shows results of targeted mutant allele modulation in the absence of homology directed repair template. Figure 7 shows that gRNA can target Normalized Indel Sequence (0) comprising SEQ ID NO: 97 and Normalized Indel Sequence (+1) comprises SEQ ID NO: 98. Figure 8A, 8B, 8C, 8D, 8E, 8F and 8G show REMEDY results in highly efficient heterozygous mutation correction using HDR between homologous chromosomes and does not Attorney Docket No.10935-031WO1 need an exogenous DNA template as shown in Figure 8A. REMEDY corrected heterozygous mutations in VCP mouse myoblasts as shown in Figure 8B and in human IBFMD patient derived skin fibroblast measured by Sanger sequencing as shown in Figure 8C. REMEDY corrected mutation in TBCD gene and the addition of HDR enhancer enhances the correction measured by Sanger sequencing as shown in Figure 8D. Figures 8E and 8F show that NGS demonstrated similar correction rate detected by Sanger sequencing. Figure 8E shows the sequence of the Non-edited, TBCD; 2305-2307 ∆GAG 48.91% (20215 reads) in SEQ ID NO: 99 and the Non-edited, TBCD; 2305-2307 ∆GAG 48.06% (19862 reads) as in SEQ ID NO: 100. Figure 8E shows REMEDY gRNA3 in the presence of HDR enhancer at 68.82% (29885 reads) comprising SEQ ID NO: 100, 9.96% (4326 reads) comprising SEQ ID NO: 99, 2.64% (1146 reads) comprising SEQ ID NO: 101, 1.95% (847 reads) comprising SEQ ID NO: 102, 1.34% (584 reads) comprising SEQ ID NO: 103, 0.79% (345 reads) comprising SEQ ID NO: 104, 0.78% (339 reads) comprising SEQ ID NO: 105. Figure 8G shows Wildtype TBCD; 2305-2307 ∆GAG comprising SED ID NO: 106 and TBCD; 2305-2307 ∆GAG gRNA3 + HDR enhancer comprising SED ID NO: 113. Figure 8G also shows that single cell cloned REMEDY edited TBCD fibroblasts confirmed the sequencing results and shows that the edits are stable after growing cells for 10 days. Figure 8G shows the Non-edited, TBCD; 2305-2307 ∆GAG comprising SED ID NO: 112, Corrected Clone 1 TBCD; 2305-2307 ∆GAG comprising SED ID NO: 107, Clone 2 TBCD; 2305-2307 ∆GAG comprising SED ID NO: 108, Clone 3 TBCD; 2305-2307 ∆GAG comprising SED ID NO: 109, Clone 4 TBCD; 2305-2307 ∆GAG comprising SED ID NO: 110 and Clone 5 TBCD; 2305-2307 ∆GAG comprising SED ID NO: 111. Figures 9A, 9B, 9C, 9D, and 9E show REMEDY corrects several heterozygous mutations in different cell types and diseases. Figures 9A and 9B shows that REMEDY corrected heterozygous mutations in ITPR3 heterozygous mutation in human skin fibroblast measured by NGS; and in human airway epithelial cells with CFTR heterozygous mutation derived from a patient with CF measured by Sanger sequencing as shown in Figures 9C and 9D. Figure 9B shows the non-edited ITPR3 reference and non-edited ITPR3 wildtype reference 52.08% (71520 reads) sequences comprising SEQ ID NO: 114, non-edited ITPR3 wildtype reference 40.02% (54963 reads) comprising SEQ ID NO: 115, non-edited ITPR3 wildtype reference 4.95% (6804 reads) comprising SEQ ID NO: 116. Figure 9B further shows the gRNA-targeted; ITPR3 wildtype sequence 54.68% (74056 reads) comprising SEQ ID NO: 117, ITPR3 wildtype sequence 30.78% (41692 reads) comprising SEQ ID NO: 118 and ITPR3 wildtype sequence 1.70% (2302 reads) comprising SEQ ID NO: 119. Figure 9B also shows gRNA + AZD7648-targeted; ITPR3 sequence 64.56% (86705 reads) comprising SEQ ID NO: 120, ITPR3 sequence 17.55% (23569 reads) Attorney Docket No.10935-031WO1 comprising SEQ ID NO: 121, ITPR3 sequence 10.92% (14667 reads) comprising SEQ ID NO: 122 and gRNA + HDR enhancer V2-targeted; ITPR3 sequence 63.82% (127444 reads) comprising SEQ ID NO: 123, ITPR3 sequence 30.22% (60334 reads) comprising SEQ ID NO: 124 and ITPR3 sequence 2.57% (5129reads) comprising SEQ ID NO: 125. Figure 9D shows the wildtype CFTR sequence comprising SEQ ID NO: 126, F508 / TGGdel CFTR sequence comprising SEQ ID NO: 127, gRNA1-targeted CFTR sequence comprising SEQ ID NO: 128, gRNA1 + AZD7648-targeted CFTR sequence comprising SEQ ID NO: 129, gRNA2-targeted CFTR sequence comprising SEQ ID NO: 130 and gRNA2 + AZD7648-targeted CFTR sequence comprising SEQ ID NO: 131. Figure 9E shows similar results in fibroblasts derived from Progeria patients measured by Sanger sequencing. REMEDY does not induce LOH, or CNV. Figure 10 shows testing allele specific gRNAs in healthy mouse fibroblast wildtype VCP reference sequence comprising SED ID NO: 197, gRNA1-targeted VCP sequence comprising SED ID NO: 198, gRNA2-targeted VCP sequence comprising SED ID NO: 199, gRNA3-targeted VCP sequence comprising SED ID NO: 200 and gRNA4-targeted VCP sequence comprising SED ID NO: 201. Figure 11 shows testing allele specific gRNAs in VCP c.464_465GG>AT of mouse myoblasts. Figure 11 shows wildtype VCP comprising SED ID NO: 202, VCP mutant sequence comprising SED ID NO: 203, gRNA2-targeted VCP mutant sequence comprising SED ID NO: 204, gRNA3-targeted VCP mutant sequence comprising SED ID NO: 205, and gRNA4-targeted VCP mutant sequence comprising SED ID NO: 206. Figure 12 shows testing REMEDY in mouse cells to detect on-target and off-targets in PAM or near-PAM gRNAs (Table 3) strategies were tested in mouse healthy fibroblasts as also shown in Figure 10 and VCP mouse myoblasts as shown in Figure 11 to study on-target and off- targets measured by Sanger and NGS sequencing. Figure 12 shows the reference VCP + / - sequence comprising SED ID NO: 207, VCP mutant sequences: non-edited 49.16% (42475 reads) comprising SED ID NO: 208, non-edited 45.57% (39023 reads) comprising SED ID NO: 209, non-edited 0.30% (258 reads) comprising SED ID NO: 210, non-edited 0.25% (217 reads) comprising SED ID NO: 211, gRNA2-targeted: VCP mutant 54.70% (31187 reads) comprising SEQ ID NO: 212, VCP mutant 7.39% (4211 reads) comprising SEQ ID NO: 213, VCP mutant 2.33% (1327 reads) comprising SEQ ID NO: 214, VCP mutant 1.69% (965 reads) comprising SEQ ID NO: 215, gRNA3-targeted: VCP mutant 47.64% (62358 reads) comprising SEQ ID NO: 216, VCP mutant 10.70% (14022 reads) comprising SEQ ID NO: 217, VCP mutant 2.35% (3070 reads) comprising SEQ ID NO: 218, VCP mutant 2.14% (2806 reads) comprising SEQ ID NO: 219, and gRNA4-targeted: VCP mutant 48.92% (72804 reads) comprising SEQ ID NO: 220, VCP mutant Attorney Docket No.10935-031WO1 22.29% (33180 reads) comprising SEQ ID NO: 221, VCP mutant 4.27% (6362 reads) comprising SEQ ID NO: 222, and VCP mutant 1.33% (1981 reads) comprising SEQ ID NO: 223. Figure 13A and 13B show testing REMEDY in VCP c.464G>A (p.Arg155His) patient derived human fibroblast targeting wildtype allele, measured by Sanger sequencing (Figure 13A) and NGS (Figure 13B). Figure 13A shows the VCP c.464G>A (p.Arg155His) sequence comprising SEQ ID NO: 224, gRNA1 guide target sequence comprising SEQ ID NO: 225 and the gRNA2 guide target sequence comprising SEQ ID NO: 226. As shown in Figure 13B, the mutant VCP reference sequence comprises SEQ ID NO: 227. Figure 13B shows the sequence of: 59.67% (1027 reads) mutant VCP comprising SEQ ID NO: 228, 6.39% (110 reads) mutant VCP comprising SEQ ID NO: 229, 6.16% (106 reads) mutant VCP comprising SEQ ID NO: 230, 4.47% (77 reads) mutant VCP comprising SEQ ID NO: 231, 2.03% (35 reads) mutant VCP comprising SEQ ID NO: 232, 0.93% (16 reads) mutant VCP comprising SEQ ID NO: 233 (row 6) or SEQ ID NO: 234 (row 7), 0.70% (12 reads) mutant VCP comprising SEQ ID NO: 235 (row 8) or SEQ ID NO: 236 (row 9), 0.46% (8 reads) mutant VCP comprising SEQ ID NO: 237, 0.41% (7 reads) mutant VCP comprising SEQ ID NO: 238 (row 11), SEQ ID NO: 239 (row 12), SED ID NO: 240 (row 13) or SEQ ID NO: 241 (row 14), 0.35% (6 reads) mutant VCP comprising SEQ ID NO: 242 (row 15) or SEQ ID NO: 243 (row 16), 0.29% (5 reads) mutant VCP comprising SEQ ID NO: 244 (row 17) or SEQ ID NO: 245 (row 18), 0.23% (4 reads) mutant VCP comprising SEQ ID NO: 246 (row 19), SEQ ID NO: 247 (row 20), SEQ ID NO: 248 (row 21), SEQ ID NO: 249 (row 22), SEQ ID NO: 250 (row 23), or SEQ ID NO: 251 (row 24). Figure 14 shows testing REMEDY in human patient-derived skin fibroblast with heterozygous mutation in TBCD (P8M2). Efficiency of REMEDY studied by deep Sanger sequencing. Figure 15 shows testing REMEDY in human patient-derived skin fibroblast with heterozygous mutation in TBCD (P8M2). Efficiency of REMEDY studied by NGS. Figure 15 shows the non-edited TBCD wildtype sequence 48.72% (60694 reads) comprising SEQ ID NO: 252, non-edited TBCD wildtype sequence 48.08% (59888 reads) comprising SEQ ID NO: 253. REMEDY gRNA-targeted: TBCD wildtype sequence 55.98% (67327 reads) comprising SEQ ID NO: 252, and TBCD wildtype sequence 15.74% (18933 reads) comprising SEQ ID NO: 253. Figure 15 also shows REMEDY gRNA+ HDR enhancer (IDT)-targeted: TBCD wildtype sequence 68.11% (79038 reads) comprising SEQ ID NO: 252, and TBCD wildtype sequence 8.28% (9608 reads) comprising SEQ ID NO: 253. Figure 15 also shows REMEDY gRNA+ AZD7648-targeted TBCD wildtype sequence 56.76% (61914 reads) comprising SEQ ID NO: 252, and REMEDY Attorney Docket No.10935-031WO1 gRNA+ AZD7648-targeted TBCD wildtype sequence 13.50% (14728 reads) comprising SEQ ID NO: 253. Figure 16 shows Sanger sequencing data of the ITPR3 gene targeted in human skin fibroblast with heterozygous mutation. Data was analyzed by ICE. DETAILED DESCRIPTION The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiment. To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various embodiments of the invention described herein, while still obtaining the beneficial results of the present disclosure. It will also be apparent that some of the desired benefits of the present disclosure can be obtained by selecting some of the features of the present disclosure without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the present disclosure are possible and can even be desirable in certain circumstances and are a part of the present disclosure. Thus, the following description is provided as illustrative of the principles of the present disclosure and not in limitation thereof. A. DEFINITIONS As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed the “less than or equal to 10”as well as “greater than or equal to 10” is also disclosed. It is also understood that the throughout the application, data is Attorney Docket No.10935-031WO1 provided in a number of different formats, and that this data represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. “Administration” or “administering” to a subject includes any route of introducing or delivering to a subject an agent. Administration can be carried out by any suitable route, including oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation, via an implanted reservoir, parenteral (e.g., subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injections or infusion techniques), and the like. "Concurrent administration", "administration in combination", "simultaneous administration" or "administered simultaneously" as used herein, means that the compounds are administered at the same point in time or essentially immediately following one another. In the latter case, the two compounds are administered at times sufficiently close that the results observed are indistinguishable from those achieved when the compounds are administered at the same point in time. “Systemic administration” refers to the introducing or delivering to a subject an agent via a route which introduces or delivers the agent to extensive areas of the subject’s body (e.g., greater than 50% of the body), for example through entrance into the circulatory or lymph systems. By contrast, “local administration” refers to the introducing or delivery to a subject an agent via a route which introduces or delivers the agent to the area or area immediately adjacent to the point of administration and does not introduce the agent systemically in a therapeutically significant amount. For example, locally administered agents are easily detectable in the local vicinity of the point of administration but are undetectable or detectable at negligible amounts in distal parts of the subject’s body. Administration includes self-administration and the administration by another. A “control” is an alternative subject or sample used in an experiment for comparison purposes. A control can be "positive" or "negative." “Complementary” or “substantially complementary” refers to the hybridization or base pairing or the formation of a duplex between nucleotides or nucleic acids, such as, for instance, between the two strands of a double stranded DNA molecule or between an oligonucleotide primer and a primer binding site on a single stranded nucleic acid. Complementary nucleotides are, generally, A and T / U, or C and G. Two single-stranded RNA or DNA molecules are said to be Attorney Docket No.10935-031WO1 substantially complementary when the nucleotides of one strand, optimally aligned and compared and with appropriate nucleotide insertions or deletions, pair with at least about 80% of the nucleotides of the other strand, usually at least about 90% to 95%, and more preferably from about 98% to 100%. Alternatively, substantial complementarity exists when an RNA or DNA strand hybridizes under selective hybridization conditions to its complement. Typically, selective hybridization will occur when there is at least about 65% complementary over a stretch of at least 14 to 25 nucleotides, at least about 75%, or at least about 90% complementary. See Kanehisa (1984) Nucl. Acids Res.12:203. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments and are also disclosed. “Composition” refers to any agent that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other undesirable physiological condition. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, a vector, polynucleotide, cells, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the term “composition” is used, then, or when a particular composition is specifically identified, it is to be understood that the term includes the composition per se as well as pharmaceutically acceptable, pharmacologically active vector, polynucleotide, salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc. A DNA sequence that "encodes" a particular RNA is a DNA nucleic acid sequence that is transcribed into RNA. A DNA polynucleotide may encode an RNA (mRNA) that is translated into protein (and therefore the DNA and the mRNA both encode the protein), or a DNA polynucleotide may encode an RNA that is not translated into protein (e.g. tRNA, rRNA, microRNA (miRNA), a "non-coding" RNA (ncRNA), a guide RNA, etc.). "Expression vector" refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed. An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system. Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked or Attorney Docket No.10935-031WO1 contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno- associated viruses) that incorporate the recombinant polynucleotide.) The “fragments,” whether attached to other sequences or not, can include insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues, provided the activity of the fragment is not significantly altered or impaired compared to the nonmodified peptide or protein. These modifications can provide for some additional property, such as to remove or add amino acids capable of disulfide bonding, to increase its bio-longevity, to alter its secretory characteristics, etc. In any case, the fragment must possess a bioactive property, such as regulating the transcription of the target gene. The term "gene" or "gene sequence" refers to the coding sequence or control sequence, or fragments thereof. A gene may include any combination of coding sequence and control sequence, or fragments thereof. Thus, a "gene" as referred to herein may be all or part of a native gene. A polynucleotide sequence as referred to herein may be used interchangeably with the term "gene”, or may include any coding sequence, non-coding sequence or control sequence, fragments thereof, and combinations thereof. The term "gene" or "gene sequence" includes, for example, control sequences upstream of the coding sequence (for example, the ribosome binding site). The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99% or higher identity over a specified region when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site or the like). Such sequences are then said to be “substantially identical.” This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 10 amino acids or 20 nucleotides in length, or more preferably over a region that is 10-50 amino acids or 20-50 nucleotides in length. As used herein, percent (%) nucleotide sequence identity is defined as the percentage of amino acids in a candidate sequence that are identical to the nucleotides in a reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment Attorney Docket No.10935-031WO1 for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software. Appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared can be determined by known methods. For sequence comparisons, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Preferably, default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. One example of an algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402, and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al. (1990) J. Mol. Biol. 215:403-410). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, an expectation (E) or 10, M=5, N=−4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a wordlength of 3, and expectation (E) of 10, and the Attorney Docket No.10935-031WO1 BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and a comparison of both strands. The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01. The term "naturally-occurring”, or "unmodified" or "wild type" as used herein as applied to a nucleic acid, a polypeptide, a cell, or an organism, refers to a nucleic acid, polypeptide, cell, or organism that is found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature, and which has not been intentionally modified by a human in the laboratory is wild type (and naturally occurring). The term “increased” or “increase” as used herein generally means an increase by a statically significant amount; for the avoidance of any doubt, “increased” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level so long as the increase is statistically significant. A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant. Attorney Docket No.10935-031WO1 The term "nucleic acid" as used herein means a polymer composed of nucleotides, e.g., deoxyribonucleotides (DNA) or ribonucleotides (RNA). The terms "ribonucleic acid" and "RNA" as used herein mean a polymer composed of ribonucleotides. The terms "deoxyribonucleic acid" and "DNA" as used herein mean a polymer composed of deoxyribonucleotides. “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. As used herein, "operatively linked" can indicate that the regulatory sequences useful for expression of the coding sequences of a nucleic acid are placed in the nucleic acid molecule in the appropriate positions relative to the coding sequence so as to effect expression of the coding sequence. This same definition is sometimes applied to the arrangement of coding sequences and / or transcription control elements (e.g. promoters, enhancers, and termination elements), and / or selectable markers in an expression vector. The term "operatively linked" can also refer to the arrangement of polypeptide segments within a single polypeptide chain, where the individual polypeptide segments can be, without limitation, a protein, fragments thereof, linking peptides, and / or signal peptides. The term operatively linked can refer to direct fusion of different individual polypeptides within the single polypeptides or fragments thereof where there are no intervening amino acids between the different segments as well as when the individual polypeptides are connected to one another via one or more intervening amino acids. The term "polynucleotide" refers to a single or double stranded polymer composed of nucleotide monomers. "Pharmaceutically acceptable" component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation of the invention and administered to a subject as described herein without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained. When used in reference to administration to a human, the term generally implies the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. "Pharmaceutically acceptable carrier" (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as Attorney Docket No.10935-031WO1 an oil / water or water / oil emulsion) and / or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as described further herein. As used herein, by a “subject” is meant an individual. Thus, the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, chickens, ducks, geese, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds. “Subject” can also include a mammal, such as a primate or a human. Thus, the subject can be a human or veterinary patient. The terms “treat,” “treating,” “treatment,” and grammatical variations thereof as used herein, include partially or completely delaying, alleviating, mitigating, or reducing the intensity of one or more attendant symptoms of a disorder or condition and / or alleviating, mitigating or impeding one or more causes of a disorder or condition. Treatments according to the disclosure may be applied preventively, prophylactically, palliatively, or remedially. Treatments are administered to a subject prior to onset (e.g., before obvious signs of a genetic disorder), during early onset (e.g., upon initial signs and symptoms of a genetic disorder), or after an established development of a genetic disorder. Prophylactic administration can occur for several days to years prior to the manifestation of symptoms of a genetic disorder. As used herein, the term, “deletion”, also called gene deletion, deficiency, or deletion mutation, refers to part of a chromosome or a sequence of DNA being left out during DNA replication. Deletion, or gene deletions can cause any number of nucleotides to be deleted from a single base to an entire piece of chromosome. “Effective amount” of an agent refers to a sufficient amount of an agent to provide a desired effect. The amount of agent that is “effective” will vary from subject to subject, depending on many factors such as the age and general condition of the subject, the particular agent, or agents, and the like. Thus, it is not always possible to specify a quantified “effective amount.” However, an appropriate “effective amount” in any subject case may be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an “effective amount” of an agent can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts. An “effective amount” of an agent necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. Attorney Docket No.10935-031WO1 “Therapeutic agent” refers to any composition that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other undesirable physiological condition (e.g., a genetic disorder). The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the terms “therapeutic agent” is used, then, or when a particular agent is specifically identified, it is to be understood that the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc. “Therapeutically effective amount” or “therapeutically effective dose” of a composition (e.g., a composition comprising an agent) refers to an amount that is effective to achieve a desired therapeutic result. In some embodiments, a desired therapeutic result is the control of cancer. In some embodiments, a desired therapeutic result is the control of metastasis. In some embodiments, a desired therapeutic result is the reduction of tumor size. In some embodiments, a desired therapeutic result is the prevention and / or treatment of relapse. Therapeutically effective amounts of a given therapeutic agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the subject. The term can also refer to an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent (e.g., amount over time), effective to facilitate a desired therapeutic effect, such as pain relief. The precise desired therapeutic effect will vary according to the condition to be treated, the tolerance of the subject, the agent and / or agent formulation to be administered (e.g., the potency of the therapeutic agent, the concentration of agent in the formulation, and the like), and a variety of other factors that are appreciated by those of ordinary skill in the art. In some instances, a desired biological or medical response is achieved following administration of multiple dosages of the composition to the subject over a period of days, weeks, or years. “CRISPR” (Clustered Regularly Interspaced Short Palindromic Repeats) loci refers to certain genetic loci encoding components of DNA cleavage systems, for example, used by bacterial and archaeal cells to destroy foreign DNA (Horvath and Barrangou, 2010, Science 327: 167-170; W02007025097, published 01 March 2007). A CRISPR locus can consist of a CRISPR array, comprising short direct repeats (CRISPR repeats) separated by short variable DNA sequences (called spacers), which can be flanked by diverse Cas (CRISPR-associated) genes. As used herein, an “effector” or “effector protein” is a protein that encompasses an activity including recognizing, binding to, and / or cleaving or nicking a polynucleotide target. An effector, Attorney Docket No.10935-031WO1 or effector protein, may also be an endonuclease. The “effector complex” of a CRISPR system includes Cas proteins involved in crRNA and target recognition and binding. Some of the component Cas proteins may additionally comprise domains involved in target polynucleotide cleavage. The term “Cas protein” refers to a polypeptide encoded by a Cas (CRISPR- associated) gene. A Cas protein includes proteins encoded by a gene in a cas locus and includes adaptation molecules as well as interference molecules. An interference molecule of a bacterial adaptive immunity complex includes endonucleases. A Cas endonuclease described herein comprises one or more nuclease domains. Contemplated herein are any Cas molecules, including Type 1, Type II, and Type II. As used herein, the term "Cas9 protein" refers to, but is not limited to, Cas9 proteins, Cas9-type proteins encoded by Cas9 orthologs, and synthetic proteins of Cas9. The term "Cas9 protein" as used herein refers to a wild type Cas9 protein from CRISPR-Cas9 type II B systems, Cas9 protein modifications, Cas9 protein variants, Cas9 orthologs and combinations of the same. The term "dCas9" as used herein refers to Cas9 protein variants that are Cas9 proteins deactivated by nuclease, also referred to as "catalytically inactive Cas9 protein", or "enzymatically inactive Cas9". Various Cas9s and their relationship with each other can be found in Gasiunas, et al. (Gasiunas G., Young, J.K., Karvelis, T. et al. A catalogue of biochemically diverse CRISPR-Cas9 orthologs. Nat Commun 11, 5512 2020, hereby incorporated by reference in its entirety for its discussion concerning Cas9 molecules). A Cas protein is further defined as a functional fragment or functional variant of a native Cas protein, or a protein that shares at least 30%, between 30% and 35%, at least 35%, between 35% and 40%, at least 40%, between 40% and 45%, at least 45%, between 45% and 50%, at least 50%, between 50% and 55%, at least 55%, between 55% and 60%, at least 60%, between 60% and 65%, at least 65%, between 65% and 70%, at least 70%, between 70% and 75%, at least 75%, between 75% and 80%, at least 80%, between 80% and 85%, at least 85%, between 85% and 90%, at least 90%, between 90% and 95%, at least 95%, between 95% and 96%, at least 96%, between 96% and 97%, at least 97%, between 97% and 98%, at least 98%, between 98% and 99%, at least 99%, between 99% and 100%, or 100% sequence identity with at least 50, between 50 and 100, at least 100, between 100 and 150, at least 150, between 150 and 200, at least 200, between 200 and 250, at least 250, between 250 and 300, at least 300, between 300 and 350, at least 350, between 350 and 400, at least 400, between 400 and 450, at least 500, or greater than 500 contiguous amino acids of a native Cas protein, and retains at least partial activity of the native sequence. Attorney Docket No.10935-031WO1 A Cas endonuclease may also include a multifunctional Cas endonuclease. The term “multifunctional Cas endonuclease” and “multifunctional Cas endonuclease polypeptide” are used interchangeably herein and includes reference to a single polypeptide that has Cas endonuclease functionality (comprising at least one protein domain that can act as a Cas endonuclease) and at least one other functionality, such as but not limited to, the functionality to form a complex (comprises at least a second protein domain that can form a complex with other proteins). In one aspect, the multifunctional Cas endonuclease comprises at least one additional protein domain relative (either internally, upstream (5’), downstream (3’), or both internally 5’ and 3’, or any combination thereof) to those domains typical of a Cas endonuclease. As used herein, the term “guide polynucleotide”, relates to a polynucleotide sequence that can form a complex with a Cas endonuclease, including the Cas endonuclease described herein, and enables the Cas endonuclease to recognize, optionally bind to, and optionally cleave a DNA target site. The guide polynucleotide sequence can be a RNA sequence, a DNA sequence, or a combination thereof (a RNA-DNA combination sequence). The terms “target site”, “target sequence”, “target site sequence,’’ target DNA”, “target locus”, “genomic target site”, “genomic target sequence”, “genomic target locus” and “protospacer”, are used interchangeably herein and refer to a polynucleotide sequence such as, but not limited to, a nucleotide sequence on a chromosome, episome, a locus, or any other DNA molecule in the genome (including chromosomal, chloroplastic, mitochondrial DNA, plasmid DNA) of a cell, at which a guide polynucleotide / Cas endonuclease complex can recognize, bind to, and optionally nick or cleave . The target site can be an endogenous site in the genome of a cell, or alternatively, the target site can be heterologous to the cell and thereby not be naturally occurring in the genome of the cell, or the target site can be found in a heterologous genomic location compared to where it occurs in nature. A “protospacer adjacent motif” (PAM) herein refers to a short nucleotide sequence adjacent to a target sequence (protospacer) that is recognized (targeted) by a guide polynucleotide / Cas endonuclease system described herein or a non-target sequence that is complementary to the target sequence. The Cas endonuclease may not successfully recognize a target DNA sequence if the target DNA sequence is not followed by a PAM sequence. The sequence and length of a PAM herein can differ depending on the Cas protein or Cas protein complex used. The PAM sequence can be of any length but is typically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 nucleotides long. Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order Attorney Docket No.10935-031WO1 to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. B. COMPOSITIONS AND METHODS Several genetic disorders are caused by heterozygous mutations. However, mutation correction via homology directed repair (HDR) in heterozygous mutations does not occur naturally. Here we induced naturally occurring HDR and mutation correction by targeting mutations in ONLY mutant alleles with no need for an HDR template. As disclosed herein, using HDR enhancers improve this process possibly by using wildtype allele as a natural healthy copy of the gene resulting in repairing the mutant allele. Disclosed herein is a system comprising gRNAs targeting only mutant allele in autosomal dominant genetic disorders and to allow healthy allele to being expressed. This enables targeting the mutant allele but not the healthy allele in cells or a subject in need (for example, a subject having a genetic disorder). This strategy can be used for any autosomal dominant inheritance disorders. Accordingly, in some aspects, disclosed herein is a system, a composition, or a kit for repairing or causing mutational correction of a mutant allele of a heterozygous gene, said system comprising a guide RNA (gRNA), wherein: a) the gRNA targets a mutant allele of a heterozygous gene, b) the mutant allele comprises one or more mutations (such as, for example, point mutations, insertions, deletions, or translocations), and c) the gRNA does not target the wild-type allele of the gene, including those systems, wherein the system is free from homology directed repair (HDR) template. In one aspect, least one of the one or more mutations is upstream the 5’ end or downstream of the 3’ end of a protospacer adjacent motif (PAM) sequence (such as, for example, NGG, NNGRR, NNGRRT, or NNNNGATT including, but not limited to AAGAA, TGGGAT, GGG, or TGG) In some aspects, the mutant allele can comprise an autosomal dominant allele including, but not limited to, an incomplete or complete autosomal dominant allele. In some aspects, the mutant allele comprises a target strand and a non-target strand complementary to the target strand. In some aspects, the gRNA is complementary to target strand. In one aspect, disclosed herein is a system for modulating a mutant allele of a gene of any preceding aspect, wherein at least one of the one or more mutations is within 7, 6, 5, 4, 3, 2, or 1 nucleotide upstream the 5’ end or within 7, 6, 5, 4, 3, 2, or 1 nucleotide downstream the 3’ end of a protospacer adjacent motif (PAM) sequence. Attorney Docket No.10935-031WO1 It should be understood and herein contemplated that the mutant allele comprises a target strand and a non-target strand complementary to the target strand, and wherein the gRNA is complementary to the target strand. Accordingly, the non-target strand comprises one or more mutations, and wherein at least one of the one or more mutations is upstream the 5’ end of the PAM sequence or downstream of the 3’ end of the PAM sequence. In some instances, the one or more mutations are within 7, 6, 5, 4, 3, 2, 1, nucleotides of the PAM sequence. Though not limited in this regard, as noted above, the mutated sequence (e.g., on the non- target strand) of the mutant allele can be within 7 nucleotides (e.g., within 6, 5, 4, 3, 2, or 1 nucleotides) at 5' side or the 3” side of the PAM sequence is included in the gRNA. Accordingly, in some aspects, disclosed herein is a method of creating a gRNA for repairing or causing mutational correction a mutant allele of a gene, said method comprising determining a mutated sequence of the mutant allele that comprises one or more mutations upstream of the 5’ end of a PAM sequence or downstream of the 3’ end of a PAM sequence; and obtaining an RNA comprising the mutated sequence thereby creating the gRNA for the mutant allele. The one or more mutations can be point mutations, insertions, deletions, or translocations. In some embodiments, the one or more mutations are point mutations. Accordingly, in some aspects, disclosed herein is a composition, system, or kit for repairing or causing mutational correction a mutant allele of a gene, said composition, system, or kit comprising a guide RNA (gRNA) sequence targeting the mutant allele of the gene comprising one or more-point mutations, wherein at least one of the one or more-point mutations is upstream the 5’ end of a protospacer adjacent motif (PAM) sequence or downstream of the 3’ end of a PAM sequence. In some embodiments, the PAM sequence comprises NGG, NNGRR, NNGRRT, or NNNNGATT. In some embodiments, the PAM sequence comprises AAGAA, TGGGAT, GGG, or TGG. Accordingly, in some aspects, disclosed herein is a composition, system, or kit for repairing or causing mutational correction a mutant allele of a gene, said composition, system, or kit comprising a guide RNA (gRNA) sequence targeting the mutant allele of the gene comprising one or more point mutations, wherein at least one of the one or more point mutations is upstream the 5’ end or downstream of the 3’ end of a protospacer adjacent motif (PAM) sequence, and wherein the PAM sequence comprises AAGAA, TGGGAT, GGG, or TGG. In some embodiments, the system, composition, or kit further comprises a Cas nuclease. As noted above, the mutant allele can be associated with a genetic disorder (e.g., a dominant-negative disorder or an autosomal dominant disorder). Accordingly, in some aspects, disclosed herein is a composition, system, or kit for modulating, repairing or causing mutational correction a mutant allele of a gene associated with a genetic disorder, said composition, system, Attorney Docket No.10935-031WO1 or kit comprising a guide RNA (gRNA) sequence targeting the mutant allele of the gene comprising one or more point mutations, wherein at least one of the one or more point mutations is upstream the 5’ end of a protospacer adjacent motif (PAM) sequence or downstream of a 3’ end of a PAM sequence, and wherein the gRNA does not target the wild-type allele of the gene. Also disclosed herein is a composition, system, or kit for treating a genetic disorder in a subject in need, said composition, system, or kit comprising a guide RNA (gRNA) sequence targeting a mutant allele of a gene associated with the genetic disorder, wherein the mutant allele comprises one or more point mutations, wherein at least one of the one or more point mutations upstream the 5’ end of a protospacer adjacent motif (PAM) sequence or downstream of a 3’ end of a PAM sequence, and wherein the gRNA does not target the wild-type allele of the gene. In some embodiments, the genetic disorder is a dominant-negative disorder. In some embodiments, the genetic disorder comprises Huntington’s disease, Marfan’s syndrome, familial hypercholesterolemia, inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal dominant hyper-IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, or KCNT1-related developmental and epileptic encephalopathy. IBMPFD is related to a mutated VCP gene, Marfan’s syndrome is related to the mutated FBN1 gene, familial hypercholesterolemia is related to a mutated APOB gene, a mutated LDLR gene or a mutated PCSK9 gene, and AD-HIES is related to a mutated STAT3 gene and / or a mutated DOCK8 gene, wherein the mutation is heterozygous. Accordingly, in some examples, the composition, system, or kit for treatment of IBMPFD can comprise a gRNA that targets a mutated VCP gene. In some examples, the composition, system, or kit for treatment of AD-HIES comprise one or more gRNAs that target a mutated STAT3 gene and / or a mutated DOCK8 gene, wherein the mutation is heterozygous. In some embodiments, the mutant allele of the VCP gene comprises SEQ ID NO: 10 or a fragment thereof. In some embodiments, the gRNA of the composition, system, or kit disclosed comprise a sequence selected from the group consisting of SEQ ID NOs: 1-9 or a fragment thereof. Accordingly, in some aspects, disclosed herein is a composition, system, or kit for repairing or causing mutational correction a mutant allele of a VCP gene in a cell or a subject in need, said composition, system, or kit comprising a guide RNA (gRNA) sequence targeting the mutant allele of the gene comprising one or more-point mutations, wherein the gRNA comprises a sequence selected from the group consisting of SEQ ID NOs: 1-9 or a fragment thereof. Also disclosed herein is a composition, system, or kit for treating IBMPFD in a subject in need, said composition, system, or kit comprising a guide RNA (gRNA) sequence targeting a mutant allele of a VCP gene, Attorney Docket No.10935-031WO1 wherein the gRNA comprises a sequence selected from the group consisting of SEQ ID NOs: 1-9 or a fragment thereof. In some aspects, the mutant allele can comprise an autosomal dominant allele including, but not limited to an incomplete or complete autosomal dominant allele. Thus, also disclosed herein is a system for repairing or causing mutational correction a mutant allele of a gene, wherein the mutant allele is an autosomal dominant allele, and wherein the autosomal dominant allele is a pathogenic autosomal dominant allele. In some aspects, the pathogenic autosomal dominant allele expresses in a mammal as a disorder selected from the group consisting of: proliferation disorder, blood disorder, vision disorder, connective tissue disorder, and protein processing disorder said disorder including, but not limited to achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, hereditary elliptocytosis, and disorders listed in Table 2. In some aspects, the autosomal dominant mutation is associated with a cancer, such as, for example, alveolar soft part sarcoma, pre-B acute lymphocytic leukemia, acute myeloid leukemia, dermatofibrosarcoma protuberans, gastrointestinal stromal tumor, giant cell fibroblastoma, granulocytic sarcoma, Kaposi’s sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, meningeal hemangiopericytoma, cutaneous fibrous histiocytoma, angiosarcoma, meningiomas, neurofibromas, schwannomas, or papillary thyroid carcinoma. In one aspect, disclosed herein is a system for repairing or causing mutational correction of a mutant allele of a gene of any preceding aspect, wherein the mutant allele is expressed in a cell that is heterozygous for the allele. In one aspect, the cell expresses CD34 on its membrane. In some embodiments, the system, composition, or kit further comprises a Cas nuclease. In some embodiments, any Cas endonuclease may be utilized, any length of gRNA may be utilized. Moreover, the gRNA may be targeted any distance from the PAM and to either the 5’ or 3’ end of the PAM. In one aspect, disclosed herein is a system for repairing or causing mutational correction a mutant allele and / or conducting homology directed repair of a mutant allele of a gene, further comprising one or more homology directed repair enhancers including, but not limited to Alt-R™, wortmannin, SCR7, L755507, EPZ5676, rucaparib, pevonedistat, brefeldin A, Alt-R HDR Enhancer V1, XL413, NU7441, trichostatin A, CRISPYTMMix, romidepsin, nedisertib, and Alt- R HDR Enhancer V2. Attorney Docket No.10935-031WO1 In some aspects, disclosed herein is a method of treating, reducing, decreasing, inhibiting, ameliorating, preventing, repairing, and / or correcting a genetic disorder in subject in need, comprising administering to the subject an effective amount of a composition comprising a guide RNA (gRNA) sequence targeting a mutant allele of a gene associated with the genetic disorder, wherein the mutant allele comprises one or more mutations within 7 (e.g., within 6, 5, 4, 3, 2, or 1 nucleotides) nucleotides upstream the 5’ end of a protospacer adjacent motif (PAM) sequence. In some embodiments, the composition further comprises a Cas endonuclease. In some embodiments, the one or more mutations are point mutations, insertions, deletions, or translocations. In some embodiments, the PAM sequence comprises NGG, NNGRR, NNGRRT, or NNNNGATT. In some embodiments, the PAM sequence comprises AAGAA, TGGGAT, GGG, or TGG. In some embodiments, the genetic disorder is a dominant disorder (for example, Huntington’s disease, Marfan’s syndrome, familial hypercholesterolemia, inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal dominant hyper-IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, or KCNT1-related developmental and epileptic encephalopathy). The TBCD associated diseases can be, for example, encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum and seborrhea-like dermatitis with psoriasiform elements. In some embodiments, the mutant allele is of VCP gene, STAT3 gene, or DOCK8. KCNT1, TC gene. In some embodiments, the gRNA comprises a sequence selected from the group consisting of SEQ ID NOs: 1-9 or a fragment thereof. In some embodiments, the gRNA targets SEQ ID NO: 10 or a fragment thereof. In some embodiments, the composition is formulated within a pharmaceutically acceptable carrier. As noted herein, the present invention also provides a system for modulating, repairing or causing mutational correction a mutant allele in a heterozygous cell, said system comprising a guide RNA (gRNA) sequence targeting the mutant allele of the gene comprising one or more mutations, wherein at least one of the one or more mutations is upstream the 5’ end or downstream of the 3’ end of a protospacer adjacent motif (PAM) sequence, wherein said system is free from an exogenous repair template. The term “exogenous repair template” means a polypeptide comprising a corrective sequence that can be “donated” to a cell for the purpose of supporting the cellular repair process, resulting in a copy of the corrective sequence replacing a mutated sequence. In the present invention, “exogenous repair template” is synonymous with “homology repair template” and “HDR template” as those terms are known in the art. Attorney Docket No.10935-031WO1 The term “homology directed repair” means correction of mutant sequences using laboratory and / or clinical interventions by humans. Prior to the present invention, HDR required an exogenous repair template. Providing HDR templates such as ssDNA, pDNA or AAV vectors can be expensive and sometimes results in biological changes in the target cells. In one embodiment of the present invention, systems that are free from HDR template polypeptides are provided, which decreases costs, reduces non-specific errors, and increases efficiency. These results are amplified when the template-free system comprises HDR enhancers. The system can be used to correct any heterozygous mutations, preferably in an ex vivo use. The system is capable of repairing at least about 75% mutant allele to wildtype allele, including at least about 75%, 76%, 77%, 78% 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100%. Also disclosed herein are methods of treating, reducing, decreasing, inhibiting, ameliorating, repairing, correcting, and / or preventing a genetic disorder (such as, for example inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal dominant hyper-IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, KCNT1-related developmental and epileptic encephalopathy, or genetic disorders associated with a mutant allele of a VCP gene, a STAT3 gene, a FBN1 gene, a APOB gene, a LDLR gene, a PCSK9 gene, a DOCK8 gene, a TBCD gene, or a KCNT1 gene) in a subject, comprising administering to the subject the system disclosed herein. For example, disclosed herein are methods of treating a genetic disorder (such as, for example inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal dominant hyper-IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, KCNT1-related developmental and epileptic encephalopathy, or genetic disorders associated with a mutant allele of a VCP gene, a STAT3 gene, a FBN1 gene, a APOB gene, a LDLR gene, a PCSK9 gene, a DOCK8 gene, a TBCD gene, or a KCNT1 gene) in a subject comprising administering to the subject a system for repairing or causing mutational correction a mutant allele of a gene, said system comprising a guide RNA (gRNA) sequence targeting the mutant allele of the gene comprising one or more mutations (including, but not limited to point mutations, insertions, deletions, or translocations), wherein at least one of the one or more mutations is upstream the 5’ end or downstream of the 3’ end of a protospacer adjacent motif (PAM) sequence (such as, for example, NGG, NNGRR, NNGRRT, or NNNNGATT including, Attorney Docket No.10935-031WO1 but not limited to AAGAA, TGGGAT, GGG, or TGG). In some instances, the one or more mutations are within 7, 6, 5, 4, 3, 2, 1, nucleotides of the PAM sequence. In one aspect disclosed herein are methods of treating, reducing, decreasing, inhibiting, ameliorating, correcting, repairing, and / or preventing a genetic disorder wherein the genetic disorder is an autosomal dominant genetic disorder (such as for example, a proliferation disorder, blood disorder, vision disorder, connective tissue disorder, and protein processing disorder including, but not limited to achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, hereditary elliptocytosis, and disorders listed in Table 2) comprising administering to the subject the system disclosed herein. For example, disclosed herein are methods of treating, reducing, decreasing, inhibiting, ameliorating, repairing, correcting, and / or preventing a genetic disorder (such as for example, a proliferation disorder, blood disorder, vision disorder, connective tissue disorder, and protein processing disorder associated with an autosomal dominant mutation including, but not limited to achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, hereditary elliptocytosis, Ablepharon macrostomia syndrome Acropectoral syndrome, Acute intermittent porphyria Adermatoglyphia, ADNP syndrome, Albright's hereditary osteodystrophy Ankylosing vertebral hyperostosis with tylosis Aphalangy- syndactyly-microcephaly syndrome Arakawa's syndrome II, Aromatase excess syndrome Autosomal dominant cerebellar ataxia, Autosomal dominant Charcot–Marie–Tooth disease type 2 with giant axons Autosomal dominant GTP cyclohydrolase I deficiency, Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Autosomal dominant nocturnal frontal lobe epilepsy, Autosomal dominant partial epilepsy with auditory features Autosomal dominant polycystic kidney disease Axenfeld–Rieger syndrome, Bainbridge–Ropers syndrome Barber–Say syndrome Beck–Fahrner syndrome Benign hereditary chorea Bethlem myopathy, Birt–Hogg–Dubé syndrome, Blepharophimosis, ptosis, epicanthus inversus syndrome Blepharoptosis-myopia-ectopia lentis syndrome Boomerang dysplasia, Bosch-Boonstra-Schaaf optic atrophy syndrome Brachydactyly-long thumb syndrome, Branchio-oto-renal syndrome Buschke–Ollendorff syndrome, Calvarial doughnut lesions-bone fragility syndrome Camptodactyly-taurinuria syndrome Camurati–Engelmann disease, CAPOS syndrome Central core disease, Cerebro-costo-mandibular syndrome, Cochleosaccular degeneration with Attorney Docket No.10935-031WO1 progressive cataracts Cohen-Gibson syndrome, Collagen disease Collagenopathy, types II and XI Collins–Pope syndrome, Coloboma of macula-brachydactyly type B syndrome Congenital distal spinal muscular atrophy, Congenital stromal corneal dystrophy Costello syndrome, Craniofacial dysostosis-diaphyseal hyperplasia syndrome Currarino syndrome, Cyprus facial neuromusculoskeletal syndrome Czech dysplasia, metatarsal type, Darier's disease GLUT1 deficiency, Dentatorubral–pallidoluysian atrophy Dermatopathia pigmentosa reticularis DiGeorge syndrome Dysfibrinogenemia, Emberger syndrome, Familial amyloid polyneuropathy Familial atrial fibrillation, Familial cutaneous collagenoma, Familial disseminated comedones without dyskeratosis Familial hypercholesterolemia, Familial male-limited precocious puberty Feingold syndrome, Felty's syndrome, Fibular aplasia-ectrodactyly syndrome Flynn–Aird syndrome, Gardner's syndrome GATA2 deficiency, GATAD2B-associated neurodevelopmental disorder Gillespie syndrome, Gray platelet syndrome, Greig cephalopolysyndactyly syndrome, Hagemoser–Weinstein–Bresnick syndrome Hajdu–Cheney syndrome Haploinsufficiency of A20, Hawkinsinuria Hay–Wells syndrome, Heart-hand syndrome, Spanish type Hemochromatosis type 4, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome Hereditary elliptocytosis, Hereditary hemorrhagic telangiectasia Hereditary mucoepithelial dysplasia Hereditary neurocutaneous angioma Hereditary spherocytosis, Holt–Oram syndrome Huntington's disease, Huntington's disease-like syndrome Hyperinsulinism-hyperammonemia syndrome Hypertrophic cardiomyopathy Hypoalphalipoproteinemia Hypochondroplasia, Hypodysfibrinogenemia, IVIC syndrome, Jackson–Weiss syndrome Jordan's Syndrome, Juberg- Hayward syndrome Juvenile-onset dystonia, Keratoendotheliitis fugax hereditaria Keratolytic winter erythema, Kniest dysplasia, Langer–Giedion syndrome Larsen syndrome, Leucine- sensitive hypoglycemia of infancy Liddle's syndrome, Marfan syndrome Marshall syndrome Marsili syndrome, Medullary cystic kidney disease Menke-Hennekam syndrome Metachondromatosis Miller–Dieker syndrome, MOMO syndrome Monilethrix MonoMAC, Multiple endocrine neoplasia Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2B, Muscular atrophy-ataxia-retinitis pigmentosa- diabetes mellitus syndrome Myelokathexis, Myotonic dystrophy, Nablus mask-like facial syndrome, Naegeli–Franceschetti–Jadassohn syndrome Nail–patella syndrome, Noonan syndrome, Oculopharyngeal muscular dystrophy Otofaciocervical syndrome, Pachyonychia congenita Pallister–Hall syndrome, Palmoplantar keratoderma with deafness PAPA syndrome, Papillorenal syndrome Parastremmatic dwarfism Pashayan syndrome Pelger–Huët anomaly Peutz–Jeghers syndrome Piebaldism, Platyspondylic lethal skeletal dysplasia, Torrance type Polydactyly, Polymerase proofreading-associated polyposis Popliteal pterygium syndrome, Attorney Docket No.10935-031WO1 Porphyria cutanea tarda Pseudoachondroplasia, RASopathy, Reis–Bucklers corneal dystrophy Romano–Ward syndrome Rosselli–Gulienetti syndrome Roussy–Lévy syndrome Rubinstein– Taybi syndrome, Saethre–Chotzen syndrome, Scalp defects-postaxial polydactyly syndrome Schmitt Gillenwater Kelly syndrome, Severe congenital neutropenia, Severe intellectual disability- progressive spastic diplegia syndrome Short QT syndrome, Singleton Merten syndrome, Spastic paraplegia 6 Spastic paraplegia 31, Spinal muscular atrophy with lower extremity predominance 1 Spinal muscular atrophy with lower extremity predominance 2A Spinal muscular atrophy with lower extremity predominance 2B Spinocerebellar ataxia, Spinocerebellar ataxia type 1 Spinocerebellar ataxia type 6, Split hand split foot-nystagmus syndrome Spondyloepimetaphyseal dysplasia, Strudwick type Spondyloepiphyseal dysplasia congenita Spondyloperipheral dysplasia, St. Helena familial genu valgum Stickler syndrome, Syndactyly-nystagmus syndrome due to 2q31.1 microduplication SYNGAP1-related intellectual disability, SYT1-associated neurodevelopmental disorder, Thumb stiffness-brachydactyly-intellectual disability syndrome Tietz syndrome, Timothy syndrome Treacher Collins syndrome, Tricho–dento–osseous syndrome, TRPM3-related neurodevelopmental disorders Tuberous sclerosis, Upington disease, Variegate porphyria, Ventricular extrasystoles with syncopal episodes-perodactyly-Robin sequence syndrome Verloes Van Maldergem Marneffe syndrome, Vitelliform macular dystrophy Von Hippel–Lindau disease Von Willebrand disease, Wallis–Zieff–Goldblatt syndrome WHIM syndrome or White sponge nevus) in a subject comprising administering to the subject a system for repairing or causing mutational correction a mutant allele of a gene, said system comprising a guide RNA (gRNA) sequence targeting the mutant allele of the gene comprising one or more mutations (including, but not limited to point mutations, insertions, deletions, or translocations), wherein at least one of the one or more mutations upstream the 5’ end or downstream of the 3’ end of a protospacer adjacent motif (PAM) sequence (such as, for example, NGG, NNGRR, NNGRRT, or NNNNGATT including, but not limited to AAGAA, TGGGAT, GGG, or TGG). Also disclosed herein are methods of treating, reducing, decreasing, inhibiting, ameliorating, correcting, repairing, and / or preventing a genetic disorder in a subject comprising administering to the subject the system disclosed herein, wherein the disorder is a cancer selected from the group consisting of alveolar soft part sarcoma, pre-B acute lymphocytic leukemia, acute myeloid leukemia, dermatofibrosarcoma protuberans, gastrointestinal stromal tumor, giant cell fibroblastoma, granulocytic sarcoma, Kaposi’s sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, meningeal hemangiopericytoma, cutaneous fibrous histiocytoma, angiosarcoma, meningiomas, neurofibromas, schwannomas, and papillary thyroid carcinoma. For example, disclosed herein are methods of treating, reducing, Attorney Docket No.10935-031WO1 decreasing, inhibiting, ameliorating, correcting, repairing, and / or preventing a genetic disorder in a subject comprising administering to the subject a system for repairing or causing mutational correction a mutant allele of a gene, said system comprising a guide RNA (gRNA) sequence targeting the mutant allele of the gene comprising one or more mutations (including, but not limited to point mutations, insertions, deletions, or translocations), wherein at least one of the one or more mutations is upstream the 5’ end or downstream of the 3’ end of a protospacer adjacent motif (PAM) sequence (such as, for example, NGG, NNGRR, NNGRRT, or NNNNGATT including, but not limited to AAGAA, TGGGAT, GGG, or TGG), wherein the disorder is selected from the group consisting of alveolar soft part sarcoma, pre-B acute lymphocytic leukemia, acute myeloid leukemia, dermatofibrosarcoma protuberans, gastrointestinal stromal tumor, giant cell fibroblastoma, granulocytic sarcoma, Kaposi’s sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, meningeal hemangiopericytoma, cutaneous fibrous histiocytoma, angiosarcoma, meningiomas, neurofibromas, schwannomas, and papillary thyroid carcinoma. In one aspect, disclosed herein are methods of repairing or causing the mutational correction of an autosomal dominant mutation (such as, for example, a mutation associated with achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, hereditary elliptocytosis, and disorders listed in Table 2) in a subject to express a wild-type allele comprising administering to the subject the system disclosed herein. For example, disclosed herein are methods of repairing an autosomal dominant mutation (such as, for example, a mutation associated with achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, hereditary elliptocytosis, and disorders listed in Table 2) in a subject to express a wild-type allele comprising administering to the subject a system for repairing or causing mutational correction a mutant allele of a gene, said system comprising a guide RNA (gRNA) sequence targeting the mutant allele of the gene comprising one or more mutations (including, but not limited to point mutations, insertions, deletions, or translocations), wherein at least one of the one or more mutations is upstream the 5’ end or downstream of the 3’ end of a protospacer adjacent motif (PAM) sequence (such as, for example, NGG, NNGRR, NNGRRT, or NNNNGATT including, but not limited to Attorney Docket No.10935-031WO1 AAGAA, TGGGAT, GGG, or TGG). In one aspect, the method does not use a homology directed repair (HDR) template. Route of Administration Genome editing systems, or cells altered or manipulated using such systems, which include the Cas9 variants disclosed herein, can be administered to subjects by any suitable mode or route, whether local or systemic. Systemic modes of administration include oral and parenteral routes. Parenteral routes include, by way of example, intravenous, intramarrow, intrarterial, intramuscular, intradermal, subcutaneous, intranasal, intrathecal, and intraperitoneal routes. Components administered systemically may be modified or formulated to target. Local modes of administration include, by way of example, intramarrow injection into the trabecular bone or intrafemoral injection into the marrow space, and infusion into the portal vein. In an embodiment, significantly smaller amounts of the components (compared with systemic approaches) may exert an effect when administered locally (for example, directly into the bone marrow) compared to when administered systemically (for example, intravenously). Local modes of administration can reduce or eliminate the incidence of potentially toxic side effects that may occur when therapeutically effective amounts of a component are administered systemically. Administration may be provided as a periodic bolus (for example, intravenously) or as continuous infusion from an internal reservoir or from an external reservoir (for example, from an intravenous bag or implantable pump). Components may be administered locally, for example, by continuous release from a sustained release drug delivery device. In addition, components may be formulated to permit release over a prolonged period of time. A release system can include a matrix of a biodegradable material or a material which releases the incorporated components by diffusion. The components can be homogeneously or heterogeneously distributed within the release system. A variety of release systems may be useful; however, the choice of the appropriate system will depend upon rate of release required by a particular application. Both non-degradable and degradable release systems can be used. Suitable release systems include polymers and polymeric matrices, non-polymeric matrices, or inorganic and organic excipients and diluents such as, but not limited to, calcium carbonate and sugar (for example, trehalose). Release systems may be natural or synthetic. However, synthetic release systems are preferred because generally they are more reliable, more reproducible and produce more defined release profiles. The release system material can be selected so that components having different molecular weights are released by diffusion through or degradation of the material. Attorney Docket No.10935-031WO1 Representative synthetic, biodegradable polymers include, for example: polyamides such as poly(amino acids) and poly(peptides); polyesters such as poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), and poly(caprolactone); poly(anhydrides); polyorthoesters; polycarbonates; and chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), copolymers and mixtures thereof. Representative synthetic, non- degradable polymers include, for example: polyethers such as poly(ethylene oxide), poly(ethylene glycol), and poly(tetramethylene oxide); vinyl polymers-polyacrylates and polymethacrylates such as methyl, ethyl, other alkyl, hydroxyethyl methacrylate, acrylic and methacrylic acids, and others such as poly(vinyl alcohol), poly(vinyl pyrolidone), and poly(vinyl acetate); poly(urethanes); cellulose and its derivatives such as alkyl, hydroxyalkyl, ethers, esters, nitrocellulose, and various cellulose acetates; polysiloxanes; and any chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), copolymers and mixtures thereof. Poly(lactide-co-glycolide) microsphere can also be used. Typically, the microspheres are composed of a polymer of lactic acid and glycolic acid, which are structured to form hollow spheres. The spheres can be approximately 15-30 microns in diameter and can be loaded with components described herein. Skilled artisans will appreciate that different components of genome editing systems can be delivered together or separately and simultaneously or non-simultaneously. Separate and / or asynchronous delivery of genome editing system components may be particularly desirable to provide temporal or spatial control over the function of genome editing systems and to limit certain effects caused by their activity. Different or differential modes as used herein refer to modes of delivery that confer different pharmacodynamic or pharmacokinetic properties on the subject component molecule, e.g., a RNA-guided nuclease molecule, gRNA, template nucleic acid, or payload. For example, the modes of delivery can result in different tissue distribution, different half-life, or different temporal distribution, e.g., in a selected compartment, tissue, or organ. Some modes of delivery, e.g., delivery by a nucleic acid vector that persists in a cell, or in progeny of a cell, e.g., by autonomous replication or insertion into cellular nucleic acid, result in more persistent expression of and presence of a component. Examples include viral, e.g., AAV or lentivirus, delivery. Delivery of the compositions to cells Attorney Docket No.10935-031WO1 There are a number of compositions and methods which can be used to deliver nucleic acids to cells, either in vitro or in vivo. These methods and compositions can largely be broken down into two classes: viral based delivery systems and non-viral based delivery systems. For example, the nucleic acids can be delivered through a number of direct delivery systems such as, electroporation, lipofection, calcium phosphate precipitation, plasmids, viral vectors, viral nucleic acids, phage nucleic acids, phages, cosmids, or via transfer of genetic material in cells or carriers such as cationic liposomes. Appropriate means for transfection, including viral vectors, chemical transfectants, or physico-mechanical methods such as electroporation and direct diffusion of DNA, are described by, for example, Wolff, J. A., et al., Science, 247, 1465-1468, (1990); and Wolff, J. A. Nature, 352, 815-818, (1991). Such methods are well known in the art and readily adaptable for use with the compositions and methods described herein. In certain cases, the methods will be modified to specifically function with large DNA molecules. Further, these methods can be used to target certain diseases and cell populations by using the targeting characteristics of the carrier. Nucleic acid-based delivery systems Transfer vectors can be any nucleotide construction used to deliver genes into cells (e.g., a plasmid), or as part of a general strategy to deliver genes, e.g., as part of recombinant retrovirus or adenovirus (Ram et al. Cancer Res.53:83-88, (1993)). As used herein, plasmid or viral vectors are agents that transport the disclosed nucleic acids, such as the gRNA and the nucleic acids encoding the Cas endonuclease, into the cell without degradation and include a promoter yielding expression of the gene in the cells into which it is delivered. In some embodiments, the gRNA and the nucleic acids encoding the Cas endonuclease are derived from either a virus or a retrovirus. Viral vectors are, for example, Adenovirus, Adeno- associated virus, Herpes virus, Vaccinia virus, Polio virus, AIDS virus, neuronal trophic virus, Sindbis and other RNA viruses, including these viruses with the HIV backbone. Also preferred are any viral families which share the properties of these viruses which make them suitable for use as vectors. Retroviruses include Murine Maloney Leukemia virus, MMLV, and retroviruses that express the desirable properties of MMLV as a vector. Retroviral vectors are able to carry a larger genetic payload, i.e., a transgene or marker gene, than other viral vectors, and for this reason are a commonly used vector. However, they are not as useful in non-proliferating cells. Adenovirus vectors are relatively stable and easy to work with, have high titers, and can be delivered in aerosol formulation, and can transfect non-dividing cells. Pox viral vectors are large and have several sites for inserting genes, they are thermostable and can be stored at room temperature. A preferred embodiment is a viral vector which has been engineered so as to suppress the immune response of Attorney Docket No.10935-031WO1 the host organism, elicited by the viral antigens. Preferred vectors of this type will carry coding regions for Interleukin 8 or 10. Viral vectors can have higher transaction (ability to introduce genes) abilities than chemical or physical methods to introduce genes into cells. Typically, viral vectors contain, nonstructural early genes, structural late genes, an RNA polymerase III transcript, inverted terminal repeats necessary for replication and encapsidation, and promoters to control the transcription and replication of the viral genome. When engineered as vectors, viruses typically have one or more of the early genes removed and a gene or gene / promotor cassette is inserted into the viral genome in place of the removed viral DNA. Constructs of this type can carry up to about 8 kb of foreign genetic material. The necessary functions of the removed early genes are typically supplied by cell lines which have been engineered to express the gene products of the early genes in trans. Retroviral Vectors A retrovirus is an animal virus belonging to the virus family of Retroviridae, including any type, subfamilies, genus, or tropisms. Retroviral vectors, in general, are described by Verma, I.M., Retroviral vectors for gene transfer. A retrovirus is essentially a package which has packed into its nucleic acid cargo. The nucleic acid cargo carries with it a packaging signal, which ensures that the replicated daughter molecules will be efficiently packaged within the package coat. In addition to the package signal, there are a number of molecules which are needed in cis, for the replication, and packaging of the replicated virus. Typically, a retroviral genome contains the gag, pol, and env genes which are involved in the making of the protein coat. It is the gag, pol, and env genes which are typically replaced by the foreign DNA that is to be transferred to the target cell. Retrovirus vectors typically contain a packaging signal for incorporation into the package coat, a sequence which signals the start of the gag transcription unit, elements necessary for reverse transcription, including a primer binding site to bind the tRNA primer of reverse transcription, terminal repeat sequences that guide the switch of RNA strands during DNA synthesis, a purine rich sequence 5' to the 3' LTR that serve as the priming site for the synthesis of the second strand of DNA synthesis, and specific sequences near the ends of the LTRs that enable the insertion of the DNA state of the retrovirus to insert into the host genome. The removal of the gag, pol, and env genes allows for about 8 kb of foreign sequence to be inserted into the viral genome, become reverse transcribed, and upon replication be packaged into a new retroviral particle. This amount of nucleic acid is sufficient for the delivery of a one-to-many genes depending on the size of each transcript. It is preferable to include either positive or negative selectable markers along with other genes in the insert. Attorney Docket No.10935-031WO1 Since the replication machinery and packaging proteins in most retroviral vectors have been removed (gag, pol, and env), the vectors are typically generated by placing them into a packaging cell line. A packaging cell line is a cell line which has been transfected or transformed with a retrovirus that contains the replication and packaging machinery but lacks any packaging signal. When the vector carrying the DNA of choice is transfected into these cell lines, the vector containing the gene of interest is replicated and packaged into new retroviral particles, by the machinery provided in cis by the helper cell. The genomes for the machinery are not packaged because they lack the necessary signals. Adenoviral Vectors The construction of replication-defective adenoviruses has been described (Berkner et al., J. Virology 61:1213-1220 (1987); Massie et al., Mol. Cell. Biol.6:2872-2883 (1986); Haj-Ahmad et al., J. Virology 57:267-274 (1986); Davidson et al., J. Virology 61:1226-1239 (1987); Zhang "Generation and identification of recombinant adenovirus by liposome-mediated transfection and PCR analysis” BioTechniques 15:868-872 (1993)). The benefit of the use of these viruses as vectors is that they are limited in the extent to which they can spread to other cell types, since they can replicate within an initial infected cell, but are unable to form new infectious viral particles. Recombinant adenoviruses have been shown to achieve high efficiency gene transfer after direct, in vivo delivery to airway epithelium, hepatocytes, vascular endothelium, CNS parenchyma and a number of other tissue sites (Morsy, J. Clin. Invest. 92:1580-1586 (1993); Kirshenbaum, J. Clin. Invest. 92:381-387 (1993); Roessler, J. Clin. Invest. 92:1085-1092 (1993); Moullier, Nature Genetics 4:154-159 (1993); La Salle, Science 259:988-990 (1993); Gomez-Foix, J. Biol. Chem. 267:25129-25134 (1992); Rich, Human Gene Therapy 4:461-476 (1993); Zabner, Nature Genetics 6:75-83 (1994); Guzman, Circulation Research 73:1201-1207 (1993); Bout, Human Gene Therapy 5:3-10 (1994); Zabner, Cell 75:207-216 (1993); Caillaud, Eur. J. Neuroscience 5:1287-1291 (1993); and Ragot, J. Gen. Virology 74:501-507 (1993)). Recombinant adenoviruses achieve gene transduction by binding to specific cell surface receptors, after which the virus is internalized by receptor-mediated endocytosis, in the same manner as wild type or replication- defective adenovirus (Chardonnet and Dales, Virology 40:462-477 (1970); Brown and Burlingham, J. Virology 12:386-396 (1973); Svensson and Persson, J. Virology 55:442-449 (1985); Seth, et al., J. Virol. 51:650-655 (1984); Seth, et al., Mol. Cell. Biol. 4:1528-1533 (1984); Varga et al., J. Virology 65:6061-6070 (1991); Wickham et al., Cell 73:309-319 (1993)). A viral vector can be one based on an adenovirus which has had the E1 gene removed and these virons are generated in a cell line such as the human 293 cell line. In another preferred embodiment both the E1 and E3 genes are removed from the adenovirus genome. Attorney Docket No.10935-031WO1 Adeno-asscociated viral vectors Another type of viral vector is based on an adeno-associated virus (AAV). This defective parvovirus is a preferred vector because it can infect many cell types and is nonpathogenic to humans. AAV type vectors can transport about 4 to 5 kb and wild type AAV is known to stably insert into chromosome 19. Vectors which contain this site-specific integration property are preferred. An especially preferred embodiment of this type of vector is the P4.1 C vector produced by Avigen, San Francisco, CA, which can contain the herpes simplex virus thymidine kinase gene, HSV-tk, and / or a marker gene, such as the gene encoding the green fluorescent protein, GFP. In another type of AAV virus, the AAV contains a pair of inverted terminal repeats (ITRs) which flank at least one cassette containing a promoter which directs cell-specific expression operably linked to a heterologous gene. Heterologous in this context refers to any nucleotide sequence or gene which is not native to the AAV or B19 parvovirus. Typically, the AAV and B19 coding regions have been deleted, resulting in a safe, noncytotoxic vector. The AAV ITRs, or modifications thereof, confer infectivity and site-specific integration, but not cytotoxicity, and the promoter directs cell-specific expression. United states Patent No.6,261,834 is herein incorporated by reference for material related to the AAV vector. The disclosed vectors thus provide DNA molecules which are capable of integration into a mammalian chromosome without substantial toxicity. The inserted genes in viral and retroviral usually contain promoters, and / or enhancers to help control the expression of the desired gene product. A promoter is generally a sequence or sequences of DNA that function when in a relatively fixed location in regard to the transcription start site. A promoter contains core elements required for basic interaction of RNA polymerase and transcription factors and may contain upstream elements and response elements. Large payload viral vectors Molecular genetic experiments with large human herpesviruses have provided a means whereby large heterologous DNA fragments can be cloned, propagated and established in cells permissive for infection with herpesviruses (Sun et al., Nature genetics 8: 33-41, 1994; Cotter and Robertson,.Curr Opin Mol Ther 5: 633-644, 1999). These large DNA viruses (herpes simplex virus (HSV) and Epstein-Barr virus (EBV), have the potential to deliver fragments of human heterologous DNA > 150 kb to specific cells. EBV recombinants can maintain large pieces of DNA in the infected B-cells as episomal DNA. Individual clones carried human genomic inserts up to 330 kb and appeared genetically stable. The maintenance of these episomes requires a specific EBV nuclear protein, EBNA1, constitutively expressed during infection with EBV. Additionally, these vectors can be used for transfection, where large amounts of protein can be generated Attorney Docket No.10935-031WO1 transiently in vitro. Herpesvirus amplicon systems are also being used to package pieces of DNA > 220 kb and to infect cells that can stably maintain DNA as episomes. Other useful systems include, for example, replicating and host-restricted non-replicating vaccinia virus vectors. Non-nucleic acid-based systems The disclosed compositions can be delivered to the target cells in a variety of ways. For example, the compositions can be delivered through electroporation, or through lipofection, or through calcium phosphate precipitation. The delivery mechanism chosen will depend in part on the type of cell targeted and whether the delivery is occurring for example in vivo or in vitro. Thus, the compositions can comprise, in addition to the disclosed compositions or vectors for example, lipids such as liposomes, such as cationic liposomes (e.g., DOTMA, DOPE, DC-cholesterol) or anionic liposomes. Liposomes can further comprise proteins to facilitate targeting a particular cell, if desired. Administration of a composition comprising a compound and a cationic liposome can be administered to the blood afferent to a target organ or inhaled into the respiratory tract to target cells of the respiratory tract. Regarding liposomes, see, e.g., Brigham et al. Am. J. Resp. Cell. Mol. Biol. 1:95-100 (1989); Felgner et al. Proc. Natl. Acad. Sci USA 84:7413-7417 (1987); U.S. Pat. No.4,897,355. Furthermore, the compound can be administered as a component of a microcapsule that can be targeted to specific cell types, such as macrophages, or where the diffusion of the compound or delivery of the compound from the microcapsule is designed for a specific rate or dosage. In the methods described above which include the administration and uptake of exogenous DNA into the cells of a subject (i.e., gene transduction or transfection), delivery of the compositions to cells can be via a variety of mechanisms. As one example, delivery can be via a liposome, using commercially available liposome preparations such as LIPOFECTIN, LIPOFECTAMINE (GIBCO-BRL, Inc., Gaithersburg, MD), SUPERFECT (Qiagen, Inc. Hilden, Germany) and TRANSFECTAM (Promega Biotec, Inc., Madison, WI), as well as other liposomes developed according to procedures standard in the art. In addition, the disclosed nucleic acid or vector can be delivered in vivo by electroporation, the technology for which is available from Genetronics, Inc. (San Diego, CA) as well as by means of a SONOPORATION machine (ImaRx Pharmaceutical Corp., Tucson, AZ). The materials may be in solution, suspension (for example, incorporated into microparticles, liposomes, or cells). These may be targeted to a particular cell type via antibodies, receptors, or receptor ligands. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Senter, et al., Bioconjugate Chem., 2:447-451, (1991); Attorney Docket No.10935-031WO1 Bagshawe, K.D., Br. J. Cancer, 60:275-281, (1989); Bagshawe, et al., Br. J. Cancer, 58:700-703, (1988); Senter, et al., Bioconjugate Chem., 4:3-9, (1993); Battelli, et al., Cancer Immunol. Immunother., 35:421-425, (1992); Pietersz and McKenzie, Immunolog. Reviews, 129:57-80, (1992); and Roffler, et al., Biochem. Pharmacol, 42:2062-2065, (1991)). These techniques can be used for a variety of other speciifc cell types. Vehicles such as "stealth" and other antibody conjugated liposomes (including lipid mediated drug targeting to colonic carcinoma), receptor mediated targeting of DNA through cell specific ligands, lymphocyte directed tumor targeting, and highly specific therapeutic retroviral targeting of murine glioma cells in vivo. The following references are examples of the use of this technology to target specific proteins to tumor tissue (Hughes et al., Cancer Research, 49:6214-6220, (1989); and Litzinger and Huang, Biochimica et Biophysica Acta, 1104:179-187, (1992)). In general, receptors are involved in pathways of endocytosis, either constitutive or ligand induced. These receptors cluster in clathrin-coated pits, enter the cell via clathrin-coated vesicles, pass through an acidified endosome in which the receptors are sorted, and then either recycle to the cell surface, become stored intracellularly, or are degraded in lysosomes. The internalization pathways serve a variety of functions, such as nutrient uptake, removal of activated proteins, clearance of macromolecules, opportunistic entry of viruses and toxins, dissociation and degradation of ligand, and receptor-level regulation. Many receptors follow more than one intracellular pathway, depending on the cell type, receptor concentration, type of ligand, ligand valency, and ligand concentration. Molecular and cellular mechanisms of receptor-mediated endocytosis have been reviewed (Brown and Greene, DNA and Cell Biology 10:6, 399-409 (1991)). Nucleic acids that are delivered to cells which are to be integrated into the host cell genome typically contain integration sequences. These sequences are often viral related sequences, particularly when viral based systems are used. These viral integration systems can also be incorporated into nucleic acids which are to be delivered using a non-nucleic acid-based system of deliver, such as a liposome, so that the nucleic acid contained in the delivery system can be come integrated into the host genome. Other general techniques for integration into the host genome include, for example, systems designed to promote homologous recombination with the host genome. These systems typically rely on sequence flanking the nucleic acid to be expressed that has enough homology with a target sequence within the host cell genome that recombination between the vector nucleic acid and the target nucleic acid takes place, causing the delivered nucleic acid to be integrated into the host genome. These systems and the methods necessary to promote homologous recombination are known to those of skill in the art. Attorney Docket No.10935-031WO1 In vivo / ex vivo As described above, the compositions can be administered in a pharmaceutically acceptable carrier and can be delivered to the subject’s cells in vivo and / or ex vivo by a variety of mechanisms well known in the art (e.g., uptake of naked DNA, liposome fusion, intramuscular injection of DNA via a gene gun, endocytosis and the like). If ex vivo methods are employed, cells or tissues can be removed and maintained outside the body according to standard protocols well known in the art. The compositions can be introduced into the cells via any gene transfer mechanism, such as, for example, calcium phosphate mediated gene delivery, electroporation, microinjection or proteoliposomes. The transduced cells can then be infused (e.g., in a pharmaceutically acceptable carrier) or homotopically transplanted back into the subject per standard methods for the cell or tissue type. Standard methods are known for transplantation or infusion of various cells into a subject. EXAMPLES The following examples are set forth below to illustrate the compositions, devices, methods, and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present invention which are apparent to one skilled in the art. Example 1. Homology directed repair using HDR template-free system Here, we discovered that our allele specific targeting approach can also initiate a naturally occurring HDR which results in correction of mutant allele. The correction might be a result of WT allele serving as a HDR template, therefore overcoming the need to provide an exogenous HDR template. It was noticed that HDR enhancer can improve this process. This strategy can be used potentially to correct ANY heterozygous mutations specifically for ex vivo Inclusion Body Myopathy with early-onset Paget and Frontotemporal Disease (IBMPFD) patients have a heterozygous mutation in the VCP gene, (50% WT and 50% mutant allele). After targeting only mutant allele using the inventive gRNA design, and in the absence of HDR template polypeptides, sequencing data showed the frequency of WT gene has increased to 73% from 50% with no addition of an HDR template. See, e.g., Figure.7. Six heterozygous mutations were corrected using the HDR template-free system herein, with at least an 80% correction efficiency. HDR enhancers are used to enhance the correction efficiency. Attorney Docket No.10935-031WO1 Example 2. High efficiency repair of heterozygous mutations without exogenous donor template using allele specific CRISPR targeting and HDR enhancers Disclosed herein is the development of REMEDY (REpair of heterozygous Mutations independent of Exogenous Donor template with high efficiencY), a genome editing strategy that allows efficient repair of heterozygous mutations in human and mouse cells without necessitating an exogenous donor DNA template. Here, in-PAM or near-PAM CRISPR strategies were used to induce a double-strand break (DSB) in mutant alleles. Following the DSB, the wild-type homologous chromosome itself serves as an endogenous DNA donor template and initiates the correction of the mutant allele. Concurrently treating the cells with HDR enhancers, such as AZD7648, further improved the efficiency of the correction. The utility of REMEDY is demonstrated in the context of five different diseases with heterozygous mutations such as cystic fibrosis, progeria, IBMPFD, ITPR3, and TBCD in human patient derived primary cells and complementary mouse model cell lines. Heterozygous mutations affect either a single allele in dominant or sex-linked inheritance patterns, or both alleles in the case of biallelic autosomal recessive inheritance. These mutations can be corrected by clustered regularly interspaced short palindromic repeats (CRISPR) mediated homology-directed repair (HDR) and exogenous DNA templates. Introducing exogenous HDR templates into the cells via electroporation, infection, lipofection, or by viral delivery approaches can not only result in low editing efficiency but cause also cell death, loss of regenerative potential, and adds additional manufacturing and financial burdens. Therefore, there is an essential need to develop a novel approach to efficiently edit heterozygous mutations independent of an exogenous DNA donor template. Herein reported is REMEDY: REpair of heterozygous Mutations independent of Exogenous Donor template with high efficiencY. In G₀-phase in human cells, double-strand breaks (DSB) result in movement of the homologous chromosomes to the DSB site and formation of a transient contact. Other studies report that CRISPR-induced DSB triggers recombination between homologous chromosome arms in fly lines. Finally, homologous chromosome exchange has been reported in mouse cells with biallelic mutations. Therefore, it is posited that this homologous recombination mechanism can be triggered between wild-type and mutant homologues chromosomes in heterozygous mutant human and mouse cells. To initiate the HDR between the homologous chromosomes, a DSB is introduced in the mutant allele. Mutant allele-specific targeting in heterozygous mutations can be achieved by designing gRNAs that contain mutated nucleotide(s) located near-PAM or in-PAM sequence. Therefore, it is hypothesized that an in-PAM or near-PAM gRNA design strategy would induce a targeted DSB only in the mutant allele and initiate the recruitment of the homologous healthy Attorney Docket No.10935-031WO1 chromosome to serve itself as endogenous DNA donor template for correction of heterozygous mutations (Figure 8A). This strategy does not require an exogenous DNA donor template for mutation correction. This approach is called REMEDY. To test REMEDY, inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) was focused on first. The disease is caused by mutations in Valosin Containing Protein (VCP) gene. Here, a mouse model of inclusion body myopathy was used with heterozygous mutation in the VCP gene (c.464_465GG>AT; p.Arg155His), one of the most frequent pathogenic variants in the VCP gene. Four mutant allele specific gRNAs were screened (table 3) to target the R155H mutation. Three gRNAs showed specificity to the mutant allele tested in healthy and VCP cells, and one (gRNA1) targeted the wild-type allele in the healthy cells, so the gRNA1 was not used for the downstream experiments (figure 10). The three mutant allele specific gRNAs were tested in a VCPR155H / +mouse myoblast cell line. All three of the tested gRNAs resulted in complete (100%) deletion of the mutant allele determined by Sanger sequencing. As it was hypothesized, a modest correction of the mutant allele without an exogenous DNA template, was observed. The frequency of wild-type allele in the cells targeted by gRNA2 increased from normalized 50% to 58% measured by Sanger sequencing analyzed by ICE (interference of CRISPR Edits) and next generation sequencing (NGS) and analyzed by CRISPResso2. Therefore, 8% of the cells were corrected to homozygous for the wild-type allele without an exogenous donor DNA template. Sanger sequencing electropherogram also showed a higher frequency of wild-type nucleotides at the position of the mutated nucleotides in the gRNA2 treated samples (Figure 8B and figure 11 and 12). To ensure that the REMEDY is not mutation and cell type specific, human VCP heterozygous mutation c.464G>A (p.Arg155His) was then targeted in a IBMPFD patient derived fibroblast line with two different gRNAs targeting the mutant allele. Sanger sequencing data showed an increase in the frequency of wild-type allele from 50% to 71% with gRNA1 and to 54% with gRNA2. The correction was again achieved without using an exogenous donor DNA template (Figure 8C and figure 13A). To ensure that the REMEDY is not disease allele specific, the wildtype allele of VCP c.464G gene was targeted in patient derived myoblasts and generated homozygous mutation of VCP c.464G>A (p.Arg155His) with high efficiency (59% mutant allele) (figure 13B and table 4). REMEDY was further tested in the context of tubulin folding cofactor D (TBCD) in human patient-derived fibroblasts. Biallelic autosomal recessive mutations in this gene result in a rare early-onset encephalopathy with neurodevelopmental and neurodegenerative features. Skin biopsy samples were collected from two different patients, each with two distinct biallelic mutations Attorney Docket No.10935-031WO1 P1M2 (TBCD; 2305-2307 ∆GAG) and P8M2 (TBCD; 2991 G>A). REMEDY for correction of each allele was performed independently. Specifically, allele specific gRNAs were designed for each of the mutations (table 5 and 6). Fibroblasts were electroporated with Cas9 / RNP targeting the mutant allele. In patient P1M2, an increase in percentage of wild-type allele was increased in the cells targeted by the mutant allele specific gRNA from 50% to 64% (Figure 8D), and in P8M2, REMEDY achieved 8% correction (figure 14 and 15) as measured by ICE and CRISPresso2. Since the REMEDY correction is regulated by HDR between homologous chromosomes, it was then hypothesized that the addition of HDR enhancers such as IDT Alt-R HDR Enhancer V2 and AZD7648 as DNA-PK inhibitors may further improve the efficiency of correction achieved by REMEDY. In P1M2, treating the cells with IDT Alt-R Enhancer V2 post Cas9 / RNP electroporation resulted in a further increase in the frequency of the wild-type allele to 83% and to 82% in the cells treated with AZD7648 as measured by ICE. This means 30% of the cells have become homozygous for wild-type TBCD. Further, NGS was performed and analyzed the data with CRISPResso2 and identified similar percentage of correction (22% wild-type homozygous TBCD). To ensure the stability of the edits and to confirm that these findings are not related to sequencing artifacts or loss of heterozygosity, single cell cloning of the cells that were targeted with allele specific gRNA3 and treated with HDR enhancer, was performed. Based on Sanger sequencing and NGS data it was expected to find one out of five clones (%20) to be fully corrected to wild-type homozygous TBCD. This was confirmed by the Sanger sequencing of five single cell cloned that were grown for more than 10 days (figure 8D-G). The NGS and Sanger sequencing on P8M2 also showed enhanced correction after treating the cells with AZD7648 and IDT HDR enhancer (50% to 70%) along with REMEDY (figure 14 and 15). Further, REMEDY was tested on a heterozygous mutation in the inositol 1,4,5 triphosphate receptor 3 (ITPR3) which regulates intracellular calcium stores, and inherited pathogenic variants can cause Charcot-Marie-Tooth disease, demyelinating, type 1J and a severe combined immunodeficiency (Lederle et al, manuscript submitted for publication, 2023). Patient-derived fibroblasts were obtained and designed a gRNA (table 7) to target only the ITPR3 allele harboring the mutation (c.7570C>T, p. Arg2524Cys). REMEDY, with the addition of HDR enhancers, again was able to significantly correct the heterozygous mutation in these cells with no need for exogenous DNA donor template, 50% to 62% with AZD7648 and to 61% with IDT HDR enhancer V2 measured by NGS and CRISPResso2 (Figure 9A and 9B) and Sanger following analysis by ICE (figure 16). Since AZD7648 and IDT HDR enhancer V2 resulted in comparable efficacy and AZD7648 is used in clinical settings, the rest of the experiments were performed using only the AZD7648 DNA-PK Attorney Docket No.10935-031WO1 inhibitor. Additionally, since ICE and CRISPResso2 showed comparable data, for the rest of experiments only Sanger sequencing was performed, and the data was analyzed with ICE. To test whether REMEDY could be used for ex vivo cell therapy applications, where clinical implications could be transformative, human airway epithelial cells collected from a patient with cystic fibrosis, were used. Allele-specific gRNAs targeting a deletion of phenylalanine 508 (F508del) in CFTR gene (table 8) were designed. A single heterozygous mutation impairs CFTR folding resulting in chloride channel dysfunction. Human bronchial epithelial cells (HBEC) harboring one copy of the F508del variant were electroporated with the Cas9 / RNP, treated the cells with AZD7468, and observed a significant increase in the frequency of wildtype allele in the cells treated with gRNA1 from 50% to 86% and to 87% with gRNA2. Confirming the potential of REMEDY for genome editing free of an exogenous donor DNA template in a cell type that has therapeutic implications for ex vivo cell therapy (Figure 9C and 9D). It was decided to further test REMEDY and see whether it can be used as an alternative for other approaches such as base editing. Base editing can also correct heterozygous mutations without an exogenous DNA template but has some limitations such as bystander off-target editing. Bystander editing happens when other Cs or Ts exist near the target site. Base editing has been used to correct a mutation in Hutchinson–Gilford progeria syndrome (HGPS or progeria) in mice. The disease is caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in the LMNA gene which encodes nuclear Lamin A and Lamin C. In previous studies, base editing corrected this mutation in patient-derived fibroblasts with an efficiency of 87–91% of the pathogenic allele. Here, REMEDY was used to correct the mutation in progeria patient-derived fibroblasts and achieved highly efficient deletion of the mutated allele and also achieved correction of mutated allele (50% to 69% wild-type allele) in the cells treated with AZD7648 post allele specific CRISPR targeting without an exogenous DNA template (Figure 9E and table 9). This data shows that REMEDY can result in comparable editing efficiency of heterozygous mutations to base editing and can be used as a reliable alternative when limitations exist. The homology repair pathway takes place during the S and G2 phases when a DNA template is available such as a sister chromatid or an exogenous DNA template. It has been shown that the HDR enhancers such as IDT HDR enhancer and AZD7648 arrest or pause the cell cycle at G1 and S at high frequency. Here, it is reported that AZD7648-mediated cell cycle synchronization favors homology repair between homologous chromosomes that are now in contact following CRISPR mediated DSB in the mutant chromosome. However, the exact mechanism remains to be verified. Attorney Docket No.10935-031WO1 REMEDY has the potential to be used in basic science and pre-clinical studies for which a heterozygous mutation needs to be corrected. It can also be potentially used to generate pathogenic homozygous mutations for in vitro studies if only wild-type allele is targeted, and the mutated homologous chromosome is used as the endogenous HDR template. Additionally, REMEDY has potential to treat patients with a wide variety of heterozygous mutations, especially if the correction can be performed ex vivo for cell therapy applications. REMEDY has several advantages over existing gene correction approaches. In the pre- clinical setting, high efficiency of correcting heterozygous mutations can be achieved by introducing donor DNA template to the cells; however, this can be cytotoxic given the initiation of DNA sensing mechanism. In the clinical setting, providing an exogenous DNA template is expensive and not widely accessible especially in low-middle income countries. For example, adeno-associated virus (AAV)- mediated HDR template delivery requires very costly manufacturing with approved AAV therapies currently costing over $2 million dollars per dose for SMA and over $3 million per dose for hemophilia. Ongoing studies are assessing the range of correction that can be achieved by REMEDY, particularly in the context of different mutation types (single nucleotide polymorphisms vs deletions of varying sizes). The allele specific gRNA approach used in REMEDY is another advantage of the method as it potentially minimizes the number of off targets since it is designed to only target the mutant allele. However, the in-PAM or near-PAM gRNA design can also be a limitation if there are no PAM sequences in close vicinity of the mutation site. This problem can be potentially solved by changing the type of endonucleases that can be used for generating DSB in the mutant allele. Tools such as Allele Analyzer can be used for allele-specific sgRNA design and for identifying potential endonucleases. Lastly, the addition of HDR enhancers improves efficiency of REMEDY. The direct comparison of two relevant enhancers validates this confirmation and enhances translation of this novel REMEDY approach. Heterozygous muatation correction via interhomolog homologous recombination has been reported by others including using using Cas9 nickase. However, it has been mostly used to correct a limited number of mutations and with relativly low frequency when only one cut was used. Here, REMEDY was used in a veriety of genetic disorders, and it is shown that the DNA-PK inhibition can significantly enhance the correction. However, the Cas9 mediated large DNA resection causing loss of heterozygosity (LOH) has been a concern. Additionally, DNA-PK inhibition may even further increase the frequency of the LOH. Therefore, to identify any LOH in REMEDY edited cells, iPSCs generated from P1M2 (TBCD; chr17; 2305-2307 ∆GAG) were used, PacBio Attorney Docket No.10935-031WO1 sequencing was performed and no evidence of LOH at the Cas9 cut site from 80mb to the chromosome end (Figure 9F) was found. Short summary: Herein, a new mechanism is demonstrated that overcomes many current barriers of gene editing by efficiently repairing heterozygous mutations without the necessity of exogenous donor DNA template. These findings were confirmed in 5 diseases, 2 species, and 3 cell types in the context of IBMPFD, TBCD, CF, Progeria, and ITPR3, which result from distinct molecular mechanisms, demonstrating the potential breadth of application of this technology. Methods: Patient Derived Fibroblasts This study was performed in compliance with the standards set by the National Institute of Health (NIH) and was reviewed and approved by the Institutional Review Board (IRB) at Nationwide Children’s Hospital (IRB number 14-00719). Written, informed consent was obtained from the participants prior to inclusion in the study. Samples from the participants were identified by numbers, not names. Patient derived human skin fibroblasts were collected under IRB and maintained in Dulbecco's modified Eagle's medium (DMEM, Gibco™, Catalog # 11960044) supplemented with GlutaMAX (Gibco™, Catalog #35050061) and 15% heat inactivated Fetal Bovine Serum (GenClone Catalog # 25-514H) FBS at 37°C and 5% CO2. Human primary Progeria dermal fibroblast cell lines were obtained from The Progeria Research Foundation (PRF) Cell and Tissue Bank. The HGPS cell lines were HGADFN367. Progeria fibroblasts were grown in DMEM media supplemented with GlutaMAX, 20% FBS, 1% Non-Essential Amino Acids (NEAA) (Thermo Fisher, Catalog # 11140050) and 1% Pen / Strep (Gibco™, Catalog # 15070-063). Patient-derived myoblasts hiPSC derived myoblasts were obtained from VCP donor patients through the Cure VCP Disease Foundation. Cells were seeded onto 10 cm culture dishes coated with Collagen (Col I, Corning, Cat. 354236) and grown in Myoblast expansion medium (iXCells, Catalog # MD- 0102A1) with 1% Pen / Strep (Gibco™, Catalog # 15070-063). Medium was changed every other day and cells were passaged once they reached 80-90% confluency using TrypLE (Gibco™ Catalog # 12604021). Mouse myoblasts and fibroblasts All animal experiments were performed in compliance with the standards set by the National Institute of Health (NIH) and were reviewed and approved by the Research Institute at Nationwide Children’s Hospital Animal Care and Use Committee (IACUC approval number: Attorney Docket No.10935-031WO1 AR18-00123). All experiments were conducted in compliance with the ARRIVE guidelines. All mice were sacrificed in accordance with ethical standards; overdose of xylazine / ketamine anesthesia was used to euthanize the mice. Skeletal muscles were collected from one VcpR155H / +mouse after euthanasia (The Jackson Laboratory, Strain #:021968). Protocol was from Shahini et al., 2018. Shortly, muscles were minced and seeded on a Matrigel #354234) coated cell culture dish in proliferation medium for release of myoblasts (high glucose DMEM, 20% FBS (ThermoFisher, Catalog #16000044), 10% horse serum (ThermoFisher, Catalog #26050070), 0.5% chicken embryo extract (Fisher Scientific, Catalog #NC9997754), 2.5 ng / ml bFGF (Peprotech, Catalog #450-33), 10 μg / ml gentamycin (Gibco, Catalog #15-710-064), 1% Antibiotic-Antimycotic (ThermoFisher, Catalog #15240062), and 2.5 μg / ml plasmocin prophylactic (Invivogen, ant-mpp). Released cells were pre-plated to purify myoblasts. Similarly, skin sample of one VcpR155H / +mouse was collected after mouse is euthanized and fibroblasts were released starting in one week. Cells were maintained as mentioned in the Patient-Derived Fibroblasts section. All animal experiments were performed according to the ethical guidelines approved by The Research Institute at Nationwide Children’s Hospital Animal Care and Use Committee (IACUC approval number: AR18-00123). Airway Epithelial cells Human bronchial epithelial cells (HBEC) were obtained from CF donor lungs through the Epithelial Cell Core at Nationwide Children’s Hospital. HBECs were cultured using Pneumacult- Ex Plus media with ROCK inhibitor (Y-27632) at 10 µM. Five days after seeding, the cells were dissociated by treatment with TrypLE and resuspended in OPTI-MEM (Gibco™, Catalog #31985070) at a concentration of 5 million cells / mL. 6 µg of Cas9 and 3.2 µg of sgRNA were mixed and incubated for 10 minutes.20 µL of cells in OPTI-MEM were added to the Cas9 / sgRNA mixture and electroporated using a Lonza 4D nucleocuvette strips. The program CA-137 with buffer setting P3 (Lonza, Catalog# V4XP-3032) was used. Five days after editing, genomic DNA was isolated from HBECs. Exon 11 locus of CFTR was amplified using PCR with an annealing temperature of 58°C and extension time of 35 sec using Q5 polymerase. Patient derived iPSCs To generate patient derived iPSCs, peripheral blood mononuclear cells (PBMCs) were isolated under approved IRB. The PBMCs were then converted to iPSCs using Sendai virus reprogramming kit (ThermoFisher, A16518) and maintained in supplemented STEMFLEX™ Attorney Docket No.10935-031WO1 Medium (ThermoFisher, A3349401) on plates coated with Vitronectin (VTN) Recombinant Human Protein, Truncated, 10mL (ThermoFisher, A31804) at 37°C and 5% CO2. Single Cell Cloning Cells were detached and diluted to 1x104cells / ml in culture media. A suspension of 5 cells / mL was prepared from the 1x104cells / mL solution by adding 25 µL to 50 mL of culture media. 200 µL of the new dilution was added to each well of a 96 well plate. The plates were monitored for 7-10 days to assess for single cell colonies. Upon reaching an appropriate cell number, PCR was performed on the isolated DNA, purified, and sent for Sanger sequencing to validate a homogeneous population. Preparation of Allele specific gRNAs VCP, TBCD, CTFR, LMNA and ITPR gRNAs were designed by using online tool Benchling (https: / / benchling.com) and synthesized by Synthego as Synthetic gRNAs resuspended in TE buffer to achieve 100 µM working concentration. Performing allele specific CRISPR in mouse myoblasts and patient derived fibroblasts, iPSCs and myoblasts Fibroblast cells were detached at least 70% confluency using TrypLE Express Enzyme (Fisher Scientific, Catalog #12-604-021). The cells were collected and counted using trypan blue. A total of 1.0x105cells were used for electroporation. The cells were electroporated using the Cas9 / RNP as 2 μL of Alt-R™ S.p. Cas9 Nuclease V3, 500 µg (IDT, Catalog # 1081059) at 62 μM, 2 μL gRNA, and 1 μL of DPBS (Corning, Catalog # 21-031-CV). The control cells received 5 µL of DPBS. the prepared Cas9 / RNP was incubated at RT for 20 minutes. The cells were resuspended in 20 μL SE electroporation buffer (Lonza, Catalog #V4SC-1096). Resuspended cells were combined with the cas9 / RNP and loaded into the electroporation cuvette provided in the Lonza kit. The cuvette was placed into the Amaxa 4D-Nucleofector X Unit (Lonza, Catalog # AAF- 1003X). The cells were electroporated with the parameters of SE buffer and a pulse code of CD- 137. Post electroporation, the cells were rested for 1 minute at RT, then using prewarmed culture media the cells were transferred to 12 well plates containing the prepared media. Cells recovered in the incubator at 37°C, 5% CO2. Human and mouse myoblasts were treated in a similar fashion with the only variation being 0.25x105cells were used per electroporation. Electroporation on iPSCs was performed using P4 electroporation buffer (Lonza, V4XP-4032) and a pulse code CA- 137. Following electroporation, cells were cultured in supplemented STEMFLEX™ Medium (ThermoFisher, A3349401) with 1X CultureSureTM CEPT Cocktail (1,000×) (FujiFilm, 033- 26071). Medium was changed to 24-hours post electroporation. The medium was replaced with Attorney Docket No.10935-031WO1 supplemented STEMFLEX™ Medium (ThermoFisher, A3349401), without antibiotics, containing 1X Y27632 Rock Inhibitor (LC Labs, Y-5301). To enhance HDR the CRISPRed cells were treated with 1 mM solution of AZD7648 (R&D Systems, Catalog # 7825 / 10) was prepared in DMSO.1 μL AZD7648 was added per 1 mL of media. The IDT HDR enhancer V2 was used at concentration of 10 μM. The media containing AZD7648 and IDT HDR enhancer V2 were removed and replaced with fresh media 24 hours after the addition of the cells. DNA isolation and PCR Genomic DNA was isolated from edited and non-edited cells using DNeasy Blood & Tissue Kit (Qiagen, Catalog #69504). Isolated DNA was subjected to PCR amplification using the Platinum™ SuperFi II PCR Master Mix (ThermoFisher, Catalog # 12368010). Following PCR, each sample was purified following the Qiagen QIAquick PCR Purification Kit (Qiagen, Catalolg # 28104). Purified samples were run on Invitrogen™ E-Gel™ Agarose Gels with SYBR™ Safe DNA Gel Stain, 2% (Fisher Scientific, Catalog # A45205) using the E-Gel™ Power Snap Electrophoresis System Starter Kit, SYBR Safe 2% (Thermofisher, Catalog # G8322ST) to validate the PCR product. All PCR primers- utilized for NGS and Sanger sequencing are described in tables 10 and 11. Sanger Sequencing Purified PCR samples along with the corresponding primers were sent to Azenta / Genewiz (www.genewiz.com) for Sanger sequencing. The received ab1 files were analyzed using ICE (ice.synthego.com). Briefly, unaffected samples of cell types similar to the patient samples were used as the control sample by which the unedited patient sample and CRISPR / cas9 edited cells were compared to. The gRNA used during a KO needs to be changed to the WT sequence without the mutation present in the patient sample. NGS Deep Sequencing Purified PCR samples were sent to the Center for Computational & Integrative Biology at Massachusetts General Hospital (dnacore.mgh.harvard.edu). Samples were run on the Illumina MiSeq with 2x100bp reads. Data was analyzed through the CRISPResso2 (crispresso.pinellolab.org / ) data analysis tool. Briefly, the tool aligns each read to all allelic variants present in the controls and matches the read to the allele that is more similar. PacBio Sequencing GATK HaplotypeCaller was used to jointly genotype the non-edited and REMEDY corrected iPSCs (allele specific gRNA + AZD7468 treated) derived from P1M2 (TBCD; chr17, Attorney Docket No.10935-031WO1 2305-2307 ∆GAG). Copy number and heterozygosity were plotted for Chr17, from 80mb to the chromosome end, with the vertical dotted gray line showing the edit site at chr17: 82924983. In the copy number plot, the Y-axis is log2-transformed coverage ratio of the treated to the untreated sample, with displacement upwards from zero indicating a copy gain and downwards indicating loss. It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the invention. Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the methods disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0002] Attorney Docket No.10935-031WO1 TABLES Table 1. Cas Subtypes. Cas subtype Signature protein — Cas3 I-A C 8 C 5 Table 2: Autosomal Dominant Disorders Ablepharon macrostomia syndrome Acropectoral syndrome Attorney Docket No.10935-031WO1 Acute intermittent porphyria Adermatoglyphia ADNP syndrome ' aly e I ant d– em ng Attorney Docket No.10935-031WO1 Hereditary hemorrhagic telangiectasia Hereditary mucoepithelial dysplasia Hereditary neurocutaneous angioma Hereditary spherocytosis ' hy ne me me ce Attorney Docket No.10935-031WO1 Split hand split foot-nystagmus syndrome Spondyloepimetaphyseal dysplasia, Strudwick type Spondyloepiphyseal dysplasia congenita Spondyloperipheral dysplasia ffe a e : age g c. _ ouse yo ass Mouse wild type VCP 5' GGAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCTGTGG SEQ ID NO: 132 3 4 5 6 7 8 9 Table 4: In-PAM or near-PAM gRNAs tested to target heterozygous mutation in VCP c.464G>A (p.Arg155His) Wild type Allele VCP 0 1 2 3 4 5 6 Attorney Docket No.10935-031WO1 gRNA targets WT allele ACATTTTTTCTTGTCCGTGGT SEQ ID NO: 147 Table 5: In-PAM or near-PAM gRNAs tested to target heterozygous mutation TBCD (P1M2) Wildtype Allele TBCD 5' GCTGAGCTTCGGAACCCCGAGGAGATGACTCGCTGTGGCTTCTCG SEQ ID NO: 148 9 0 1 2 3 4 Table 6: In-PAM or near-PAM gRNAs tested to target heterozygous mutation TBCD (P8M2) Wild type Allele TBCD 5' TTGTTAGCTCACACATTTTAAATTTCAGGATTTGCCAGACTGTTG SEQ ID NO: 155 6 7 8 9 Table 7: In-PAM or near-PAM gRNAs tested to target heterozygous mutation ITPR3 Wild type Allele ITPR3 60 61 62 63 64 Table 8: In-PAM or near-PAM gRNAs tested to target heterozygous mutation CFTR Wildtype Allele CFTR 5 Attorney Docket No.10935-031WO1 3' GTGGTAATTTCTTTTATAGTAGAAACCACAAAGGATACTACTTATATCT SEQ ID NO: 166 Mutant Allele CFTR F508del mutation:1521-1523 CTT 7 8 9 0 Table 9: In-PAM or near-PAM gRNAs tested to target heterozygous mutation LMNA Human LMNA Wildtype 5' AGCCCAGGTGGGCGGACCCATCTCCTCTGG SEQ ID NO: 183 4 5 6 7 8 Table 10: Primers used for sanger sequencing Sanger Sequencing Primer Sequence Table 11: Primers used for Next Generation Sequencing Attorney Docket No.10935-031WO1 NGS Primer VCP-NEO-NGS-Fwd TGGTCCTGTACTTGACACCTCT SEQ ID NO: 189 REFERENCES 1. Ferrari, S. et al. Choice of template delivery mitigates the genotoxic risk and adverse impact of editing in human hematopoietic stem cells. Cell Stem Cell 29, 1428-1444.e9 (2022). 2. Gandhi, M., Evdokimova, V. N., Cuenco, K. T., Bakkenist, C. J. & Nikiforov, Y. E. Homologous chromosomes move and rapidly initiate contact at the sites of double-strand breaks in genes in G₀-phase human cells. Cell Cycle 12, 547–552 (2013). 3. Brunner, E. et al. CRISPR-induced double-strand breaks trigger recombination between homologous chromosome arms. Life Sci. Alliance 2, e201800267 (2019). 4. Wang, D. et al. Cas9-mediated allelic exchange repairs compound heterozygous recessive mutations in mice. Nat. Biotechnol.36, 839–842 (2018). 5. Wu, J., Tang, B. & Tang, Y. Allele-specific genome targeting in the development of precision medicine. Theranostics 10, 3118–3137 (2020). 6. Koblan, L. W. et al. In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice. Nature 589, 608–614 (2021). 7. Conant, D. et al. Inference of CRISPR edits from Sanger trace data. CRISPR J. 5, 123–130 (2022). Attorney Docket No.10935-031WO1 8. Clement, K. et al. CRISPResso2 provides accurate and rapid genome editing sequence analysis. Nat. Biotechnol.37, 224–226 (2019). 9. Selvaraj, S. et al. High-efficiency transgene integration by homology-directed repair in human primary cells using DNA-PKcs inhibition. Nat. Biotechnol. (2023) doi:10.1038 / s41587-023-01888-4. 10. Jensen, T. J. et al. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell 83, 129–135 (1995). 11. Sharma, V. & Shukla, R. Progeria: A rare genetic syndrome. Indian J. Clin. Biochem.35, 3– 7 (2020). 12. Porto, E. M., Komor, A. C., Slaymaker, I. M. & Yeo, G. W. Base editing: advances and therapeutic opportunities. Nat. Rev. Drug Discov.19, 839–859 (2020). 13. Fok, J. H. L. et al. AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity. Nat. Commun.10, 5065 (2019). 14. Keough, K. C. et al. AlleleAnalyzer: a tool for personalized and allele-specific sgRNA design. Genome Biol.20, 167 (2019). 15. Tomita, A. et al. Inducing multiple nicks promotes interhomolog homologous recombination to correct heterozygous mutations in somatic cells. Nat. Commun.14, 5607 (2023). 16. Ma et al. Correction of a pathogenic gene mutation in human embryos. Yearb. Pediatr. Endocrinol. (2018) doi:10.1530 / ey.15.14.10. 17. Kosicki, M. et al. Cas9-induced large deletions and small indels are controlled in a convergent fashion. Nat. Commun.13, 3422 (2022). 18. Adikusuma, F., Williams, N., Grutzner, F., Hughes, J. & Thomas, P. Targeted deletion of an entire chromosome using CRISPR / Cas9. Mol. Ther.25, 1736–1738 (2017). 19. Deshpande, R. A. et al. Genome-wide analysis of DNA-PK-bound MRN cleavage products supports a sequential model of DSB repair pathway choice. Nat. Commun.14, 5759 (2023). 20. Park, S. H. et al. Comprehensive analysis and accurate quantification of unintended large gene modifications induced by CRISPR-Cas9 gene editing. Sci. Adv.8, eabo7676 (2022). 21. Shahini, A. et al. Efficient and high yield isolation of myoblasts from skeletal muscle. Stem Cell Res.30, 122–129 (2018). Attorney Docket No. 10935-031WO1 SEQUENCES SEQ ID NO: 1 - GCACGCATCCCACCATGGAC SEQ ID NO: 2 - GACATTTTTCTTGTCCATGG SEQ ID NO: 3 - ACATTTTTCTTGTCCATGGT SEQ ID NO: 4 - GACATTTTTCTTGTCCATGG SEQ ID NO: 5 - GGAGACATTTTTCTTGTCCA SEQ ID NO: 6 - CCACAGCACGCATCCCACCA SEQ ID NO: 7 - GGAGATATTTTTCTTGTCCA SEQ ID NO: 8 - GATATTTTTCTTGTCCATGG SEQ ID NO: 9 - ATATTTTTCTTGTCCATGGT SEQ ID NO: 10 - CACAGTGATCCACTGCGAAGGGGAGCCTATCAAACGAGAGGTGAGTTTTC TCCCTG SEQ ID NO: 11 - ATATTTTTCTTGTCCGGGGT SEQ ID NO: 12 - TGAACTCCACAGCACGCATCCCACCCCGGACAAGAAAAATATCTCCTATA ATACAAAGCAATACAAGTGCAATTA SEQ ID NO: 13 - TGAACTCCACAGCACGCATCCCACCNCCGGACAAGAAAAATATCTCCTAT AATACAAAGCAATACAAGTGCAATT SEQ ID NO: 14 - NNGRRT SEQ ID NO: 15 - NNNNGATT SEQ ID NO: 16 - NNGRR SEQ ID NO: 17 - AAGAA SEQ ID NO: 18 - TGGGAT SEQ ID NO: 19 - GGAGACATTTTTCTTGTCCG SEQ ID NO: 20 - TTGCTCTCGCAGGAGACATTTTTCTTGTCCaTGGTGGGATGCGTGCTGTGG AGTTCAAAGTGGTGGAAACAGATCCTAGCCCTT Attorney Docket No. 10935-031WO1 SEQ ID NO: 21 - AACGAGAGCGTCCTCTGTAAAAAGAACAGGtACCACCCTACGCACGACAC CTCAAGTTTCACCACCTTTGTCTAGGATCGGGAA SEQ ID NO: 22 - GDIFLVHGGMRAVEFKVVETDPSP SEQ ID NO: 23 - ACATTTTTCTTGTCCGTGGT SEQ ID NO: 24 - CGCAGGAGACGTTTTTCTTGTCCGTGGTGGGATGCGTGCTGTGGAGTTCA AAGTGGTGGAAACAGATCCTAGCCC SEQ ID NO: 25 - CGCAGGAGACATTTTTCTTGTCCGTNGGTGGGATGCGTGCTGTGGAGTTC AAAGTGGTGGAAACAGATCCTAGCC SEQ ID NO: 26 - TGTTTGCTCTCGCAGGAGACATTTTTCTTGTCCATGGTGGGATGCGTGCTG TGGAGTTCAAAGTGG SEQ ID NO: 27 - TGTTTGCTCTCGCAGGAGACATTTTTCTTGTCCGTGGTGGGATGCGTGCTG TGGAGTTCAAAGTGG SEQ ID NO: 28 - TGAACTCCACAGCACGCATCCCACCNACGGACAAGAAAAATGTCTCCTGC GAGAGCAAACAGTACAAGCACAGTT SEQ ID NO: 29 - TGAACTCCACAGCACGCATCCCACCNACGGACAAGAAAAATGTCTCCTGC GAGAGCAAACAGTACAAGCACAGTT SEQ ID NO: 30 - TCCACCACTTTGAACTCCACAGCACGCATCCCACCACGGACAAGAAAAAT GTCTCCTGCGAGAGCA SEQ ID NO: 31 - GACATTTTTCTTGTCCGTGG SEQ ID NO: 32 - TCGCAGGAGACATTTTTCTTGTCCGTGGTGGGATGCGTGCTGTGGAGTTCA AAGTGGTGGAAACAGATCCTAGCC Attorney Docket No. 10935-031WO1 SEQ ID NO: 33 - GAACTCCACAGCACGCATCCCACCACGGACAAGAAAAATGTCTCCTGCGA GAGCAAACAGTACAAGCACAGTTAG SEQ ID NO: 34 - CTCTCGCAGGAGACATTTTTCTTGTCCGTGGTGGGATGCGTGCTGTGGAGT TCAAAGTGGTGGAAACAGATGGTA SEQ ID NO: 35 - CTCTCGCAGGAGACATTTTTCTTGTNCCGTGGTGGGATGCGTGCTGTGGAG TTCAAAGTGGTGGAAACAGATCCT SEQ ID NO: 36 - CTCTCGCAGGAGACATTTTTCTTGTCGTGGTGGGATGCGTGCTGTGGAGTT CAAAGTGGTGGAAACAGATCCTA SEQ ID NO: 37 - CTCTCGCAGGAGACATTTTTCTTGCCGTGGTGGGATGCGTGCTGTGGAGTT CAAAGTGGTGGAAACAGATCCTA SEQ ID NO: 38 - CTCTCGCAGGAGACATTTTTCTTGGTGGGATGCGTGCTGTGGAGTTCAAA GTGGTGGAAACAGATCCTA SEQ ID NO: 39 - CTCTCGCAGGAGACATTTTTCTTGTGGTGGGATGCGTGCTGTGGAGTTCAA AGTGGTGGAAACAGATCCTA SEQ ID NO: 40 - CTCTCGCAGGAGACATTTTTCTTGCGTGGTGGGATGCGTGCTGTGGAGTTC AAAGTGGTGGAAACAGATCCTA SEQ ID NO: 41 - GTACTGTTTGCTCTCGCAGGAGACATTTTTCTTGTCCGTGGGGGGATGGGT GGTGGGGAGTTCAAA SEQ ID NO: 42 - GTACTGTTTGCTCTCGCAGGAGACATTTTTCTTGTCCGTGGTGGGATGCGT GCTGTGGAGTTCAAA SEQ ID NO: 43 - GGAGACATTTTTCTTGTCCG Attorney Docket No. 10935-031WO1 SEQ ID NO: 44 - CTCCACAGCACGCATCCCACCACGGACAAGAAAAATGTCTCCTGCGAGAG CAAACAGTACAAGCACAGTTAGAGG SEQ ID NO: 45 - CTCCACAGCACGCATCCCACCACGGNACAAGAAAAATGTCTCCTGCGAGA GCAAACAGTACAAGCACAGTTAGAG SEQ ID NO: 46 - CCACTTTGAACTCCACAGCACGCATCCCACCACGGACAAGAAAAATGTCT CCTGCGAAAGCAAACA SEQ ID NO: 47 - CCACTTTGAACTCCACAGCACGCATCCCACCACGGACAAGAAAAATGTCT CCTGCGAGAGCAAACA SEQ ID NO: 48 - TGAACTCCACAGCACGCATCCCACCACGGACAAGAAAAATGTCTCCTGCG AGAGCAAACAGTACAAGCACAGTTA SEQ ID NO: 49 - GAACTCCACAGCACGCATCCCACCACGGACAAGAAAAATGTCTCCTGCGA GAGCAAACAGTACAAGCACAGTTAG SEQ ID NO: 50 - CTCCACAGCACGCATCCCACCACGGACAAGAAAAATGTCTCCTGCGAGAG CAAACAGTACAAGCACAGTTAGAGG SEQ ID NO: 51 - GAACTCCACAGCACGCATCCCACCACGGACAAGAAAAATGTCTCCTGCGA GAGCAAACAGTACAAGCACAGTTCG SEQ ID NO: 52 - ACTCCACAGCACGCATCCCACCCAGGACAAGAAAAATGTCTCCTGCGAGA GCAAACAGTACAAGCACAGTTAGAG SEQ ID NO: 53 - GCACGCATCCCACCACGGAC SEQ ID NO: 54 - ATTATAGGAGATATTTTTCTTGTCCatGGTGGGATGCGTGCTGTGGAGTTCA AAGTTGTAGAGACAGATCCCAGCCCTTA Attorney Docket No. 10935-031WO1 SEQ ID NO: 55 - TAATATCCTCTATAAAAAGAACAGGtaCCACCCTACGCACGACACCTCAAG TTTCAACATCTCTGTCTAGGGTCGGGAAT SEQ ID NO: 56 - GDIFLVHGGMRAVEFKVVETDPSPY SEQ ID NO: 57 - GGAGATATTTTTCTTGTCCG SEQ ID NO: 58 - CTCCACAGCACGCATCCCACCCCGGACAAGAAAAATATCTCCTATAATAC AAAGCAATACAAGTGCAATTAGAGG SEQ ID NO: 59 - CTCCACAGCACGCATCCCACCCCGGNNACAAGAAAAATATCTCCTATAAT ACAAAGCAATACAAGTGCAATTAGA SEQ ID NO: 60 - CAACTTTGAACTCCACAGCACGCATCCCACCCCGGACAAGAAAAATATCT CCTATAATACAAAGCA SEQ ID NO: 61 - GATATTTTTCTTGTCCGGGG SEQ ID NO: 62 - GAACTCCACAGCACGCATCCCACCCCGGACAAGAAAAATATCTCCTATAA TACAAAGCAATACAAGTGCAATTAG SEQ ID NO: 63 - GAACTCCACAGCACGCATCCCACCCNCGGACAAGAAAAATATCTCCTATA ATACAAAGCAATACAAGTGCAATTA SEQ ID NO: 64 - CTACAACTTTGAACTCCACAGCACGCATCCCACCCCGGACAAAAAAAATA TCTCCTATAATACAAA SEQ ID NO: 65 - CTACAACTTTGAACTCCACAGCACGCATCCCACCCCGGACAAGAAAAATA TCTCCTATAATACAAA SEQ ID NO: 66 - TGAACTCCACAGCACGCATCCCACCCCGGACAAGAAAAATATCTCCTATA ATACAAAGCAATACAAGTGCAATTA Attorney Docket No. 10935-031WO1 SEQ ID NO: 67 - TGAACTCCACAGCACGCATCCCACCNCCGGACAAGAAAAATATCTCCTAT AATACAAAGCAATACAAGTGCAATT SEQ ID NO: 68 - TCTACAACTTTGAACTCCACAGCACGCATCCCACCCCGGACAAAAAAAAT ATCTCCTATAATACAA SEQ ID NO: 69 - TCTACAACTTTGAACTCCACAGCACGCATCCCACCCCGGACAAGAAAAAT ATCTCCTATAATACAA SEQ ID NO: 70 - CCACAGCACGCATCCCACCC SEQ ID NO: 71 - TAGGAGATATTTTTCTTGTCCGGGGGGGATGCGTGCTGTGGAGTTCAAAG TTGTAGAGACAGATCCCAGCCCTT SEQ ID NO: 72 - TAGGAGATATTTTTCTTGTCCGGGGGGATGCGTGCTGTGGAGTTCAAAGTT GTAGAGACAGATCCCAGCCCTT SEQ ID NO: 73 - TAGGAGATATTTTTCTTGTCCGGGGNTGGGATGCGTGCTGTGGAGTTCAA AGTTGTAGAGACAGATCCCAGCCCT SEQ ID NO: 74 - TAGGAGATATTTTTCTTGTCCGGGGATGCGTGCTGTGGAGTTCAAAGTTGT AGAGACAGATCCCAGCCCTT SEQ ID NO: 75 - TAGGAGATATTTTTCTTGTCCGGGGGATGCGTGCTGTGGAGTTCAAAGTTG TAGAGACAGATCCCAGCCCTT SEQ ID NO: 76 - TAGGAGATATTTTTCTTGTCCTGGGATGCGTGCTGTGGAGTTCAAAGTTGT AGAGACAGATCCCAGCCCTT SEQ ID NO: 77 - TAGGAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCTGTGGAGTTCAAA GTTGTAGAGACAGATCCCAGCCCTT Attorney Docket No. 10935-031WO1 SEQ ID NO: 78 - TAGGAGATATTTTTCTTGTCCGGGGGGATGCGTGCTGTGGAGTTCAAAGTT GTAGAGACAGATCCCAGCCCTT SEQ ID NO: 79 - CTTTGTATTATAGGAGATATTTTTCTTGTCCGGGGGGGATGCGTGTTGTGG AGTTCAAAGTTGAAA SEQ ID NO: 80 - CTTTGTATTATAGGAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCTGTG GAGTTCAAAGTTGTA SEQ ID NO: 81 - GTATTATAGGAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCTGTGGAGT TCAAAGTTGTAGAGACAGATCCCA SEQ ID NO: 82 - GTATTGCTTTGTATTATAGGAGATATTTTTCTTGTCCGGGGTGGGATGCGT GCTGTGGAGTTCAAA SEQ ID NO: 83 - TTATAGGAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCTGTGGAGTTCA AAGTTGTAGAGACAGATCCCAGCC SEQ ID NO: 84 - TTGCTTTGTATTATAGGAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCT GTGGAGTTCAAAGTT SEQ ID NO: 85 - TATAGGAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCTGTGGAGTTCAA AGTTGTAGAGACAGATCCCAGCCC SEQ ID NO: 86 - TGCTTTGTATTATAGGAGATATTTTTCTTGTCCGGGGTGGGATGCGTGATG TGGAGTTCAAAGTTG SEQ ID NO: 87 - GDIFLVHGGMRAVEF SEQ ID NO: 88 - NNNNNNNNNNNNNNNNNNNNMPAM SEQ ID NO: 89 - NNNNNNNNNNNNNNNNNNNMNPAM SEQ ID NO: 90 - NNNNNNNNNNNNNNNNNNMNNPAM Attorney Docket No. 10935-031WO1 SEQ ID NO: 91 - NNNNNNNNNNNNNNNNNMNNNPAM SEQ ID NO: 92 - NNNNNNNNNNNNNNNNMNNNNPAM SEQ ID NO: 93 - NNNNNNNNNNNNNNNMNNNNNPAM SEQ ID NO: 94 - ACACAGTGATCCACTGCGAAGGGGAGCCTATCAAACGAGAGGTGAGTTTT CTCCCTG SEQ ID NO: 95 - TGTGTCACTAGGTGACGCTTCCCCTCGGATAGTTTGCTCTCCACTCAAAAG AGGGAC SEQ ID NO: 96 - DTVIHCEGEPIKRE SEQ ID NO: 97 - TGAACTCCACAGCACGCATCCCACCCCGGACAAGAAAAATATCTCCTATA ATACAAAGCAATACAAGTGCAATTA SEQ ID NO: 98 – TGAACTCCACAGCACGCATCCCACCNCCGGACAAGAAAAATATCTCCTAT AATACAAAGCAATACAAGTGCAATT SEQ ID NO: 99 – AGATGACTCGCTGTGGCT . SEQ ID NO: 100 – AGGAGATGACTCGCTGTGGCT . SEQ ID NO: 101 – AGACTCGCTGTGGCT . SEQ ID NO: 102 – AGAGACTCGCTGTGGCT . SEQ ID NO: 103 – AGATTGACTCGCTGTGGCT . SEQ ID NO: 104 – AAGCTGTGGCT . SEQ ID NO: 105 – AGGAGATGACTTGCTGTGGCT . SEQ ID NO: 106 – AACCCCGAGGAGATGACTCGCTGTGG . SEQ ID NO: 107 – AACCCCGAGGAGATGACTCGCTGTGG . SEQ ID NO: 108 – AACCCCGAAGCCACTCCCCGTGGCTT . SEQ ID NO: 109 – AACCCCCAAGACATGACTCGCTGTGGC . SEQ ID NO: 110 – AACCCCGATGTGACTTGTCGTTGGGGC . SEQ ID NO: 111 – AACCCCGAGGAGATGACTCGCTGTGG . SEQ ID NO: 112 – AACCCCGAGGAGATGACTCGCTGTGG . SEQ ID NO: 113 – AACCCCGAGGAGATGACTCGCTGTGG Attorney Docket No. 10935-031WO1 SEQ ID NO: 114 – CTGACCTGCGTAGTGAGAAG SEQ ID NO: 115 – CTGACCTGTGTAGTGAGAAG SEQ ID NO: 116 – CTGACCTGTGAGTGAGAAG SEQ ID NO: 117 – CTGACCTGCGTAGTGAGAAG SEQ ID NO: 118 – CTGACCTGTGAGTGAGAAG SEQ ID NO: 119 – CTGACCTGTGAGAAG SEQ ID NO: 120 – CTGACCTGCGTAGTGAGAAG SEQ ID NO: 121 – CTGACCTGTGTAGTGAGAAG SEQ ID NO: 122 – CTGACCTGTGAGTGAGAAG SEQ ID NO: 123 – CTGACCTGCGTAGTGAGAAG SEQ ID NO: 124 – CTGACCTGTGTAGTGAGAAG SEQ ID NO: 125 – CTGACCTGTGAGTGAGAAG SEQ ID NO: 126 – TGGCACCATTAAAGAAAATATCATTGGT SEQ ID NO: 127 – CACCATTAAAGAAAATATCATCGTTG SEQ ID NO: 128 – TGGCACCATTAAAGAAAATATCATCTTT SEQ ID NO: 129 – TGGCACCATTAAAGAAAATATCATCTTTGGTG SEQ ID NO: 130 – TGGCACCATTAAAGAAAATATCATCTTTGGT SEQ ID NO: 131 – TGGCACCATTAAAGAAAATATCATCTTTGGT SEQ ID NO: 197 –CCCACCCCGGACAAGAAAAATATCTCCT SEQ ID NO: 198 – CCACAGCACGCATCCCCCCCGAACAAAA SEQ ID NO: 199 – ACGCATCCCACCCCGGACAAGAAAAATA SEQ ID NO: 200 – AGCACGCATCCCACCCCGGACAAGAAAA SEQ ID NO: 201 – CAGCACGCATCCCACCCCGGACAAGAAA SEQ ID NO: 202 – CCCACCCCGGACAAGAAAAATATCTCCT SEQ ID NO: 203 – CCCACCCCGGACAAGAAAAATATCTCCT SEQ ID NO: 204 – CCCACCCCGGACAAGAAAAATATCTCCT SEQ ID NO: 205 – CCCACCCCGGACAAAAAAAATATCT SEQ ID NO: 206 – CCCACCCCGGACAAAAAAAATATCTCCT SEQ ID NO: 207 – GAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCTGTGGA Attorney Docket No. 10935-031WO1 SEQ ID NO: 208 – GAGATATTTTTCTTGTCCATGGTGGGATGCGTGCTGTGGA SEQ ID NO: 209 – GAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCTGTGGA SEQ ID NO: 210 – GAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCAGTGGA SEQ ID NO: 211 – GAGATATTTTTCTTGTCCATGGTGGGATGCGTGCAGTGGA SEQ ID NO: 212 – GAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCTGTGGA SEQ ID NO: 213 – AGATATTTTTCTTGTTCCATGGTGGGATGCGTGCTGTGGA SEQ ID NO: 214 – GAGATATTTTTCTTGTTCCATGGGGGATGCGTGCTGTGGA SEQ ID NO: 215 – GAGATATTTTTCTTGTCATGGTGGGATGCGTGCTGTGGA SEQ ID NO: 216 – GAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCTGTGGA SEQ ID NO: 217 – GAGATATTTTTCTTGTCCAATGGTGGGATGCGTGCTGTGG SEQ ID NO: 218 – GAGATATTTTTCTTGTCCTGGTGGGATGCGTGCTGTGGA SEQ ID NO: 219 – GAGATATTTTTCTTGTCCAGTGGGATGCGTGCTGTGGA SEQ ID NO: 220 – GAGATATTTTTCTTGTCCGGGGTGGGATGCGTGCTGTGGA SEQ ID NO: 221 – GAGATATTTTTCTTGTCCATTGGTGGGATGCGTGCTGTGG SEQ ID NO: 222 – GAGATATTTTTCTTGTCCAGGTGGGATGCGTGCTGTGGA SEQ ID NO: 223 – GAGATATTTTTCTTGTCCGGTGGGATGCGTGCTGTGGA SEQ ID NO: 224 – GGAGACATTTTTCTTGTCCGTGGTGGGATGC Attorney Docket No. 10935-031WO1 SEQ ID NO: 225 – GGAGACATTTTTCTTGTCCATGGTGGGATGC SEQ ID NO: 226 – GGAGACATTTTTCTTGTCCATGGTGGGATGC SEQ ID NO: 227 – GAGACATTTTTCTTGTCCGTGGTGGGATGCGTGCTGTGGA SEQ ID NO: 228 – GAGACATTTTTCTTGTCCATGGTGGGATGCGTGCTGTGGA SEQ ID NO: 229 – GAGACATTTTTCTTGTCCGTGGTGGGATGCGTGCTGTGGA SEQ ID NO: 230 – GAGACATTTTTCTTGTCCGTTGGTGGGATGCGTGCTGTGG SEQ ID NO: 231 – GAGACATTTTTCTTGTCCGTGGGATGCGTGCTGTGGA SEQ ID NO: 232 – GAGACATTTTTCTTGTGGGATGCGTGCTGTGGA SEQ ID NO: 233 – GAGACATTTTTCTTGTCCATTGGTGGGATGCGTGCTGTGG SEQ ID NO: 234 – GAGACATTTTTCTTGGGATGCGTGCTGTGGA SEQ ID NO: 235 – GAGACATTTTTCTTGTCCGTGCTGTGGA SEQ ID NO: 236 – GAGACATTTTTCTTGGTGGGATGCGTGCTGTGGA SEQ ID NO: 237 – ACTTTGTGCGTGCTGTGGA SEQ ID NO: 238 – GAGACATTTTTCTTGTCCGGTGGGATGCGTGCTGTGGA SEQ ID NO: 239 – TTTGTCTGATGAGTGGGATGCGTGCTGTGGA SEQ ID NO: 240 – GAGACATTTTTCTTGTCCGGGTGGGATGCGTGCTGTGGA SEQ ID NO: 241 – ACTTTGTGGGATGCGTGCTGTGGA SEQ ID NO: 242 – GAGACATTTTTCTTGTCCACTGCGAAGGGGAGCC SEQ ID NO: 243 – GTGGGATGCGTGCTGTGGA SEQ ID NO: 244 – GATGCGTGCTGTGGA SEQ ID NO: 245 – TTTGTCTTGTAGTTGGGATGCGTGCTGTGGA SEQ ID NO: 246 – GAGTTCTCACTGGTGGGATGCGTGCTGTGGA SEQ ID NO: 247 – GAGACATTTTCTTGTCCATGGTGGGATGCGTGCTGTGGA Attorney Docket No. 10935-031WO1 SEQ ID NO: 248 – GAGACATTTTTCTTGTCCAGGTGGGATGCGTGCTGTGGA SEQ ID NO: 249 – GAGCGTGGGATGCGTGCTGTGGA SEQ ID NO: 250 – GTGGGATGCGTGCTGTGGA SEQ ID NO: 251 – GAGACATTTTTCTTGTCCATATGGTGGGATGCGTGCTGTG SEQ ID NO: 252 – ACATTTTAAATTTCAGGATT SEQ ID NO: 253 – ACATTTTAAATTTCGGGATT

Claims

Attorney Docket No. 10935-031WO1 CLAIMS What is claimed is:

1. A system for repairing a mutation in a mutant allele of a heterozygous gene, said system comprising a guide RNA (gRNA), wherein: a. the gRNA targets a mutant allele of a heterozygous gene, b. the mutant allele comprises one or more mutations, and c. the gRNA does not target the wild-type allele of the gene; and wherein the system is free from exogenous homology directed repair (HDR) template.

2. The system of claim 1, wherein the system further comprises a Cas endonuclease.

3. The system of claim 1, wherein the system further comprises an HDR enhancer to enhance intra-homologous recombination.

4. The system of claim 3, wherein the HDR enhancer is a DNA-dependent protein kinase (DNA-PK) Inhibitor.

5. The system of claim 4, wherein the DNA-PK Inhibitor is selected from the group comprising of AZD7648, LY294002, Compound 401, PIK-75 HCl, KU-0060648, CC-115, PP121, SF2523, YU238259, LTURM34, Nedisertib (M3814), Samotolisib (LY3023414), Wortmannin, NU7441 (KU-57788), PI-103, T0070907, Torin 2, Alt-R™, SCR7, L755507, EPZ5676, rucaparib, pevonedistat, brefeldin A, Alt-R HDR Enhancer V1, XL413, trichostatin A, CRISPYTMMix, romidepsin, nedisertib, and Alt-R HDR Enhancer V2 and NU7026.

6. The system of claim 1, wherein the mutant allele comprises a target strand and a non- target strand complementary to the target strand.

7. The system of any one of claims 1-6, wherein the gRNA is complementary to target strand.

8. The system of any one of claims 6 or 7, wherein the non-target strand comprises one or more mutations, and wherein at least one of the one or more mutations is within 7 nucleotides upstream the 5’ end of a protospacer adjacent motif (PAM) sequence.Attorney Docket No. 10935-031WO1 9. The system of any one of claims 1-8, wherein at least one of the one or more mutations is within 6, 5, 4, 3, 2, or 1 nucleotide upstream the 5’ end of the PAM sequence.

10. The system of any one of claims 1-9, wherein the one or more mutations are point mutations, insertions, deletions, or translocations.

11. The system of any one of claims 8-10, wherein the PAM sequence comprises NGG, NNGRR, NNGRRT, or NNNNGATT.

12. The system of claim 11, wherein the PAM sequence further comprises AAGAA, TGGGAT, GGG, or TGG.

13. The system of any one of claims 1-12, wherein the mutant allele is associated with a genetic disorder.

14. The system of claim 13, wherein the genetic disorder is a dominant-negative disorder.

15. The system of any one of claims 13 or 14, wherein the genetic disorder comprises Huntington’s disease, Marfan’s syndrome, familial hypercholesterolemia, inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal dominant hyper-IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, or KCNT1-related developmental and epileptic encephalopathy.

16. The system of any one of claims 1-15, wherein the mutant allele is of a VCP gene, a STAT3 gene, a FBN1 gene, a APOB gene, a LDLR gene, a PCSK9 gene, a DOCK8 gene, a TBCD gene, or a KCNT1 gene.

17. The system of claim 16, wherein the mutant allele of the VCP gene comprises SEQ ID NO: 10 or a fragment thereof.

18. The system of any one of claims 1-17, wherein the gRNA comprises a sequence selected from the group consisting of SEQ ID NOs: 1-9 or a fragment thereof.

19. The system of claim 1-18, wherein the mutant allele is autosomal dominant allele.Attorney Docket No. 10935-031WO1 20. The system of claim 19, wherein the autosomal dominant allele is a pathogenic autosomal dominant allele.

21. The system of claim 20, wherein the pathogenic autosomal dominant allele expresses in a mammal as a disorder selected from the group consisting of: proliferation disorder, blood disorder, vision disorder, connective tissue disorder, and protein processing disorder.

22. The system of any of claims 20-21, wherein the pathogenic autosomal dominant allele expresses in a mammal as a disorder selected from the group consisting of: achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, and hereditary elliptocytosis.

23. The system of any of claims 20-22, wherein the pathogenic autosomal dominant allele expresses in a mammal as a disorder selected from the group consisting of: Ablepharon macrostomia syndrome Acropectoral syndrome, Acute intermittent porphyria Adermatoglyphia, ADNP syndrome, Albright's hereditary osteodystrophy Ankylosing vertebral hyperostosis with tylosis Aphalangy-syndactyly-microcephaly syndrome Arakawa's syndrome II, Aromatase excess syndrome Autosomal dominant cerebellar ataxia, Autosomal dominant Charcot–Marie–Tooth disease type 2 with giant axons Autosomal dominant GTP cyclohydrolase I deficiency, Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Autosomal dominant nocturnal frontal lobe epilepsy, Autosomal dominant partial epilepsy with auditory features Autosomal dominant polycystic kidney disease Axenfeld–Rieger syndrome, Bainbridge–Ropers syndrome Barber–Say syndrome Beck–Fahrner syndrome Benign hereditary chorea Bethlem myopathy, Birt–Hogg– Dubé syndrome, Blepharophimosis, ptosis, epicanthus inversus syndrome Blepharoptosis- myopia-ectopia lentis syndrome Boomerang dysplasia, Bosch-Boonstra-Schaaf optic atrophy syndrome Brachydactyly-long thumb syndrome, Branchio-oto-renal syndrome Buschke– Ollendorff syndrome, Calvarial doughnut lesions-bone fragility syndrome Camptodactyly- taurinuria syndrome Camurati–Engelmann disease, CAPOS syndrome Central core disease, Cerebro-costo-mandibular syndrome, Cochleosaccular degeneration with progressiveAttorney Docket No. 10935-031WO1 cataracts Cohen-Gibson syndrome, Collagen disease Collagenopathy, types II and XI Collins– Pope syndrome, Coloboma of macula-brachydactyly type B syndrome Congenital distal spinal muscular atrophy, Congenital stromal corneal dystrophy Costello syndrome, Craniofacial dysostosis-diaphyseal hyperplasia syndrome Currarino syndrome, Cyprus facial neuromusculoskeletal syndrome Czech dysplasia, metatarsal type, Darier's disease GLUT1 deficiency, Dentatorubral–pallidoluysian atrophy Dermatopathia pigmentosa reticularis DiGeorge syndrome Dysfibrinogenemia, Emberger syndrome, Familial amyloid polyneuropathy Familial atrial fibrillation, Familial cutaneous collagenoma, Familial disseminated comedones without dyskeratosis Familial hypercholesterolemia, Familial male- limited precocious puberty Feingold syndrome, Felty's syndrome, Fibular aplasia-ectrodactyly syndrome Flynn–Aird syndrome, Gardner's syndrome GATA2 deficiency, GATAD2B- associated neurodevelopmental disorder Gillespie syndrome, Gray platelet syndrome, Greig cephalopolysyndactyly syndrome, Hagemoser–Weinstein–Bresnick syndrome Hajdu–Cheney syndrome Haploinsufficiency of A20, Hawkinsinuria Hay–Wells syndrome, Heart-hand syndrome, Spanish type Hemochromatosis type 4, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome Hereditary elliptocytosis, Hereditary hemorrhagic telangiectasia Hereditary mucoepithelial dysplasia Hereditary neurocutaneous angioma Hereditary spherocytosis, Holt–Oram syndrome Huntington's disease, Huntington's disease- like syndrome Hyperinsulinism-hyperammonemia syndrome Hypertrophic cardiomyopathy Hypoalphalipoproteinemia Hypochondroplasia, Hypodysfibrinogenemia, IVIC syndrome, Jackson–Weiss syndrome Jordan's Syndrome, Juberg-Hayward syndrome Juvenile-onset dystonia, Keratoendotheliitis fugax hereditaria Keratolytic winter erythema, Kniest dysplasia, Langer–Giedion syndrome Larsen syndrome, Leucine-sensitive hypoglycemia of infancy Liddle's syndrome, Marfan syndrome Marshall syndrome Marsili syndrome, Medullary cystic kidney disease Menke-Hennekam syndrome Metachondromatosis Miller–Dieker syndrome, MOMO syndrome Monilethrix MonoMAC, Multiple endocrine neoplasia Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2B, Muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome Myelokathexis, Myotonic dystrophy, Nablus mask-like facial syndrome, Naegeli–Franceschetti–Jadassohn syndrome Nail–patella syndrome, Noonan syndrome, Oculopharyngeal muscular dystrophy Otofaciocervical syndrome, Pachyonychia congenita Pallister–Hall syndrome, PalmoplantarAttorney Docket No. 10935-031WO1 keratoderma with deafness PAPA syndrome, Papillorenal syndrome Parastremmatic dwarfism Pashayan syndrome Pelger–Huët anomaly Peutz–Jeghers syndrome Piebaldism, Platyspondylic lethal skeletal dysplasia, Torrance type Polydactyly, Polymerase proofreading- associated polyposis Popliteal pterygium syndrome, Porphyria cutanea tarda Pseudoachondroplasia, RASopathy, Reis–Bucklers corneal dystrophy Romano–Ward syndrome Rosselli–Gulienetti syndrome Roussy–Lévy syndrome Rubinstein–Taybi syndrome, Saethre–Chotzen syndrome, Scalp defects-postaxial polydactyly syndrome Schmitt Gillenwater Kelly syndrome, Severe congenital neutropenia, Severe intellectual disability- progressive spastic diplegia syndrome Short QT syndrome, Singleton Merten syndrome, Spastic paraplegia 6 Spastic paraplegia 31, Spinal muscular atrophy with lower extremity predominance 1 Spinal muscular atrophy with lower extremity predominance 2A Spinal muscular atrophy with lower extremity predominance 2B Spinocerebellar ataxia, Spinocerebellar ataxia type 1 Spinocerebellar ataxia type 6, Split hand split foot-nystagmus syndrome Spondyloepimetaphyseal dysplasia, Strudwick type Spondyloepiphyseal dysplasia congenita Spondyloperipheral dysplasia, St. Helena familial genu valgum Stickler syndrome, Syndactyly-nystagmus syndrome due to 2q31.1 microduplication SYNGAP1-related intellectual disability, SYT1-associated neurodevelopmental disorder, Thumb stiffness- brachydactyly-intellectual disability syndrome Tietz syndrome, Timothy syndrome Treacher Collins syndrome, Tricho–dento–osseous syndrome, TRPM3-related neurodevelopmental disorders Tuberous sclerosis, Upington disease, Variegate porphyria, Ventricular extrasystoles with syncopal episodes-perodactyly-Robin sequence syndrome Verloes Van Maldergem Marneffe syndrome, Vitelliform macular dystrophy Von Hippel–Lindau disease Von Willebrand disease, Wallis–Zieff–Goldblatt syndrome WHIM syndrome, and White sponge nevus.

24. The system of any of claims 1-23, wherein the mutant allele is expressed in a cell that is heterozygous for the allele.

25. The system of claim 24, wherein the cell expresses CD34 on its cell surface membrane.

26. The system of claim 25, wherein the CD34 expressing cell is a cell associated with alveolar soft part sarcoma, pre-B acute lymphocytic leukemia, acute myeloid leukemia,Attorney Docket No. 10935-031WO1 dermatofibrosarcoma protuberans, gastrointestinal stromal tumor, giant cell fibroblastoma, granulocytic sarcoma, Kaposi’s sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, meningeal hemangiopericytoma, cutaneous fibrous histiocytoma, angiosarcoma, meningiomas, neurofibromas, schwannomas, and papillary thyroid carcinoma.

27. A method of treating a genetic disorder in a subject, comprising administering to the subject the system of any one of claims 1-26.

28. A method of treating a genetic disorder in a subject, comprising administering to the subject a system comprising a Cas endonuclease and a guide RNA (gRNA), wherein: a. the gRNA targets a mutant allele of a heterozygous gene, b. the mutant allele comprises one or more mutations, and c. the gRNA does not target the wild-type allele of the gene; and wherein the system is free from exogenous homology directed repair (HDR) template.

29. The system of claim 28, wherein the system comprises a Cas endonuclease.

30. The method of claim 28, wherein the system further comprises an HDR enhancer to enhance intra-homologous recombination.

31. The method of claim 28, wherein the HDR enhancer.is a DNA-dependent protein kinase (DNA-PK) Inhibitor.

32. The method of claim 28, wherein the DNA-PK Inhibitor is selected from the group comprising of AZD7648, LY294002, Compound 401, PIK-75 HCl, KU-0060648, CC-115, PP121, SF2523, YU238259, LTURM34, Nedisertib (M3814), Samotolisib (LY3023414), Wortmannin, NU7441 (KU-57788), PI-103, T0070907, Torin 2, Alt-R™, SCR7, L755507, EPZ5676, rucaparib, pevonedistat, brefeldin A, Alt-R HDR Enhancer V1, XL413, trichostatin A, CRISPYTMMix, romidepsin, nedisertib, and Alt-R HDR Enhancer V2 and NU7026.

33. The method of claim 28, wherein the mutant allele comprises a target strand and a non- target strand complementary to the target strand.Attorney Docket No. 10935-031WO1 34. The method of any one of claims 28-33, wherein the gRNA is complementary to target strand.

35. The method of any one of claims 33 or 34, wherein the non-target strand comprises one or more mutations, and wherein at least one of the one or more mutations is within 7 nucleotides upstream the 5’ end of a protospacer adjacent motif (PAM) sequence.

36. The method of any one of claims 28-35, wherein at least one of the one or more mutations is within 6, 5, 4, 3, 2, or 1 nucleotide upstream the 5’ end of the PAM sequence.

37. The method of any one of claims 28-36, wherein the one or more mutations are point mutations, insertions, deletions, or translocations.

38. The method of any one of claims 35-37, wherein the PAM sequence comprises NGG, NNGRR, NNGRRT, or NNNNGATT.

39. The method of claim 38, wherein the PAM sequence further comprises AAGAA, TGGGAT, GGG, or TGG.

40. The method of any one of claims 28-39, wherein the mutant allele is associated with a genetic disorder.

41. The method of claim 40, wherein the genetic disorder is a dominant-negative disorder.

42. The method of any one of claims 40 or 41, genetic disorder comprises Huntington’s disease, Marfan’s syndrome, familial hypercholesterolemia, inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal dominant hyper-IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, or KCNT1-related developmental and epileptic encephalopathy.

43. The method of any one of claims 28-42, wherein the mutant allele is of a VCP gene, a STAT3 gene, a FBN1 gene, a APOB gene, a LDLR gene, a PCSK9 gene, a DOCK8 gene, a TBCD gene, or a KCNT1 gene.Attorney Docket No. 10935-031WO1 44. The method of claim 43, wherein the mutant allele of the VCP gene comprises SEQ ID NO: 10 or a fragment thereof.

45. The method of any one of claims 28-44, wherein the gRNA comprises a sequence selected from the group consisting of SEQ ID NOs: 1-9 or a fragment thereof.

46. The method of claim 28-45, wherein the mutant allele is autosomal dominant allele.

47. The method of claim 46, wherein the autosomal dominant allele is a pathogenic autosomal dominant allele.

48. The method of claim 47, wherein the pathogenic autosomal dominant allele expresses in a mammal as a disorder selected from the group consisting of: proliferation disorder, blood disorder, vision disorder, connective tissue disorder, and protein processing disorder.

49. The method of any of claims 47-48, wherein the pathogenic autosomal dominant allele expresses in a mammal as a disorder selected from the group consisting of: achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, and hereditary elliptocytosis.

50. The method of any of claims 47-49, wherein the pathogenic autosomal dominant allele expresses in a mammal as a disorder selected from the group consisting of: Ablepharon macrostomia syndrome Acropectoral syndrome, Acute intermittent porphyria Adermatoglyphia, ADNP syndrome, Albright's hereditary osteodystrophy Ankylosing vertebral hyperostosis with tylosis Aphalangy-syndactyly-microcephaly syndrome Arakawa's syndrome II, Aromatase excess syndrome Autosomal dominant cerebellar ataxia, Autosomal dominant Charcot–Marie–Tooth disease type 2 with giant axons Autosomal dominant GTP cyclohydrolase I deficiency, Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Autosomal dominant nocturnal frontal lobe epilepsy, Autosomal dominant partial epilepsy with auditory features Autosomal dominant polycystic kidney disease Axenfeld–Rieger syndrome, Bainbridge–Ropers syndrome Barber–Say syndrome Beck–Fahrner syndrome Benign hereditary chorea Bethlem myopathy, Birt–Hogg–Attorney Docket No. 10935-031WO1 Dubé syndrome, Blepharophimosis, ptosis, epicanthus inversus syndrome Blepharoptosis- myopia-ectopia lentis syndrome Boomerang dysplasia, Bosch-Boonstra-Schaaf optic atrophy syndrome Brachydactyly-long thumb syndrome, Branchio-oto-renal syndrome Buschke– Ollendorff syndrome, Calvarial doughnut lesions-bone fragility syndrome Camptodactyly- taurinuria syndrome Camurati–Engelmann disease, CAPOS syndrome Central core disease, Cerebro-costo-mandibular syndrome, Cochleosaccular degeneration with progressive cataracts Cohen-Gibson syndrome, Collagen disease Collagenopathy, types II and XI Collins– Pope syndrome, Coloboma of macula-brachydactyly type B syndrome Congenital distal spinal muscular atrophy, Congenital stromal corneal dystrophy Costello syndrome, Craniofacial dysostosis-diaphyseal hyperplasia syndrome Currarino syndrome, Cyprus facial neuromusculoskeletal syndrome Czech dysplasia, metatarsal type, Darier's disease GLUT1 deficiency, Dentatorubral–pallidoluysian atrophy Dermatopathia pigmentosa reticularis DiGeorge syndrome Dysfibrinogenemia, Emberger syndrome, Familial amyloid polyneuropathy Familial atrial fibrillation, Familial cutaneous collagenoma, Familial disseminated comedones without dyskeratosis Familial hypercholesterolemia, Familial male- limited precocious puberty Feingold syndrome, Felty's syndrome, Fibular aplasia-ectrodactyly syndrome Flynn–Aird syndrome, Gardner's syndrome GATA2 deficiency, GATAD2B- associated neurodevelopmental disorder Gillespie syndrome, Gray platelet syndrome, Greig cephalopolysyndactyly syndrome, Hagemoser–Weinstein–Bresnick syndrome Hajdu–Cheney syndrome Haploinsufficiency of A20, Hawkinsinuria Hay–Wells syndrome, Heart-hand syndrome, Spanish type Hemochromatosis type 4, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome Hereditary elliptocytosis, Hereditary hemorrhagic telangiectasia Hereditary mucoepithelial dysplasia Hereditary neurocutaneous angioma Hereditary spherocytosis, Holt–Oram syndrome Huntington's disease, Huntington's disease- like syndrome Hyperinsulinism-hyperammonemia syndrome Hypertrophic cardiomyopathy Hypoalphalipoproteinemia Hypochondroplasia, Hypodysfibrinogenemia, IVIC syndrome, Jackson–Weiss syndrome Jordan's Syndrome, Juberg-Hayward syndrome Juvenile-onset dystonia, Keratoendotheliitis fugax hereditaria Keratolytic winter erythema, Kniest dysplasia, Langer–Giedion syndrome Larsen syndrome, Leucine-sensitive hypoglycemia of infancy Liddle's syndrome, Marfan syndrome Marshall syndrome Marsili syndrome, Medullary cystic kidney disease Menke-Hennekam syndrome Metachondromatosis Miller–Dieker syndrome,Attorney Docket No. 10935-031WO1 MOMO syndrome Monilethrix MonoMAC, Multiple endocrine neoplasia Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2B, Muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome Myelokathexis, Myotonic dystrophy, Nablus mask-like facial syndrome, Naegeli–Franceschetti–Jadassohn syndrome Nail–patella syndrome, Noonan syndrome, Oculopharyngeal muscular dystrophy Otofaciocervical syndrome, Pachyonychia congenita Pallister–Hall syndrome, Palmoplantar keratoderma with deafness PAPA syndrome, Papillorenal syndrome Parastremmatic dwarfism Pashayan syndrome Pelger–Huët anomaly Peutz–Jeghers syndrome Piebaldism, Platyspondylic lethal skeletal dysplasia, Torrance type Polydactyly, Polymerase proofreading- associated polyposis Popliteal pterygium syndrome, Porphyria cutanea tarda Pseudoachondroplasia, RASopathy, Reis–Bucklers corneal dystrophy Romano–Ward syndrome Rosselli–Gulienetti syndrome Roussy–Lévy syndrome Rubinstein–Taybi syndrome, Saethre–Chotzen syndrome, Scalp defects-postaxial polydactyly syndrome Schmitt Gillenwater Kelly syndrome, Severe congenital neutropenia, Severe intellectual disability- progressive spastic diplegia syndrome Short QT syndrome, Singleton Merten syndrome, Spastic paraplegia 6 Spastic paraplegia 31, Spinal muscular atrophy with lower extremity predominance 1 Spinal muscular atrophy with lower extremity predominance 2A Spinal muscular atrophy with lower extremity predominance 2B Spinocerebellar ataxia, Spinocerebellar ataxia type 1 Spinocerebellar ataxia type 6, Split hand split foot-nystagmus syndrome Spondyloepimetaphyseal dysplasia, Strudwick type Spondyloepiphyseal dysplasia congenita Spondyloperipheral dysplasia, St. Helena familial genu valgum Stickler syndrome, Syndactyly-nystagmus syndrome due to 2q31.1 microduplication SYNGAP1-related intellectual disability, SYT1-associated neurodevelopmental disorder, Thumb stiffness- brachydactyly-intellectual disability syndrome Tietz syndrome, Timothy syndrome Treacher Collins syndrome, Tricho–dento–osseous syndrome, TRPM3-related neurodevelopmental disorders Tuberous sclerosis, Upington disease, Variegate porphyria, Ventricular extrasystoles with syncopal episodes-perodactyly-Robin sequence syndrome Verloes Van Maldergem Marneffe syndrome, Vitelliform macular dystrophy Von Hippel–Lindau disease Von Willebrand disease, Wallis–Zieff–Goldblatt syndrome WHIM syndrome, and White sponge nevus.Attorney Docket No. 10935-031WO1 51. The method of any of claims 28-50, wherein the mutant allele is expressed in a cell that is heterozygous for the allele.

52. The method of claim 51, wherein the cell expresses CD34 on its cell surface membrane.

53. The method of claim 25, wherein the CD34 expressing cell is a cell associated with alveolar soft part sarcoma, pre-B acute lymphocytic leukemia, acute myeloid leukemia, dermatofibrosarcoma protuberans, gastrointestinal stromal tumor, giant cell fibroblastoma, granulocytic sarcoma, Kaposi’s sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, meningeal hemangiopericytoma, cutaneous fibrous histiocytoma, angiosarcoma, meningiomas, neurofibromas, schwannomas, and papillary thyroid carcinoma.

54. The method of claim 40, wherein the disorder is selected from the group consisting of alveolar soft part sarcoma, pre-B acute lymphocytic leukemia, acute myeloid leukemia, dermatofibrosarcoma protuberans, gastrointestinal stromal tumor, giant cell fibroblastoma, granulocytic sarcoma, Kaposi’s sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, meningeal hemangiopericytoma, cutaneous fibrous histiocytoma, angiosarcoma, meningiomas, neurofibromas, schwannomas, and papillary thyroid carcinoma.

55. A method of repairing or causing mutational correction of an autosomal dominant mutation associated with a genetic disorder in a subject to express a wild-type allele comprising administering to the subject the system comprising a Cas endonuclease and a guide RNA (gRNA), wherein: a. the gRNA targets a mutant allele of a heterozygous gene, b. the mutant allele comprises one or more mutations, and c. the gRNA does not target the wild-type allele of the gene; and wherein the repair does not comprise the use of an exogenous homology directed repair template.

56. The method of claim 55, wherein the system further comprises an HDR enhancer to enhance intra-homologous recombination.Attorney Docket No. 10935-031WO1 57. The method of claim 56, wherein the HDR enhancer.is a DNA-dependent protein kinase (DNA-PK) Inhibitor.

58. The method of claim 55, wherein the DNA-PK Inhibitor is selected from the group comprising of AZD7648, LY294002, Compound 401, PIK-75 HCl, KU-0060648, CC-115, PP121, SF2523, YU238259, LTURM34, Nedisertib (M3814), Samotolisib (LY3023414), Wortmannin, NU7441 (KU-57788), PI-103, T0070907, Torin 2, Alt-R™, SCR7, L755507, EPZ5676, rucaparib, pevonedistat, brefeldin A, Alt-R HDR Enhancer V1, XL413, trichostatin A, CRISPYTMMix, romidepsin, nedisertib, and Alt-R HDR Enhancer V2 and NU7026.

59. The method of claim 55, wherein the mutant allele comprises a target strand and a non- target strand complementary to the target strand.

60. The method of any one of claims 55-59, wherein the gRNA is complementary to target strand.

61. The method of any one of claims 59 or 60, wherein the non-target strand comprises one or more mutations, and wherein at least one of the one or more mutations is within 7 nucleotides upstream the 5’ end of a protospacer adjacent motif (PAM) sequence.

62. The method of any one of claims 55-61, wherein at least one of the one or more mutations is within 6, 5, 4, 3, 2, or 1 nucleotide upstream the 5’ end of the PAM sequence.

63. The method of any one of claims 55-62, wherein the one or more mutations are point mutations, insertions, deletions, or translocations.

64. The method of any one of claims 61-63, wherein the PAM sequence comprises NGG, NNGRR, NNGRRT, or NNNNGATT.

65. The method of claim 64, wherein the PAM sequence further comprises AAGAA, TGGGAT, GGG, or TGG.

66. The method of any one of claims 55-65, wherein the mutant allele is associated with a genetic disorder.Attorney Docket No. 10935-031WO1 67. The method of claim 66, wherein the genetic disorder is a dominant-negative disorder.

68. The method of any one of claims 66 or 67, genetic disorder comprises Huntington’s disease, Marfan’s syndrome, familial hypercholesterolemia, inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or autosomal dominant hyper-IgE syndrome (AD-HIES), tubulin folding cofactor D (TBCD) associated diseases, or KCNT1-related developmental and epileptic encephalopathy.

69. The method of any one of claims 55-68, wherein the mutant allele is of a VCP gene, a STAT3 gene, a FBN1 gene, a APOB gene, a LDLR gene, a PCSK9 gene, a DOCK8 gene, a TBCD gene, or a KCNT1 gene.

70. The method of claim 69, wherein the mutant allele of the VCP gene comprises SEQ ID NO: 10 or a fragment thereof.

71. The method of any one of claims 55-70, wherein the gRNA comprises a sequence selected from the group consisting of SEQ ID NOs: 1-9 or a fragment thereof.

72. The method of claim 55-71, wherein the mutant allele is autosomal dominant allele.

73. The method of claim 72, wherein the autosomal dominant allele is a pathogenic autosomal dominant allele.

74. The method of claim 73, wherein the pathogenic autosomal dominant allele expresses in a mammal as a disorder selected from the group consisting of: proliferation disorder, blood disorder, vision disorder, connective tissue disorder, and protein processing disorder.

75. The method of any of claims 73-74, wherein the pathogenic autosomal dominant allele expresses in a mammal as a disorder selected from the group consisting of: achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, and hereditary elliptocytosis.Attorney Docket No. 10935-031WO1 76. The method of any one of claims 73-75, wherein the pathogenic autosomal dominant allele expresses in a mammal as a disorder selected from the group consisting of achondroplasia, osteogenesis imperfecta, Huntington disease, Marfan syndrome, neurofibromatosis, von Willebrand disease, antithrombin III deficiency, porphyria, hemorrhagic telangiectasia, familial hypercholesterolemia, myotonic dystrophy, multiple endocrine neoplasia syndrome, hereditary spherocytosis, hereditary elliptocytosis, Ablepharon macrostomia syndrome Acropectoral syndrome, Acute intermittent porphyria Adermatoglyphia, ADNP syndrome, Albright's hereditary osteodystrophy Ankylosing vertebral hyperostosis with tylosis Aphalangy-syndactyly-microcephaly syndrome Arakawa's syndrome II, Aromatase excess syndrome Autosomal dominant cerebellar ataxia, Autosomal dominant Charcot–Marie–Tooth disease type 2 with giant axons Autosomal dominant GTP cyclohydrolase I deficiency, Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Autosomal dominant nocturnal frontal lobe epilepsy, Autosomal dominant partial epilepsy with auditory features Autosomal dominant polycystic kidney disease Axenfeld–Rieger syndrome, Bainbridge–Ropers syndrome Barber–Say syndrome Beck–Fahrner syndrome Benign hereditary chorea Bethlem myopathy, Birt–Hogg– Dubé syndrome, Blepharophimosis, ptosis, epicanthus inversus syndrome Blepharoptosis- myopia-ectopia lentis syndrome Boomerang dysplasia, Bosch-Boonstra-Schaaf optic atrophy syndrome Brachydactyly-long thumb syndrome, Branchio-oto-renal syndrome Buschke– Ollendorff syndrome, Calvarial doughnut lesions-bone fragility syndrome Camptodactyly- taurinuria syndrome Camurati–Engelmann disease, CAPOS syndrome Central core disease, Cerebro-costo-mandibular syndrome, Cochleosaccular degeneration with progressive cataracts Cohen-Gibson syndrome, Collagen disease Collagenopathy, types II and XI Collins– Pope syndrome, Coloboma of macula-brachydactyly type B syndrome Congenital distal spinal muscular atrophy, Congenital stromal corneal dystrophy Costello syndrome, Craniofacial dysostosis-diaphyseal hyperplasia syndrome Currarino syndrome, Cyprus facial neuromusculoskeletal syndrome Czech dysplasia, metatarsal type, Darier's disease GLUT1 deficiency, Dentatorubral–pallidoluysian atrophy Dermatopathia pigmentosa reticularis DiGeorge syndrome Dysfibrinogenemia, Emberger syndrome, Familial amyloid polyneuropathy Familial atrial fibrillation, Familial cutaneous collagenoma, Familial disseminated comedones without dyskeratosis Familial hypercholesterolemia, Familial male-Attorney Docket No. 10935-031WO1 limited precocious puberty Feingold syndrome, Felty's syndrome, Fibular aplasia-ectrodactyly syndrome Flynn–Aird syndrome, Gardner's syndrome GATA2 deficiency, GATAD2B- associated neurodevelopmental disorder Gillespie syndrome, Gray platelet syndrome, Greig cephalopolysyndactyly syndrome, Hagemoser–Weinstein–Bresnick syndrome Hajdu–Cheney syndrome Haploinsufficiency of A20, Hawkinsinuria Hay–Wells syndrome, Heart-hand syndrome, Spanish type Hemochromatosis type 4, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome Hereditary elliptocytosis, Hereditary hemorrhagic telangiectasia Hereditary mucoepithelial dysplasia Hereditary neurocutaneous angioma Hereditary spherocytosis, Holt–Oram syndrome Huntington's disease, Huntington's disease- like syndrome Hyperinsulinism-hyperammonemia syndrome Hypertrophic cardiomyopathy Hypoalphalipoproteinemia Hypochondroplasia, Hypodysfibrinogenemia, IVIC syndrome, Jackson–Weiss syndrome Jordan's Syndrome, Juberg-Hayward syndrome Juvenile-onset dystonia, Keratoendotheliitis fugax hereditaria Keratolytic winter erythema, Kniest dysplasia, Langer–Giedion syndrome Larsen syndrome, Leucine-sensitive hypoglycemia of infancy Liddle's syndrome, Marfan syndrome Marshall syndrome Marsili syndrome, Medullary cystic kidney disease Menke-Hennekam syndrome Metachondromatosis Miller–Dieker syndrome, MOMO syndrome Monilethrix MonoMAC, Multiple endocrine neoplasia Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2B, Muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome Myelokathexis, Myotonic dystrophy, Nablus mask-like facial syndrome, Naegeli–Franceschetti–Jadassohn syndrome Nail–patella syndrome, Noonan syndrome, Oculopharyngeal muscular dystrophy Otofaciocervical syndrome, Pachyonychia congenita Pallister–Hall syndrome, Palmoplantar keratoderma with deafness PAPA syndrome, Papillorenal syndrome Parastremmatic dwarfism Pashayan syndrome Pelger–Huët anomaly Peutz–Jeghers syndrome Piebaldism, Platyspondylic lethal skeletal dysplasia, Torrance type Polydactyly, Polymerase proofreading- associated polyposis Popliteal pterygium syndrome, Porphyria cutanea tarda Pseudoachondroplasia, RASopathy, Reis–Bucklers corneal dystrophy Romano–Ward syndrome Rosselli–Gulienetti syndrome Roussy–Lévy syndrome Rubinstein–Taybi syndrome, Saethre–Chotzen syndrome, Scalp defects-postaxial polydactyly syndrome Schmitt Gillenwater Kelly syndrome, Severe congenital neutropenia, Severe intellectual disability- progressive spastic diplegia syndrome Short QT syndrome, Singleton Merten syndrome,Attorney Docket No. 10935-031WO1 Spastic paraplegia 6 Spastic paraplegia 31, Spinal muscular atrophy with lower extremity predominance 1 Spinal muscular atrophy with lower extremity predominance 2A Spinal muscular atrophy with lower extremity predominance 2B Spinocerebellar ataxia, Spinocerebellar ataxia type 1 Spinocerebellar ataxia type 6, Split hand split foot-nystagmus syndrome Spondyloepimetaphyseal dysplasia, Strudwick type Spondyloepiphyseal dysplasia congenita Spondyloperipheral dysplasia, St. Helena familial genu valgum Stickler syndrome, Syndactyly-nystagmus syndrome due to 2q31.1 microduplication SYNGAP1-related intellectual disability, SYT1-associated neurodevelopmental disorder, Thumb stiffness- brachydactyly-intellectual disability syndrome Tietz syndrome, Timothy syndrome Treacher Collins syndrome, Tricho–dento–osseous syndrome, TRPM3-related neurodevelopmental disorders Tuberous sclerosis, Upington disease, Variegate porphyria, Ventricular extrasystoles with syncopal episodes-perodactyly-Robin sequence syndrome Verloes Van Maldergem Marneffe syndrome, Vitelliform macular dystrophy Von Hippel–Lindau disease Von Willebrand disease, Wallis–Zieff–Goldblatt syndrome WHIM syndrome, and White sponge nevus.

77. The method of claim 55, wherein the disorder is selected from the group consisting of alveolar soft part sarcoma, pre-B acute lymphocytic leukemia, acute myeloid leukemia, dermatofibrosarcoma protuberans, gastrointestinal stromal tumor, giant cell fibroblastoma, granulocytic sarcoma, Kaposi’s sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, meningeal hemangiopericytoma, cutaneous fibrous histiocytoma, angiosarcoma, meningiomas, neurofibromas, schwannomas, and papillary thyroid carcinoma.

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