Methods of editing a disease-associated gene using adenosine deaminase base editors, including for the treatment of genetic disease

Abstract

The invention provides compositions comprising novel programmable adenosine base editor systems (e.g., ABE8) that provide methods of treating a disease or disorder, (e.g., Parkinson's disease, Hurler syndrome, Rett syndrome, or Stargardt disease) in a subject by administering to the subject a programmable adenosine base editor system (e.g., ABE8) that have increased efficiency and methods of using these adenosine deaminase variants for editing a disease-associated gene.

Description

METHODS OF EDITING A DISEASE-ASSOCIATED GENE USING ADENOSINE DEAMINASE BASE EDITORS, INCLUDING FOR THE TREATMENT OF GENETIC DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 805,271 filed on February 13, 2019; U.S. Provisional Application No. 62 / 852,228 filed on May 23, 2019; U.S. Provisional Application No. 62 / 852,224 filed on May 23, 2019; U.S. Provisional Application No. 62 / 873,138 filed on July 11, 2019; U.S. Provisional Application No. 62 / 888,867 filed on August 19, 2019; U.S. Provisional Application No. 62 / 931,722 filed on November 6, 2019; U.S. Provisional Application No. 62 / 941,569 filed on November 27, 2019; U.S. Provisional Application No. 62 / 966,526 filed on January 27, 2020, the disclosures of which are hereby incorporated by reference in their entirety. INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Absent any indication otherwise, publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entireties. BACKGROUND OF THE DISCLOSURE Targeted editing of nucleic acid sequences, for example, the targeted cleavage or the targeted modification of genomic DNA is a highly promising approach for the study of gene function and also has the potential to provide new therapies for human genetic diseases. Currently available base editors include cytidine base editors (e.g., BE4) that convert target C+G base pairs to T*A and adenine base editors (e.g., ABE7.10) that convert A*T to G+C. There is a need in the art for improved base editors capable of inducing modifications within a target sequence with greater specificity and efficiency. SUMMARY OF THE DISCLOSURE The invention provides compositions comprising novel adenine base editors (e.g., ABES) that have increased efficiency and methods of using base editors comprising adenosine deaminase variants for editing a target sequence. In some aspects, provided herein, is a method of treating a neurological disorder in a subject, the method comprising: administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a target gene or a regulatory element thereof associated with the neurological disorder in the subject, thereby treating the neurological disorder in the subject. In another embodiment of this aspect, the target gene is an alpha-L-iduronidase (IDUA) gene and the neurological disease is Hurler syndrome. In one embodiment of this aspect, the target gene is a leucine-rich repeat kinase-2 (LRRK?2) gene and the neurological disease is Parkinson’s disease. In one embodiment of this aspect, the target gene is a methyl CpG binding protein 2 (MECP2) gene and the neurological disease is Rett syndrome. In another embodiment of this aspect, the target gene is an ATP-binding cassette subfamily member 4 (ABCA4) gene and the neurological disease is Stargardt disease. In some aspects, provided herein, is a method of treating Hurler syndrome in a subject, the method comprising administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in an alpha-L-iduronidase (IDUA) gene or a regulatory element thereof in the subject, thereby treating Hurler syndrome in the subject. In some embodiments, the administration ameliorates at least one symptom related to Hurler syndrome. In some embodiments, the administration results in faster amelioration of at least one symptom related to Hurler syndrome as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase. In some embodiments, the IDUA gene or regulatory element thereof comprises a SNP associated with Hurler syndrome. In some embodiments, the A-to-G nucleobase alteration is at the SNP associated with Hurler syndrome. In some embodiments, the SNP associated with Hurler syndrome results in a W402X or a W401X amino acid mutation in an IDUA polypeptide as numbered in SEQ ID NO: 4, or a variant thereof, encoded by the IDUA gene, wherein X is a stop codon. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a non-wild type nucleobase that results in one or more ameliorated symptoms of Hurler syndrome. In some embodiments, the A-to-G alteration at the SNP associated with Hurler Syndrome changes a stop codon to a tryptophan in an IDUA polypeptide encoded by the IDUA gene. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the JDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the IDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome. In some embodiments, the sgRNA comprises a nucleic acid sequence selected from the group consisting of: 5'- GACUCUAGGCAGAGGUCUCAA -3', 5'- ACUCUAGGCAGAGGUCUCAA-3', 5'- CUCUAGGCCGAAGUGUCGC -3', and 5'- GCUCUAGGCCGAAGUGUCGC-3". In some aspects, provided herein, is a method of treating Parkinson’s disease in a subject, the method comprising: administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration a leucine-rich repeat kinase-2 (LRRK2) gene or a regulatory element thereof in the subject, thereby treating Parkinson’s disease in the subject. In some embodiments, the administration ameliorates at least one symptom related to Parkinson’s disease. In some embodiments, the administration results in faster amelioration of at least one symptom related to Parkinson’s disease as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase. In some embodiments, the LRRK2 gene or regulatory element thereof comprises a SNP associated with Parkinson’s disease. In some embodiments, the A-to-G nucleobase alteration is at the SNP associated with Parkinson’s disease. In some embodiments, the SNP associated with Parkinson Disease results in a A419V, a R1441C, a R1441H, or a G2019S amino acid mutation in a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof, encoded by the LRRK2 gene. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Parkinson’s disease to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Parkinson's disease to a non-wild type nucleobase that results in one or more ameliorated symptoms of Parkinson’s disease. In some embodiments, the A-to-G nucleobase alteration changes a Cysteine or Histidine to an Arginine in a LRRK2 polypeptide encoded by the LRRK2 gene. In some embodiments, the A-to-G alteration changes a Serine to a Glycine in a LRRK2 polypeptide encoded by the LRRK2 gene. In some embodiments, the A-to-G alteration replaces the Cysteine (C) or Histidine (H) with an Arginine (R) at position 144 or replaces the Serine with a Glycine (G) at position 2019 of a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof, encoded by the LRRK2 gene. In some aspects, provided herein, is a method of treating Parkinson’s disease in a subject, the method comprising: administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration at a SNP in a LRRK2 gene associated with Parkinson’s disease, wherein the SNP does not encode a G2019S mutation in a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof. In some embodiments, the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 ora corresponding position thereof. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the LRRK2 gene or regulatory element thereof comprising the SNP associated with Parkinson’s Disease. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the LRRK2 gene or regulatory element thereof comprising the SNP associated with Parkinson Disease. In some embodiments, the sgRNA comprises a nucleic acid sequence: 5'-AAGCGCAAGCCUGGAGGGAA -3'; or 5'- ACUACAGCAUUGCUCAGUAC-3". In some aspects, provided herein, is a method of treating Rett syndrome in a subject, the method comprising administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a methyl CpG binding protein 2 (MECP2) gene or a regulatory element thereof in the subject, thereby treating Rett syndrome in the subject. In some embodiments, the administration ameliorates at least one symptom related to Rett syndrome. In some embodiments, the administration results in faster amelioration of at least one symptom related to Rett syndrome as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase. In some embodiments, the MECP2 gene or regulatory element thereof comprises a SNP associated with Rett syndrome. In some embodiments, the A-to-G nucleobase alteration is at the SNP associated with Rett Syndrome. In some embodiments, the SNP associated with Rett syndrome results in a R106W or a T158M amino acid mutation in a MECP2 polypeptide as numbered in SEQ ID NO: 5, ora variant thereof, encoded by the MECP2 gene. In some embodiments, the SNP associated with Rett syndrome results in a R255X or a R270X amino acid mutation in a MECP2 polypeptide encoded by the MECP2 gene, wherein X is a stop codon, In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a non-wild type nucleobase that results in ameliorated Rett syndrome symptoms. In some embodiments, the A-to-G nucleobase alteration at the SNP associated with Rett Syndrome changes a stop codon to tryptophan in MECP2 polypeptide. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the MECP2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the MECP2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of: 5'- CUUUUCACUUCCUGCCGGGG-3', 5'-AGCUUCCAUGUCCAGCCUUC-3', 5'- ACCAUGAAGUCAAAAUCAUU-3', and 5'- GCUUUCAGCCCCGUUUCUUG-3". In some aspects, provided herein, is a method of treating Stargardt disease in a subject, the method comprising administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in an ATP-binding cassette subfamily member 4 (ABCA4) gene or a regulatory element thereof in the subject, thereby treating Stargardt disease in the subject. In some embodiments, the administration ameliorates at least one symptom related to Stargardt disease. In some embodiments, the administration results in faster amelioration of at least one symptom related to Stargardt disease as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase. In some embodiments, the ABCA4 gene comprises a SNP associated with Stargardt disease. In some embodiments, the A-to-G nucleobase alteration is at the SNP associated with Stargardt disease. In some embodiments, the SNP associated with Stargardt disease results in a A1038V or a G1961E amino acid mutation in an ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof, encoded by the ABCA4 gene. In some embodiments, the SNP associated with Stargardt disease results in a G1961E amino acid mutation in the ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof, In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a non-wild type nucleobase that results in one or more ameliorated symptoms of Stargardt disease. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt disease. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt Disease. In some embodiments, the sgRNA comprises the sequence 5'- CUCCAGGGCGAACUUCGACACACAGC-3". In various aspects, the treatment described herein results in ameliorated symptoms of the neurological disorder compared to treatment with a base editor comprising an adenosine deaminase domain without the amino acid substitutions. In some aspects, provided herein, is a method of editing a target gene or regulatory element thereof associated with a neurological disorder, the method comprising contacting the target gene or regulatory element thereof with (i) an adenosine base editor and (ii) a guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a target gene or a regulatory element thereof associated with the neurological disorder. In one embodiment of this aspect, the target gene is a leucine-rich repeat kinase-2 (LRRK2) gene and the neurological disease is Parkinson’s disease. In another embodiment of this aspect, the target gene is an alpha-L- iduronidase (IDUA) gene and the neurological disease is Hurler syndrome. In one embodiment of this aspect, the target gene is a methyl CpG binding protein 2 (MECP2) gene and the neurological disease is Rett syndrome. In another embodiment of this aspect, the target gene is an ATP-binding cassette subfamily member 4 (ABCA4) gene and the neurological disease is Stargardt disease. In some aspects, provided herein, is a method of editing a leucine-rich repeat kinase-2 (LRRK?2) gene or a regulatory element thereof, the method comprising contacting the LRRK2 gene or regulatory element thereof with (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in the LRRK2 gene a regulatory element thereof. In some embodiments, the A-to-G nucleobase alteration is at the SNP associated with Parkinson’s disease. In some embodiments, the SNP associated with Parkinson Disease results in a A419V, a R1441C, a R1441H, or a G2019S amino acid mutation in a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof, encoded by the LRRK2 gene. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Parkinson’s disease to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Parkinson's disease to a non-wild type nucleobase that results in one or more ameliorated symptoms of Parkinson’s disease. In some embodiments, the A-to-G nucleobase alteration changes a Cysteine or Histidine to an Arginine in a LRRK2 polypeptide encoded by the LRRK2 gene. In some embodiments, the A-to-G alteration changes a Serine to a Glycine in a LRRK2 polypeptide encoded by the LRRK2 gene. In some embodiments, the A-to-G alteration replaces the Cysteine (C) or Histidine (H) with an Arginine (R) at position 144 or replaces the Serine with a Glycine (G) at position 2019 of a LRRK?2 polypeptide as numbered in SEQ ID NO: 3, ora variant thereof, encoded by the LRRK2 gene. In some aspects, provided herein, is a method of editing a leucine-rich repeat kinase-2 (LRRK?2) gene or a regulatory element thereof, the method comprising contacting the LRRK2 gene or regulatory element thereof with (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration at a SNP in a LRRK2 gene, wherein the SNP does not encode a G2019S mutation in a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof. In some embodiments, the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 ora corresponding position thereof. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the LRRK?2 gene or regulatory element thereof comprising the SNP associated with Parkinson’s Disease. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the LRRK2 gene or regulatory element thereof comprising the SNP associated with Parkinson Disease. In some embodiments, the sgRNA comprises a nucleic acid sequence: 5'- AAGCGCAAGCCUGGAGGGAA -3'; or 5-ACUACAGCAUUGCUCAGUAC-3". In some aspects, provided herein, is a method of editing an alpha-L-iduronidase (IDUA) gene or a regulatory element thereof, the method comprising contacting the IDUA gene or regulatory element thereof with (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in the IDUA gene or a regulatory element thereof. In some embodiments, the IDUA gene or regulatory element thereof comprises a SNP associated with Hurler syndrome. In some embodiments, the A~to-G nucleobase alteration is at the SNP associated with Hurler syndrome. In some embodiments, the SNP associated with Hurler syndrome results in a W402X or a W401X amino acid mutation in an IDUA polypeptide as numbered in SEQ ID NO: 4, or a variant thereof, encoded by the IDUA gene, wherein X is a stop codon. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a non-wild type nucleobase that results in one or more ameliorated symptoms of Hurler syndrome. In some embodiments, the A-to-G alteration at the SNP associated with Hurler Syndrome changes a stop codon to a tryptophan in an IDUA polypeptide encoded by the IDUA gene. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the JDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the IDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome. In some embodiments, the sgRNA comprises a nucleic acid sequence selected from the group consisting of: 5'- GACUCUAGGCAGAGGUCUCAA - 3',5'- ACUCUAGGCAGAGGUCUCAA-3', 5'- CUCUAGGCCGAAGUGUCGC -3', and 5'- GCUCUAGGCCGAAGUGUCGC-3". In some aspects, provided herein, is a method of editing a methyl CpG binding protein 2 (MECP2) gene or regulatory element thereof, the method comprising administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in the MECP2 gene or a regulatory element thereof. In some embodiments, the MECP2 gene or regulatory element thereof comprises a SNP associated with Rett syndrome. In some embodiments, the A-to-G nucleobase alteration is at the SNP associated with Rett Syndrome. In some embodiments, the SNP associated with Rett syndrome results in a R106W or a T158M amino acid mutation in a MECP2 polypeptide as numbered in SEQ ID NO: 5, or a variant thereof, encoded by the MECP2 gene. In some embodiments, the SNP associated with Rett syndrome results in a R255X or a R270X amino acid mutation in a MECP2 polypeptide encoded by the MECP2 gene, wherein X is a stop codon. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a non-wild type nucleobase that results in one or more ameliorated symptoms of Rett syndrome. In some embodiments, the A- to-G nucleobase alteration at the SNP associated with Rett Syndrome changes a stop codon to tryptophan in MECP2 polypeptide. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the MECP2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the MECP2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of: 5°- CUUUUCACUUCCUGCCGGGG-3’, 5’-AGCUUCCAUGUCCAGCCUUC-3, 5°- ACCAUGAAGUCAAAAUCAUU-3’, and 5°- GCUUUCAGCCCCGUUUCUUG-3’. In some aspects, provided herein, is a method of editing an ATP binding cassette subfamily member 4 (ABCA4) gene or regulatory element thereof, the method comprising contacting the ABCA4 gene or regulatory element thereof with (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in the ABCA4 gene or a regulatory element thereof. In some embodiments, the administration ameliorates at least one symptom related to Stargardt disease. In some embodiments, the administration results in faster amelioration of at least one symptom related to Stargardt disease as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase. In some embodiments, the ABCA4 gene comprises a SNP associated with Stargardt disease. In some embodiments, the A-to-G nucleobase alteration is at the SNP associated with Stargardt disease. In some embodiments, the SNP associated with Stargardt disease results in a A1038V, or a G1961E amino acid mutation in an ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof, encoded by the ABCA4 gene. In some embodiments, the SNP associated with Stargardt disease results in a G1961E amino acid mutation in the ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof, In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a non-wild type nucleobase that results in one or more ameliorated symptoms of Stargardt disease. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt Disease. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt Disease. In some embodiments, the sgRNA comprises the sequence 5'- CUCCAGGGCGAACUUCGACACACAGC-3". In various embodiments of the above aspects, the contacting is in a cell. In some embodiments, the contacting results in less than 10% indels in a genome in the cell, wherein indel rate is measured by mismatch frequency between sequences flanking the single nucleotide modification and an unmodified sequence. In some embodiments, the contacting results in less than 5% indels in a genome in the cell, wherein indel rate is measured by mismatch frequency between sequences flanking the single nucleotide modification and an unmodified sequence. In some embodiments, the contacting results in less than 1% indels in a genome in the cell, wherein indel rate is measured by mismatch frequency between sequences flanking the single nucleotide modification and an unmodified sequence. In various embodiments of the above aspects, the cell is a neuron. In some embodiments, the contacting is in a population of cells. In some embodiments, the contacting results in the A-to-G nucleobase alteration in at least 40% of the population of cells after the contacting step. In some embodiments, the contacting results in the A-to-G nucleobase alteration in at least 50% of the population of cells after the contacting step. In some embodiments, the contacting results in the A-to-G nucleobase alteration in at least 70% of the population of cells after the contacting step. In some embodiments, at least 90% of the cells are viable after the contacting step. In some embodiments, the population of cells was not enriched after the contacting step. In some embodiments, the population of cells are neurons. In some embodiments, the contacting is in vivo or ex vivo. In various aspects and embodiments above, the polynucleotide programmable DNA binding domain is a Cas9. In some embodiments, the Cas9 is a SpCas9, a SaCas9, or a variant thereof. In some embodiments, the polynucleotide programmable DNA binding domain comprises a modified SpCas9 having an altered protospacer-adjacent motif (PAM) specificity. In some embodiments, the Cas9 has specificity for a PAM sequence selected from the group consisting of NGG, NGA, NGCG, NGN, NNGRRT, NNNRRT, NGCG, NGCN, NGTN, and NGC; wherein Nis A, G, C, or T; and wherein R is A or G. In some embodiments, the polynucleotide programmable DNA binding domain is a nuclease inactive variant. In some embodiments, the polynucleotide programmable DNA binding domain is a nickase variant. In some embodiments, the nickase variant comprises an amino acid substitution D10A or a corresponding amino acid substitution thereof. In various aspects and embodiments provided herein, the adenosine deaminase domain comprises a TadA domain. In some embodiments, the adenosine deaminase comprises a TadA deaminase comprising a V82S§ alteration and / or a T166R alteration. In various aspects and embodiments above, the adenosine deaminase further comprises one or more of the following alterations: Y147T, Y147R, Q154S, Y123H, Q154R, or a combination thereof. In various aspects and embodiments provided herein, the adenosine deaminase comprises a combination of alterations selected from the group consisting of: Y147R + Q154R +Y123H; Y147R + Q154R + [76Y; Y147R + Q154R + T166R; Y147T + Q154R; Y147T + Q154S; and Y123H + Y147R + Q154R + I76Y. In various aspects and embodiments provided herein, the adenosine base editor domain comprises an adenosine deaminase monomer. In various aspects and embodiments provided herein, the adenosine base editor comprises an adenosine deaminase dimer. In some embodiments, the TadA deaminase is a TadA*8 variant. In some embodiments, the TadA*8 variant is selected from the group consisting of: TadA*8.1, TadA*8.2, TadA*8.3, TadA*8.4, TadA*8.5, TadA*8.6, TadA*8.7, TadA*8.8, TadA*8.9, TadA*8.10, TadA*8.11, TadA*8.12, and TadA*8.13. In some embodiments, the adenosine base editor is an ABES base editor selected from the group consisting of: ABES.1, ABES.2, ABE8.3, ABES.4, ABES.5, ABES.6, ABES.7, ABE8.8, ABES.9, ABES.10, ABES.11, ABES.12, and ABES.13. In some aspects, provided herein, is a cell produced by the method described in various aspects and embodiments disclosed herein. In some aspects, provided herein, is a population of cells produced by the method described in various aspects and embodiments disclosed herein. In some aspects, provided herein, is a base editor system comprising (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a target gene or a regulatory element thereof associated with the neurological disorder. In one embodiment of the above aspect, the target gene is a leucine-rich repeat kinase-2 (LRRK2) gene and the neurological disease is Parkinson’s disease. In another embodiment of this aspect, the target gene is an alpha-L- iduronidase (IDUA) gene and the neurological disease is Hurler syndrome. In one embodiment of this aspect, the target gene is a methyl CpG binding protein 2 (MECP2) gene and the neurological disease is Rett syndrome. In another embodiment of this aspect, the target gene is an ATP-binding cassette subfamily member 4 (ABCA4) gene and the neurological disease is Stargardt disease. In some aspects, provided herein, is a base editor system comprising (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 ora corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a LRRK2 gene a regulatory element thereof In some embodiments, the A-to-G nucleobase alteration is at a SNP associated with Parkinson’s disease in the LRRK?2 gene or regulatory element thereof. In some embodiments, the SNP associated with Parkinson Disease results in a A419V, a R1441C, aR1441H, ora G2019S amino acid mutation in a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof, encoded by the LRRK2 gene. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Parkinson’s disease to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Parkinson’s disease to a non-wild type nucleobase that results in ameliorated Parkinson’s symptoms. In some embodiments, the A- to-G nucleobase alteration changes a Cysteine or Histidine to an Arginine in a LRRK2 polypeptide encoded by the LRRK2 gene. In some embodiments, the A-to-G alteration changes a Serine to a Glycine in a LRRK2 polypeptide encoded by the LRRK2 gene. In some embodiments, the A-to-G alteration replaces the Cysteine (C) or Histidine (H) with an Arginine (R) at position 144 or replaces the Serine with a Glycine (G) at position 2019 of a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof, encoded by the LRRK2 gene. In some embodiments, the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the LRRK?2 gene or regulatory element thereof comprising the SNP associated with Parkinson’s Disease. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the LRRK?2 gene or regulatory element thereof comprising the SNP associated with Parkinson Disease. In some embodiments, the sgRNA comprises a nucleic acid sequence: 5'-AAGCGCAAGCCUGGAGGGAA -3'; or 5'- ACUACAGCAUUGCUCAGUAC-3". In some aspects, provided herein, is a base editor system comprising (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in an alpha-L-iduronidase (IDUA) gene or a regulatory element thereof. In some embodiments, the IDUA gene or regulatory element thereof comprises a SNP associated with Hurler syndrome. In some embodiments, the A-to-G nucleobase alteration is at the SNP associated with Hurler syndrome. In some embodiments, the SNP associated with Hurler syndrome results in a W402X or a W401X amino acid mutation in an IDUA polypeptide as numbered in SEQ ID NO: 4, or a variant thereof, encoded by the IDUA gene, wherein X is a stop codon. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a non-wild type nucleobase that results in one or more ameliorated symptoms of Hurler syndrome. In some embodiments, the A-to-G alteration at the SNP associated with Hurler Syndrome changes a stop codon to a tryptophan in an IDUA polypeptide encoded by the IDUA gene. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the IDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the IDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome. In some embodiments, the sgRNA comprises a nucleic acid sequence selected from the group consisting of: 5'- GACUCUAGGCAGAGGUCUCAA -3', 5'- ACUCUAGGCAGAGGUCUCAA-3', 5'- CUCUAGGCCGAAGUGUCGC -3', and 5'- GCUCUAGGCCGAAGUGUCGC-3". In some aspects, provided herein, is a base editor system comprising (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ IDNO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a methyl CpG binding protein 2 (MECP2) gene or regulatory element thereof. In some embodiments, the MECP2 gene or regulatory element thereof comprises a SNP associated with Rett syndrome. In some embodiments, the A-to-G nucleobase alteration is at the SNP associated with Rett Syndrome. In some embodiments, the SNP associated with Rett syndrome results in a R106 W or a T158M amino acid mutation in a MECP2 polypeptide as numbered in SEQ ID NO: 5, or a variant thereof, encoded by the MECP2 gene. In some embodiments, the SNP associated with Rett syndrome results in a R255X or a R270X amino acid mutation in a MECP2 polypeptide encoded by the MECP2 gene, wherein X is a stop codon. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a non-wild type nucleobase that results in one or more ameliorated symptoms of Rett syndrome. In some embodiments, the A- to-G nucleobase alteration at the SNP associated with Rett Syndrome changes a stop codon to tryptophan in MECP2 polypeptide. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the MECP2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the MECP2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of: 5'- CUUUUCACUUCCUGCCGGGG-3', 5'-AGCUUCCAUGUCCAGCCUUC-3, 5'- ACCAUGAAGUCAAAAUCAUU-3", and 5'- GCUUUCAGCCCCGUUUCUUG-3". In some aspects, provided herein, is a base editor system comprising contacting (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ IDNO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in an ATP binding cassette subfamily member 4 (ABCA4) gene or regulatory element thereof. In some embodiments, the administration ameliorates at least one symptom related to Stargardt disease. In some embodiments, the administration results in faster amelioration of at least one symptom related to Stargardt disease as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase. In some embodiments, the ABCA4 gene comprises a SNP associated with Stargardt disease. In some embodiments, the A-to-G nucleobase alteration is at the SNP associated with Stargardt disease. In some embodiments, the SNP associated with Stargardt disease results in a A1038V, or a G1961E amino acid mutation in an ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof, encoded by the ABCA4 gene. In some embodiments, the SNP associated with Stargardt disease results in a G1961E amino acid mutation in the ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a wild type nucleobase. In some embodiments, the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a non-wild type nucleobase that results in ameliorated Stargardt Disease symptoms. In some embodiments, the guide polynucleotide comprises a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt Disease. In some embodiments, the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt Disease. In some embodiments, the sgRNA comprises the sequence 5'- CUCCAGGGCGAACUUCGACACACAGC-3". In various aspects and embodiments provided herein, the polynucleotide programmable DNA binding domain is a Cas9. In some embodiments, the Cas9 is a SpCas9, a SaCas9, or a variant thereof. In some embodiments, the polynucleotide programmable DNA binding domain comprises a modified SpCas9 having an altered protospacer-adjacent motif (PAM) specificity. In some embodiments, the Cas9 has specificity for a PAM sequence selected from the group consisting of NGG, NGA, NGCG, NGN, NNGRRT, NNNRRT, NGCG, NGCN, NGTN, and NGC, wherein Nis A, G, C, or T and wherein Ris A or G. In some embodiments, the polynucleotide programmable DNA binding domain is a nuclease inactive variant. In some embodiments, the polynucleotide programmable DNA binding domain is a nickase variant. In some embodiments, the nickase variant comprises an amino acid substitution D10A or a corresponding amino acid substitution thereof. In various aspects and embodiments provided herein, the adenosine deaminase domain comprises a TadA domain. In some embodiments, the adenosine deaminase comprises a TadA deaminase comprising a V82S alteration and / or a T166R alteration. In various aspects and embodiments provided herein, the adenosine deaminase further comprises one or more of the following alterations: Y147T, Y147R, Q154S, Y123H, Q154R, or a combination thereof. In various aspects and embodiments provided herein, the adenosine deaminase comprises a combination of alterations selected from the group consisting of: Y147R + Q154R +Y123H; Y147R + Q154R + 176Y; Y147R + Q154R + T166R; Y147T + Q154R; Y147T + Q154S; and Y123H + Y147R + Q154R + 176Y. In some embodiments, the adenosine base editor domain comprises an adenosine deaminase monomer. In some embodiments, the adenosine base editor comprises an adenosine deaminase dimer. In various aspects and embodiments provided herein, the TadA deaminase is a TadA*8 variant. In some embodiments, the TadA*8 variant is selected from the group consisting of: TadA*8.1, TadA*8.2, TadA*8.3, TadA*8.4, TadA*8.5, TadA*8.6, TadA*8.7, TadA*8.8, TadA*8.9, TadA*8.10, TadA*8.11, TadA*8.12, and TadA*8.13. In some embodiments, the adenosine base editor is an ABES base editor selected from the group consisting of: ABES.1, ABES.2, ABES.3, ABES 4, ABES.5, ABES.6, ABES.7, ABES.8, ABES.9, ABES.10, ABES.11, ABES.12, and ABES.13. In some aspects, provided herein, is a vector comprising the nucleic acid sequence encoding the adenosine base editor described herein. In some aspects, provided herein, is a vector comprising the nucleic acid sequence encoding the adenosine base editor and the guide polynucleotide described herein. In some embodiments, the vector is a viral vector, a lentiviral vector, or an AAV vector, In some aspects, provided herein, is a cell comprising the base editor system or the vector described herein. In some embodiments, the cell is a central nervous system cell. In some embodiments, the cell is a neuron. In some embodiments, the cell is a photoreceptor. In some embodiments, the cell is in vitro, in vivo, or ex vivo. In some aspects, provided herein, is a pharmaceutical composition comprising the base editor, the vector, or the cell described herein and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition described herein further comprises a lipid. In another embodiment, the pharmaceutical composition described herein further comprises a virus. In some aspects, provided herein, is a kit comprising the base editor or the vector described herein. In various embodiments of the methods described herein, at least one nucleotide of the guide polynucleotide comprises a non-naturally occurring modification. In various embodiments of the methods described herein, at least one nucleotide of the nucleic acid sequence comprises a non-naturally occurring modification. In various embodiments, at least one nucleotide of the nucleic acid sequence of the base editor system comprises a non- naturally occurring modification. In some embodiments, the non-naturally occurring modification is a chemical modification. In some embodiments, the chemical modification is a 2’-O-methylation. In some embodiments, the nucleic acid sequence comprises a phosphorothioate. The description and examples herein illustrate embodiments of the present disclosure in detail. It is to be understood that this disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this disclosure, which are encompassed within its scope. The practice of some embodiments disclosed herein employ, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See for example Sambrook and Green, Molecular Cloning: A Laboratory Manual, 4th Edition (2012); the series Current Protocols in Molecular Biology (F. M. Ausubel, ef al. eds.), the series Methods In Enzymology (Academic Press, Inc.), PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th Edition (RI. Freshney, ed. (2010). The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Although various features of the present disclosure can be described in the context of a single embodiment, the features can also be provided separately or in any suitable combination. Conversely, although the present disclosure can be described herein in the context of separate embodiments for clarity, the present disclosure can also be implemented in a single embodiment. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and in view of the accompanying drawings as described hereinbelow. Definitions The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton ef al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or,” unless stated otherwise, and is understood to be inclusive. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting. As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include™) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure. The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, / .e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, such as within 5-fold or within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed. Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48. 49, or 50. Reference in the specification to “some embodiments,” “an embodiment,” “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosures. By “abasic base editor” is meant an agent capable of excising a nucleobase and inserting a DNA nucleobase (A, T, C, or G). Abasic base editors comprise a nucleic acid glycosylase polypeptide or fragment thereof. In one embodiment, the nucleic acid glycosylase is a mutant human uracil DNA glycosylase comprising an Asp at amino acid 204 (e.g., replacing an Asn at amino acid 204) in the following sequence, or corresponding position in a uracil DNA glycosylase, and having cytosine-DNA glycosylase activity, or active fragment thereof. In one embodiment, the nucleic acid glycosylase is a mutant human uracil DNA glycosylase comprising an Ala, Gly, Cys, or Ser at amino acid 147 (e.g., replacing a Tyr at amino acid 147) in the following sequence, or corresponding position in a uracil DNA glycosylase, and having thymine-DNA glycosylase activity, or an active fragment thereof. The sequence of exemplary human uracil-DNA glycosylase, isoform 1, follows: 1 mgvfclgpwg lgrklrtpgk gplgllsrlc gdhlgaipak kapaggeepg tppssplsae 61 gldrigrnka aallrlaarn vpvgfgeswk khlsgefgkp yfiklmgfva eerkhytvyp 121 pphgvftwtqg medikdvkvv ilggdpyhgp ngahglcefsv qrpvppppsl eniykelstd 181 iedfvhpghg dlsgwakqgv lllmavltvr ahganshker gwegftdavv swlngnsngl 241 vfllwgsyaq kkgsaidrkr hhvlgtahps plsvyrgffg crhfsktnel lgksgkkpid 301 wkel The sequence of human uracil-DNA glycosylase, isoform 2, follows: 1 miggktlysf fspsparkrh apspepavqg tgvagvpees gdaaaipakk apaggeepgt 61 ppssplsaeq ldrigrnkaa allrlaarnv pvgfgeswkk hlsgefgkpy fiklmgfvae 121 erkhytvypp phgvftwtgm cdikdvkvvi lgqgdpyhgpn gahglcfsvg rpvppppsle 181 niykelstdi edfvhpghgd lsgwakqgvl llnavltvra hganshkerg wegftdavvs 241 wlngnsnglv fllwgsyagk kgsaidrkrh hvlgtahpsp lsvyrgffgc rhfsktnell 301 gksgkkpidw kel In other embodiments, the abasic editor is any one of the abasic editors described in PCT / JP2015 / 080958 and US20170321210, which are incorporated herein by reference. In particular embodiments, the abasic editor comprises a mutation at a position shown in the sequence above in bold with underlining or at a corresponding amino acid in any other abasic editor or uracil deglycosylase known in the art. In one embodiment, the abasic editor comprises a mutation at Y147, N204, L272, and / or R276, or corresponding position. In another embodiment, the abasic editor comprises a Y147A or Y147G mutation, or corresponding mutation. In another embodiment, the abasic editor comprises a N204D mutation, or corresponding mutation. In another embodiment, the abasic editor comprises a L272A mutation, or corresponding mutation. In another embodiment, the abasic editor comprises a R276E or R276C mutation, or corresponding mutation. By “adenosine deaminase” is meant a polypeptide or fragment thereof capable of catalyzing the hydrolytic deamination of adenine or adenosine. In some embodiments, the deaminase or deaminase domain is an adenosine deaminase catalyzing the hydrolytic deamination of adenosine to inosine or deoxy adenosine to deoxyinosine. In some embodiments, the adenosine deaminase catalyzes the hydrolytic deamination of adenine or adenosine in deoxyribonucleic acid (DNA). The adenosine deaminases (e.g., engineered adenosine deaminases, evolved adenosine deaminases) provided herein may be from any organism, such as a bacterium. In some embodiments, the adenosine deaminase is a TadA deaminase. In some embodiments, the TadA deaminase is TadA variant. In some embodiments, the TadA variant is a TadA*8. In some embodiments, the deaminase or deaminase domain is a variant of a naturally occurring deaminase from an organism, such as a human, chimpanzee, gorilla, monkey, cow, dog, rat, or mouse. In some embodiments, the deaminase or deaminase domain does not occur in nature. For example, in some embodiments, the deaminase or deaminase domain is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9% identical to a naturally occurring deaminase. For example, deaminase domains are described in International PCT Application Nos. PCT / 2017 / 045381 (WO 2018 / 027078) and PCT / US2016 / 058344 (WO 2017 / 070632), each of which is incorporated herein by reference for its entirety. Also, see Komor, A.C, et al., “Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage” Nature 533, 420-424 (2016), Gaudelli, NM, ef al., “Programmable base editing of A*T to G+C in genomic DNA without DNA cleavage” Nature 551, 464-471 (2017); Komor, A.C., ef al., “Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity” Science Advances 3:eaa04774 (2017) ), and Rees, HA, etal., “Base editing: precision chemistry on the genome and transcriptome of living cells.” Nat Rev Genet. 2018 Dec;19(12):770-788. doi: 10.1038 / s41576-018-0059-1, the entire contents of which are hereby incorporated by reference. A wild type TadA(wt) adenosine deaminase has the following sequence (also termed TadA reference sequence): MSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLVHNNRVIGEGWNRPIGRHDPTAHAE IMA LRQGGLVMQONYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARDAKTGAAGSLMDVLHHP GMNHRVEITEGILADECAALLSDFFRMRRQEIKAQKKAQSSTD (SEQ ID NO: 2). In some embodiments, the adenosine deaminase comprises an alteration in the following sequence: MSEVEFSHEY WMRHALTLAK RARDEREVPV GAVLVLNNRV IGEGWNRAIG LHDPTAHAEI MALRQGGLVM QNYRLIDATL YVTFEPCVMC AGAMIHSRIG RVVFGVRNAK TGAAGSLMDV LHYPGMNHRV EITEGILADE CAALLCYFFR MPRQVEFNAQK KAQSSTD (also termed TadA*7.10). In some embodiments, TadA*7.10 comprises at least one alteration. In some embodiments, TadA*7.10 comprises an alteration at amino acid 82 and / or 166. In particular embodiments, a variant of the above-referenced sequence comprises one or more of the following alterations: Y147T, Y147R, Q154S, Y123H, V82S, T166R, and / or Q154R. The alteration Y123H is also referred to herein as HI123H (the alteration H123Y in TadA*7.10 reverted back to Y123H (wt)). In other embodiments, a variant of the TadA*7.10 sequence comprises a combination of alterations selected from the group consisting of: Y147T + Q154R; Y147T + Q154S; Y147R + Q1548S; V82S + Q1548; V828 + Y147R; V82S + Q154R; V82S + Y123H; I76Y + V82S; V82S + Y123H + Y147T; V82S + Y123H + Y147R; V82S + Y123H + QI54R; Y147R + Q154R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R,; Y123H + Y147R + Q154R + I76Y; V82S + Y123H + Y147R + Q154R; and I76Y + V82S + Y123H + Y147R + Q154R. In other embodiments, the invention provides adenosine deaminase variants that include deletions, e.g., TadA*8, comprising a deletion of the C terminus beginning at residue 149, 150, 151, 152, 153, 154, 155, 156, or 157. In other embodiments, the adenosine deaminase variant is a TadA (e.g., TadA*8) monomer comprising one or more of the following alterations: Y147T, Y147R, Q154S, Y123H, V82S, T166R, and / or Q154R. In other embodiments, the adenosine deaminase variant is TadA (e.g., TadA*8) a monomer comprising a combination of alterations selected from the group consisting of: Y147T + QI54R; Y147T + Q154S; Y147R + Q154S; V82S + Q1548S; V82S + Y147R; V82S + Q154R; V82S + Y123H; I76Y + V82S,; V82S + Y123H + Y147T, V82S + Y123H + Y147R; V82S + Y123H + Q154R; Y147R + Q154R +Y123H; Y147R + Q154R + 176Y; Y147R + QI54R + T166R; Y123H + Y147R + Q154R + I76Y; V82S + Y123H + Y147R + Q154R; and I76Y + V82S + Y123H + Y147R + Q154R. In still other embodiments, the adenosine deaminase variant is a homodimer comprising two adenosine deaminase domains (e.g., TadA*8) each having one or more of the following alterations Y147T, Y147R, Q154S, Y123H, V82S, T166R, and / or Q154R. In other embodiments, the adenosine deaminase variant is a homodimer comprising two adenosine deaminase domains (e.g., TadA*8) each having a combination of alterations selected from the group consisting of: Y147T + Q154R; Y147T + Q154S; Y147R + Q154S; V82S + Q154S; V82S + Y147R; V82S + Q154R; V82S + Y123H; I76Y + V82S; V82S + Y123H + Y147T; V82S + Y123H + Y147R; V82S + Y123H + Q154R; Y147R + Q154R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R; Y123H + Y147R + Q154R + 176Y; V82S + Y123H + Y147R + Q154R; and I76Y + V82S + Y123H + Y147R + Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a wild-type TadA adenosine deaminase domain and an adenosine deaminase variant domain (e.g., TadA*8) comprising one or more of the following alterations Y147T, Y147R, Q154S, Y123H, V82S, T166R, and / or Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a wild-type TadA adenosine deaminase domain and an adenosine deaminase variant domain (e.g. Tad A*8) comprising a combination of alterations selected from the group consisting of: Y147T + Q154R; Y147T + Q154S; Y147R + Q154S; V82S + Q154S; V82S + Y147R; V82S + Q154R; V82S + Y123H; I76Y + V82S; V82S + Y123H + Y147T, V82S + Y123H + Y147R; V828 + Y123H + Q154R; Y147R + Q154R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R; Y123H + Y147R + Q154R + 176Y; V82S + Y123H + Y147R + Q154R; and I76Y + V82S + Y123H + Y147R + Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a TadA*7.10 domain and an adenosine deaminase variant domain (e.g., TadA*8) comprising one or more of the following alterations Y147T, Y147R, Q154S, Y123H, V82S, T166R, and / or Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a TadA*7.10 domain and an adenosine deaminase variant domain (e.g. TadA*8) comprising a combination of the following alterations: Y147T + Q154R; Y147T + Q154S; Y147R + Q1548S; V82S + Q1548; V828 + Y147R; V82S + Q154R; V82S + Y123H; I76Y + V82S; V82S + Y123H + Y147T, V82S + Y123H + Y147R; V82S + Y123H + Q154R; Y147R + QI54R +Y123H; Y147R + Q154R + 176Y; Y147R + Q154R + T166R; Y123H + Y147R + Q154R +176Y; V82S + Y123H + Y147R + Q154R; or I76Y + V82S + Y123H + Y147R + Q154R. In one embodiment, the adenosine deaminase is a TadA*8 that comprises or consists essentially of the following sequence or a fragment thereof having adenosine deaminase activity: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAH AEIMALRQGGLVMONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLIMD VLHYPGMNHRVEITEGILADECAALLCTFFRMPROVEFNAQKKAQSSTD. In some embodiments, the TadA*8 is truncated. In some embodiments, the truncated TadA*8 is missing 1, 2,3, 4, 5,6, 7,8,9, 10, 11, 12, 13, 14, 15, 6, 17, 18, 19, or 20 N-terminal amino acid residues relative to the full length TadA*8. In some embodiments, the truncated TadA*8 is missing 1,2,3,4,5,6,7,8,9,10, 11, 12, 13, 14, 15, 6, 17, 18, 19, or 20 C-terminal amino acid residues relative to the full length TadA*8. In some embodiments the adenosine deaminase variant is a full-length TadA*8. In particular embodiments, an adenosine deaminase heterodimer comprises a TadA*8 domain and an adenosine deaminase domain selected from one of the following: In particular embodiments, an adenosine deaminase heterodimer comprises a TadA*8 domain and an adenosine deaminase domain selected from one of the following: Escherichia coli TadA: MRRAFITGVFFLSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLVHNNRVIGEGWNRPIGR HDPTAHAE IMALRQGGLVMONYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARDAKTGA AGSILMDVLHHPGMNHRVEITEGILADECAALLSDFFRMRRQEIKAQKKAQSSTD E.coli TadA (N-terminal truncated): MSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLVHNNRVIGEGWNRPIGRHDPTAHAEIMA LRQGGLVMQONYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARDAKTGAAGSLMDVLHHP GMNHRVEITEGILADECAALLSDFFRMRRQOEIKAQKKAQSSTD Staphylococcus aureus (S. aureus) TadA: MGSHMTNDIYFMTLAIEEAKKAAQLGEVPIGAIITKDDEVIARAHNLRETLQQPTAHAEHIA IERAAKVLGSWRLEGCTLYVTLEPCVMCAGT IVMSRIPRVVYGADDPKGGCSGSLMNLLQQS NFNHRAIVDKGVLKEACSTLLTTFFKNLRANKKSTN Bacillus subtilis (B. subtilis) TadA: MTQDELYMKEAIKEAKKAEEKGEVPIGAVLVINGEIIARAHNLRETEQRSIAHAEMLVIDEA CKALGTWRLEGATLYVTLEPCPMCAGAVVLSRVEKVVFGAFDPKGGCSGTLMNLLQEERFNH QAEVVSGVLEEECGGMLSAFFRELRKKKKAARKNLSE Salmonella typhimurium (S. typhimurium) TadA: MPPAFITGVTSLSDVELDHEYWMRHALTLAKRAWDEREVPVGAVLVHNHRVIGEGWNRPIGR HDPTAHAE IMALRQGGLVLONYRLLDTTLYVTLEPCVMCAGAMVHSRIGRVVFGARDAKTGA AGSLIDVLHHPGMNHRVEIIEGVLRDECATLLSDFFRMRRQE IKALKKADRAEGAGPAV Shewanella putrefaciens (8S. putrefaciens) TadA: MDEYWMQVAMOMAEKAEAAGEVPVGAVLVKDGOQTIATGYNLSISQHDPTAHAETLCLRSAGK KLENYRLLDATLYITLEPCAMCAGAMVHSRIARVVYGARDEKTGAAGTVVNLLQHPAFNHQV EVTSGVLAEACSAQLSRFFKRRRDEKKALKLAQRAQQOGIE Haemophilus influenzae F3031 (H. influenzae) TadA: MDAAKVRSEFDEKMMRYALELADKAFALGEIPVGAVLVDDARNI IGEGWNLSIVQSDPTAHA EITALRNGAKNIQONYRLLNSTLYVTLEPCTMCAGAILHSRIKRLVFGASDYKTGAIGSRFHF FDDYKMNHTLEITSGVLAEECSQKLSTFFQKRREEKKIEKALLKSLSDK Caulobacter crescentus (C. crescentus) TadA: MRTDESEDQDHRMMRLALDAARAARAEAGETPVGAVILDPSTGEVIATAGNGPIAAHDPTAHA EIAAMRAAAAKLGNYRLTDLTLVVTLEPCAMCAGAISHARIGRVVFGADDPKGGAVVHGPKE FAQPTCHWRPEVTGGVLADESADLLRGFFRARRKAKI Geobacter sulfurreducens (G. sulfurreducens) TadA; MSSLKKTPIRDDAYWMGKAIREAAKAAARDEVPIGAVIVRDGAVIGRGHNLREGSNDPSAHA EMIAIRQAARRSANWRLTGATLYVTLEPCLMCMGAIILARLERVVFGCYDPKGGAAGSLYDL SADPRLNHQVRLSPGVCQEECGTMLSDFFRDLRRRKKAKATPALFIDERKVPPEP TadA*7.10 MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAE IMA LRQGGLVMQONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD Additional TadA7.10 or TadA7.10 variants contemplated as a component of a heterodimer with a TadA*8 include: GSSGSETPGTSESATPESSGSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGE GWNRAIGLHDPTAHAEIMALRQGGLVMONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFG VRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVENAQKKAQSSTD TadA7.10 CP65 TAHAE IMALRQGGLVMONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGS LMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVENAQKKAQSSTDGSSGSETPGTS ESATPESSGSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDP TadA7.10 CP83 YRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYPGMNHRVEITE GILADECAALLCYFFRMPRQVFNAQKKAQSSTDGSSGSETPGTSESATPESSGSEVEFSHEY WMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAE IMALRQGGLVMQON TadA7.10 CP136 MNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTDGSSGSETPGTSESATPESSG SEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAE IMAL ROGGLVMONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSIMDVLHYPG TadA7.10 C-truncate GSSGSETPGTSESATPESSGSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGE GWNRAIGLHDPTAHAEIMALRQGGLVMONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVEG VRNAKTGAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVEN TadA7.10 C-truncate 2 GSSGSETPGTSESATPESSGSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGE GWNRAIGLHDPTAHAEIMALRQGGLVMONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVEG VRNAKTGAAGSILMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQO TadA7.10 deltas9-66+C-truncate GSSGSETPGTSESATPESSGSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGE GWNRAHAE IMALRQGGLVMQONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGA AGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVEN TadA7.10 delta 59-66 GSSGSETPGTSESATPESSGSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGE GWNRAHAE IMALRQGGLVMONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGA AGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPROVFNAQKKAQSSTD. In some embodiments, the adenosine deaminase variant comprises an alteration in TadA7.10. In some embodiments, TadA7.10 comprises an alteration at amino acid 82 or 166. In particular embodiments, a variant in the above-referenced sequence comprises one or more of the following alterations: Y147T, Y147R, Q154S, Y123H, V82S, T166R, and Q154R. In other embodiments, the adenosine deaminase variant comprises a combination of alterations selected from the group consisting of Y147R + Q154R +Y123H; Y147R + Q154R +176Y; Y147R + Q154R + T166R; Y147T + Q154R; Y147T + Q154S; and Y123H + Y147R + Q154R + 176Y. In other embodiments, the invention provides adenosine deaminase variants that include deletions, e.g., TadA7.10 comprising a deletion of the C terminus beginning at residue 149, 150, 151, 152, 153, 154, 155, 156, or 157. In other embodiments, the adenosine deaminase variant is a Tad A monomer comprising one or more of the following alterations: Y147T, Y147R, Q154S, Y123H, V82S, T166R, Q154R. In other embodiments, the adenosine deaminase variant is a monomer comprising the following alterations: Y147R + Q154R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R; Y147T + Q154R; Y147T + Q154S; and Y123H + Y147 R + Q154R + I76Y. In still other embodiments, the adenosine deaminase variant is a homodimer comprising two adenosine deaminase domains each having one or more of the following alterations Y147T, Y147R, Q154S, Y123H, V828, T166R, Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a wild-type adenosine deaminase domain or a TadA7.10 domain and an adenosine deaminase variant domain comprising one or more of the following alterations Y147T, Y147R, Q154S, Y123H, V82S, T166R, Q154R. In other embodiments, the adenosine deaminase variant is a heterodimer comprising a TadA7.10 domain and an adenosine deaminase variant of TadA7.10 comprising the following alterations: Y147R + QI54R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R; Y147T + Q154R; Y147T + Q154S; and Y123H + Y147R + Q154R + 176Y. “Administering” is referred to herein as providing one or more compositions described herein to a patient or a subject. By way of example and without limitation, composition administration, e.g., injection, can be performed by intravenous (i.v.) injection, sub-cutaneous (s.c.) injection, intradermal (i.d.) injection, intraperitoneal (i.p.) injection, or intramuscular (i.m.) injection. One or more such routes can be employed. Parenteral administration can be, for example, by bolus injection or by gradual perfusion over time. In some embodiments, parenteral administration includes infusing or injecting intravascularly, intravenously, intramuscularly, intraarterially, intrathecally, intratumorally, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoidly and intrasternally. Alternatively, or concurrently, administration can be by the oral route. By “agent” is meant any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof. By “alteration” is meant a change (e.g. increase or decrease) in the structure, expression levels or activity of a gene or polypeptide as detected by standard art known methods such as those described herein. As used herein, an alteration includes a change in a polynucleotide or polypeptide sequence or a change in expression levels, such as a 10% change, a 25% change, a 40% change, a 50% change, or greater. By “ameliorate” is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease. By “analog” is meant a molecule that is not identical, but has analogous functional or structural features. For example, a polynucleotide or polypeptide analog retains the biological activity of a corresponding naturally-occurring polynucleotide or polypeptide, while having certain modifications that enhance the analog's function relative to a naturally occurring polynucleotide or polypeptide. Such modifications could increase the analog's affinity for DNA, efficiency, specificity, protease or nuclease resistance, membrane permeability, and / or half-life, without altering, for example, ligand binding. An analog may include an unnatural nucleotide or amino acid. By "base editor (BE)" or "nucleobase editor (NBE)" is meant an agent that binds a polynucleotide and has nucleobase modifying activity. In various embodiment, the base editor comprises a nucleobase modifying polypeptide (e.g, a deaminase) and a nucleic acid programmable nucleotide binding domain in conjunction with a guide polynucleotide (e.g, guide RNA). In various embodiments, the agent is a biomolecular complex comprising a protein domain having base editing activity, i.e., a domain capable of modifying a base (e.g, A, T, C, G, or U) within a nucleic acid molecule (e.g., DNA). In some embodiments, the polynucleotide programmable DNA binding domain is fused or linked to a deaminase domain. In one embodiment, the agent is a fusion protein comprising a domain having base editing activity. In another embodiment, the protein domain having base editing activity is linked to the guide RNA (e.g., via an RNA binding motif on the guide RNA and an RNA binding domain fused to the deaminase). In some embodiments, the domain having base editing activity is capable of deaminating a base within a nucleic acid molecule. In some embodiments, the base editor is capable of deaminating one or more bases within a DNA molecule. In some embodiments, the base editor is capable of deaminating an adenosine (A) within DNA. In some embodiments, the base editor is an adenosine base editor (ABE). By “cytidine deaminase” is meant a polypeptide or fragment thereof capable of catalyzing a deamination reaction that converts an amino group to a carbonyl group. In some embodiments the cytidine deaminase has at least about 85% identity to APOBEC or AID. In one embodiment, the cytidine deaminase converts cytosine to uracil or 5-methylcytosine to thymine. PmCDAI, which is derived from Petromyzon marinus (Petromyzon marinus cytosine deaminase 1, “PmCDA1”), AID (Activation-induced cytidine deaminase; AICDA), which is derived from a mammal (e.g, human, swine, bovine, horse, monkey etc.), and APOBEC are exemplary cytidine deaminases. In some embodiments, the base editor is a reprogrammable base editor fused to a deaminase (e.g., an adenosine deaminase or cytidine deaminase). In some embodiments, the base editor is a Cas9 fused to a deaminase (e.g., an adenosine deaminase or cytidine deaminase). In some embodiments, the base editor is a nuclease-inactive Cas9 (dCas9) fused to a deaminase (e.g., an adenosine deaminase or cytidine deaminase). In some embodiments, the Cas9 is a circular permutant Cas9 (e.g., spCas9 or saCas9). Circular permutant Cas9s are known in the art and described, for example, in Oakes ef a / ., Cell 176, 254-267, 2019. In some embodiments, the base editor is fused to an inhibitor of base excision repair, for example, a UGI domain, or a dISN domain, In some embodiments, the fusion protein comprises a Cas9 nickase fused to a deaminase and an inhibitor of base excision repair, such as a UGI or dISN domain. In other embodiments, the base editor is an abasic base editor. In some embodiments, the base editor is an adenosine base editor (ABE). In some embodiments, an adenosine deaminase is evolved from TadA. In some embodiments, the base editors of the present invention comprise a napDNAbp domain with an internally fused catalytic (e.g., deaminase) domain. In some embodiments, the napDNAbp is a Cas12a (Cpfl) with an internally fused deaminase domain. In some embodiments, the napDNAbp is a Cas12b (c2c1) with an internally fused deaminase domain. In some embodiments, the napDNAbp is a Casl2c (c2c3) with an internally fused deaminase domain. In some embodiments, the napDNAbp is a Casl2d (CasX) with an internally fused deaminase domain. In some embodiments, the napDNADbp is a Cas12e (CasY) with an internally fused deaminase domain. In some embodiments, the napDNAbp is a Cas12g with an internally fused deaminase domain. In some embodiments, the napDNAbp is a Cas12h with an internally fused deaminase domain. In some embodiments, napDNAbp is a Cas12i with an internally fused deaminase domain. In some embodiments, the base editor is a catalytically dead Cas12 (dCas12) fused to a deaminase domain. In some embodiments, the base editor is a Casl2 nickase (nCasl2) fused to a deaminase domain. In some embodiments, base editors are generated (e.g., ABE8) by cloning an adenosine deaminase variant (e.g., TadA*8) into a scaffold that includes a circular permutant Cas9 (e.g., spCAS9 or saCAS9) and a bipartite nuclear localization sequence. Circular permutant Cas9s are known in the art and described, for example, in Oakes ef al., Cell 176, 254-267, 2019. Exemplary circular permutants follow where the bold sequence indicates sequence derived from Cas9, the italics sequence denotes a linker sequence, and the underlined sequence denotes a bipartite nuclear localization sequence. CP5 (with MSP “NGC=Pam Variant with mutations Regular Cas9 likes NGG” PID=Protein Interacting Domain and “D10A” nickase): EIGKATAKYFFYSNIMNFFKTE I TLANGE IRKRPLIE TNGE TGE IVWDKGRDFATVRKVLSM PQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWD PKKY GGFMQPTVAY SVLVVAKVEK GKSKKLKSVKELLGI TIMERSSFEKNPIDFLEAKGYKEVKKDLI IKLPKY SLFELENGRKRM LASAKFLOKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISE FSKRVILADANLDKVLSAYNKHRDKPIREQAENI THLE TLTNLGAPRAFKYFDTTIARKEYR STKEVLDATLIHQSITGLYETRIDLSQLGGDGGSGGSGGSGGSGGSGGSGGMDKKY SIGLAT GTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGE TAEATRLKRTARRRYT RRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTI YHLRKKLVDS TDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEFIQLVQTYNQLFE ENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLA EDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTE ITKAPLSASM IKRYDEHHQDLTLLKALVRQQLPEKYKE IFFDQSKNGYAGY IDGGASQEEFYKFIKPILEKM DGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGE LHAILRRQEDFYPFLKDNREKIEKILT FRIPYYVGPLARGNSRFAWMTRKSEE TI TPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKV LPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYF KKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREM IEERLKTYAHLFDDKVMKQLKRRRY TGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNF MQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDE LVKVMGRHK PENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLONEKLYLYYLQ NGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKM KNYWRQLLNAKLITQRKFDNLTKAERGGLSE LDKAGFIKRQLVE TRQI TKHVAQILDSRMNT KYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAVVGTALIKKY PK LESEFVYGDYKVYDVRKMIAKSEQEGADKRTADGSEFESPKKKRKV* In some embodiments, the ABES is selected from a base editor from Table 6-9, 13, or 14 infra. In some embodiments, ABES contains an adenosine deaminase variant evolved from TadA. In some embodiments, the adenosine deaminase variant of ABES8 is a TadA*8 variant as described in Table 7, 9, 13 or 14 infra. In some embodiments, the adenosine deaminase variant is TadA*7.10 variant (e.g. TadA*8) comprising one or more of an alteration selected from the group of Y147T, Y147R, Q154S, Y123H, V82S, T166R, and / or Q154R. In various embodiments, ABE8 comprises TadA*7.10 variant (e.g. TadA*8) with a combination of alterations selected from the group consisting of Y147T + Q154R; Y147T + Q1548; Y147R + Q1548; V82S + Q1548; V828 + Y147R; V82S + Q154R; V82S + Y123H; 176Y + V828; V82S + Y123H + Y147T, V82S + Y123H + Y147R; V82S + Y123H + QI54R; Y147R + Q154R +Y123H; Y147R + Q154R + I76Y; Y147R + Q154R + T166R; Y123H + Y147R + Q154R + I76Y; V82S + Y123H + Y147R + Q154R,; and I76Y + V82S + Y123H + Y147R + Q154R. In some embodiments ABES is a monomeric construct. In some embodiments, ABES is a heterodimeric construct. In some embodiments, the ABE8 base editor comprises the sequence: MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMA LROGGLVMQONYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKTGAAGSLMDVLHYP GMNHRVEITEGILADECAALLCTFFRMPROVEFNAQKKAQSSTD. In some embodiments, the polynucleotide programmable DNA binding domain is a CRISPR associated (e.g, Cas or Cpfl) enzyme. In some embodiments, the base editor is a catalytically dead Cas9 (dCas9) fused to a deaminase domain. In some embodiments, the base editor is a Cas9 nickase (nCas9) fused to a deaminase domain. In some embodiments, the base editor is fused to an inhibitor of base excision repair (BER). In some embodiments, the inhibitor of base excision repair is a uracil DNA glycosylase inhibitor (UGI). In some embodiments, the inhibitor of base excision repair is an inosine base excision repair inhibitor, Details of base editors are described in International PCT Application Nos. PCT / 2017 / 045381 (WO 2018 / 027078) and PCT / US2016 / 058344 (WO 2017 / 070632), each of which is incorporated herein by reference for its entirety. Also see Komor, A.C., et al, “Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage” Nature 533, 420-424 (2016); Gaudelli, N.M,, ef al., “Programmable base editing of AT to G+C in genomic DNA without DNA cleavage” Nature 551, 464-471 (2017); Komor, A.C, et al., “Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity” Science Advances 3:eaa04774 (2017), and Rees, HA, ef al., “Base editing: precision chemistry on the genome and transcriptome of living cells” Nat Rev Genet. 2018 Dec;19(12):770-788. doi: 10.1038 / s41576-018-0059-1, the entire contents of which are hereby incorporated by reference. By way of example, a cytidine base editor as used in the base editing compositions, systems and methods described herein has the following nucleic acid sequence (8877 base pairs), (Addgene, Watertown, MA; Komor AC, et al., 2017, Sci Adv., 30;3(8):eaa04774. doi: 10.1126 / sciadv.aa04774) as provided below. Polynucleotide sequences having at least 95% or greater identity to the BE4 nucleic acid sequence are also encompassed. lL atatgccaag tacgcccecct attgacgtca atgacggtaa atggeccgece tggcattatg 61 cccagtacat gaccttatgg gactttecta cttggcagta catctacgta ttagtcatcg 121 ctattaccat ggtgatgcgg ttttggcagt acatcaatgg gcgtggatag cggtttgact 181 cacggggatt tccaagtctc caccccattg acgtcaatgg gagtttgttt tggcaccaaa 241 atcaacggga ctttccaaaa tgtcgtaaca actccgcccc attgacgcaa atgggcggta 301 ggcgtgtacg gtgggaggtc tatataagca gagctggttt agtgaaccgt cagatccget 361 agagatccge ggccgctaat acgactcact atagggagag cegcecaccat gagctcagag 421 actggcccag tggctgtgga ccccacattyg agacggcgga tcgageccca tgagtttgag 481 gtattcecttecyg atccgagaga gcectecgcaag gagacctgec tgctttacga aattaattgg 541 gggggccgge actccatttg gcgacataca tcacagaaca ctaacaagca cgtcgaagtc 601 aacttcatcg agaagttcac gacagaaaga tatttctgtc cgaacacaag gtgcagcatt 661 acctggtttc tcagctggag cccatgcggc gaatgtagta gggccatcac tgaattcctg 721 tcaaggtatc cccacgtcac tctgtttatt tacatcgcaa ggctgtacca ccacgctgac 781 ccccgcaatc gacaaggcct gcgggatttg atctcttcag gtgtgactat ccaaattatg 841 actgagcagyg agtcaggata ctgcetggaga aactttgtga attatagccce gagtaatgaa 901 gcccactgge ctaggtatce ccatctgtgg gtacgactgt acgttettga actgtactge 961 atcatactgg gcetgectee ttgtctcaac attctgagaa ggaagcagece acagctgaca 1021 ttctttacca tegetctteca gtettgteat taccagegac tgcceccaca cattctetgg 1081 gccaccgggt tgaaatctgg tggttcttct ggtggttcta gcggcagega gactccecggg 1141 acctcagagt ccgccacacc cgaaagttct ggtggttctt ctggtggttce tgataaaaag 1201 tattctattg gtttagccat cggcactaat tccgttggat gggctgtcat aaccgatgaa 1261 tacaaagtac cttcaaagaa atttaaggtg ttggggaaca cagaccgtca ttcgattaaa 1321 aagaatctta teggtgccct cctattegat agtggcgaaa cggcagagge gactcgectyg 1381 aaacgaaccy cteggagaag gtatacacgt cgcaagaacc gaatatgtta cttacaagaa 1441 atttttagca atgagatgge caaagttgac gattetttcet ttcacegttt ggaagagtce 1501 ttcettgteyg aagaggacaa gaaacatgaa cggcacccca tctttggaaa catagtagat 1561 gaggtggcat atcatgaaaa gtacccaacg atttatcacc tcagaaaaaa gctagttgac 1621 tcaactgata aagcggacct gaggttaatc tacttggctc ttgcccatat gataaagttc 1681 cgtgggcact ttctcattga gggtgatcta aatccggaca actcggatgt cgacaaactg 1741 ttcatccagt tagtacaaac ctataatcag ttgtttgaag agaaccctat aaatgcaagt 1801 ggcgtggatg cgaaggctat tcttagcgcc cgcctctcta aatcccgacg gctagaaaac 1861 ctgatcgcac aattacccgg agagaagaaa aatgggttgt tcggtaacct tatagcgcte 1921 tcactaggcc tgacaccaaa ttttaagtcg aacttcgact tagctgaaga tgccaaattg 1981 cagcttagta aggacacgta cgatgacgat ctcgacaatc tactggcaca aattggagat 2041 cagtatgcgg acttattttt ggctgccaaa aaccttageg atgcaatcct cctatctgac 2101 atactgagag ttaatactga gattaccaag gcgcegttat cegettcaat gatcaaaagg 2161 tacgatgaac atcaccaaga cttgacactt ctcaaggccc tagtccgtca gcaactgect 2221 gagaaatata aggaaatatt ctttgatcag tcgaaaaacg ggtacgcagg ttatattgac 2281 ggcggagcga gtcaagagga attctacaag tttatcaaac ccatattaga gaagatggat 2341 gggacggaag agttgcttgt aaaactcaat cgcgaagatc tactgcgaaa gcagcggact 2401 ttcgacaacy gtagcattce acatcaaatc cacttaggeg aattgcatge tatacttaga 2461 aggcaggagyg atttttatce gttcctcaaa gacaatcegtyg aaaagattga gaaaatccta 2521 acctttegeca taccttacta tgtgggacce ctggeccgag ggaactctey gttecgecatgg 2581 atgacaagaa agtccgaaga aacgattact ccatggaatt ttgaggaagt tgtcgataaa 2641 ggtgcgtcag ctcaatcgtt catcgagagg atgaccaact ttgacaagaa tttaccgaac 2701 gaaaaagtat tgcctaagca cagtttactt tacgagtatt tcacagtgta caatgaactc 2761 acgaaagtta agtatgtcac tgagggcatg cgtaaacccg cctttctaag cggagaacag 2821 aagaaagcaa tagtagatct gttattcaag accaaccgca aagtgacagt taagcaattg 2881 aaagaggact actttaagaa aattgaatgc ttcgattctg tcgagatctc cggggtagaa 2941 gatcgattta atgcgtcact tggtacgtat catgacctcc taaagataat taaagataag 3001 gacttcctygg ataacgaaga gaatgaagat atcttagaag atatagtgtt gactcttacce 3061 ctctttgaag atcgggaaat gattgaggaa agactaaaaa catacgctca cctgttegac 3121 gataaggtta tgaaacagtt aaagaggcgt cgctatacgg gctggggacy attgtcgegg 3181 aaacttatca acgggataag agacaagcaa agtggtaaaa ctattctcga ttttctaaag 3241 agcgacggct tcgccaatag gaactttatg cagctgatcc atgatgactc tttaaccttce 3301 aaagaggata tacaaaaggc acaggtttcc ggacaagggg actcattgca cgaacatatt 3361 gcgaatcttg ctggttcgcc agccatcaaa aagggcatac tccagacagt caaagtagtg 3421 gatgagctag ttaaggtcat gggacgtcac aaaccggaaa acattgtaat cgagatggca 3481 cgcgaaaatc aaacgactca gaaggggcaa aaaaacagtc gagageggat gaagagaata 3541 gaagagggta ttaaagaact gggcagcecag atcttaaagg agcatcctgt ggaaaatacc 3601 caattgcaga acgagaaact ttacctctat tacctacaaa atggaaggga catgtatgtt 3661 gatcaggaac tggacataaa ccgtttatct gattacgacg tcgatcacat tgtaccccaa 3721 tcctttttga aggacgattc aatcgacaat aaagtgctta cacgetcgga taagaaccga 3781 gggaaaagtg acaatgttcc aagcgaggaa gtcgtaaaga aaatgaagaa ctattggcgg 3841 cagctcctaa atgcgaaact gataacgcaa agaaagttcg ataacttaac taaagctgag 3901 aggggtggct tgtctgaact tgacaaggcc ggatttatta aacgtcagcet cgtggaaacc 3961 cgccaaatca caaagcatgt tgcacagata ctagattccc gaatgaatac gaaatacgac 4021 gagaacgata agctgattcg ggaagtcaaa gtaatcactt taaagtcaaa attggtgtcg 4081 gacttcagaa aggattttca attctataaa gttagggaga taaataacta ccaccatgcg 4141 cacgacgctt atcttaatge cgtcgtaggg accgcactca ttaagaaata cccgaagcta 4201 gaaagtgagt ttgtgtatgg tgattacaaa gtttatgacg tccgtaagat gatcgcgaaa 4261 agcgaacagg agataggcaa ggctacagcc aaatacttet tttattctaa cattatgaat 4321 ttctttaaga cggaaatcac tctggcaaac ggagagatac gcaaacgacc tttaattgaa 4381 accaatgggg agacaggtga aatcgtatgg gataagggcc gggacttcge gacggtgaga 4441 aaagttttgt ccatgcccca agtcaacata gtaaagaaaa ctgaggtgca gaccggagygg 4501 ttttcaaagg aatcgattct tccaaaaagg aatagtgata agctcatcge tcgtaaaaag 4561 gactgggacc cgaaaaagta cggtggcettce gatagcecta cagttgecta ttctgtecta 4621 gtagtggcaa aagttgagaa gggaaaatcc aagaaactga agtcagtcaa agaattattg 4681 gggataacga ttatggagcyg ctegtctttt gaaaagaacc ccatcgactt ccttgaggceg 4741 aaaggttaca aggaagtaaa aaaggatctc ataattaaac taccaaagta tagtoctgttt 4801 gagttagaaa atggccgaaa acggatgttg gctagcgeceg gagagettca aaaggggaac 4861 gaactcgcac taccgtctaa atacgtgaat ttcctgtatt tagcgtccca ttacgagaag 4921 ttgaaaggtt cacctgaaga taacgaacag aagcaacttt ttgttgagca gcacaaacat 4981 tatctcgacg aaatcataga gcaaatttcg gaattcagta agagagtcat cctagctgat 5041 gccaatctgg acaaagtatt aagcgcatac aacaagcaca gggataaacc catacgtgag 5101 caggcggaaa atattatcca tttgtttact cttaccaacc tcggcgctce agccgcattce 5161 aagtattttyg acacaacgat agatcgcaaa cgatacactt ctaccaagga ggtgctagac 5221 gcgacactga ttcaccaatc catcacggga ttatatgaaa ctcggataga tttgtcacag 5281 cttgggggtyg actctggtgyg ttctggagga tectggtggtt ctactaatct gtcagatatt 5341 attgaaaagg agaccggtaa gcaactggtt atccaggaat ccatcctcat gctececcagag 5401 gaggtggaag aagtcattgg gaacaagccg gaaagcgata tactcgtgca caccgcctac 5461 gacgagagca ccgacgagaa tgtcatgctt ctgactagcg acgcccctga atacaagcct 5521 tgggctctgg tcatacagga tagcaacggt gagaacaaga ttaagatgct ctctggtggt 5581 tctggaggat ctggtggttc tactaatctg tcagatatta ttgaaaagga gaccggtaag 5641 caactggtta teccaggaatce catcctecatg cteocccagagyg aggtggaaga agtcattggg 5701 aacaagccgyg aaagcgatat actcegtgeac accgectacyg acgagagcac cgacgagaat 5761 gtcatgctte tgactagcga cgceccctgaa tacaagectt gggetetggt catacaggat 5821 agcaacggtyg agaacaagat taagatgcetc tctggtggtt ctcccaagaa gaagaggaaa 5881 gtctaaccygg tcatcatcac catcaccatt gagtttaaac ccgctgatca gcctcgactg 5941 tgccttctag ttgccagcca tctgttgttt geccecctccec cgtgecttece ttgaccctgg 6001 aaggtgccac tcccactgtc ctttcctaat aaaatgagga aattgcatcg cattgtctga 6061 gtaggtgtca ttctattctg gggggtgggg tggggcagga cagcaagggg gaggattggg 6121 aagacaatag caggcatgct ggggatgegg tgggctctat cttetgal 9 gg! 9g 6181 ccagctgggg ctcgataccg tcgacctcta gctagagectt ggcgtaatca tggtcatagce 6241 tgtttcctgt gtgaaattgt tatccgctca caattccaca caacatacga gccggaagcea 6301 taaagtgtaa agcctagggt gcctaatgag tgagctaact cacattaatt gcgttgeget 6361 cactgccege tttccagteyg ggaaacctgt cgtgccaget gecattaatga atcggccaac 6421 gcgcggggag aggcggtttyg cgtattggge getetteege ttectegete actgactcge 6481 tgcgctcggt cgttcggctg cggcgagegg tatcagctca ctcaaaggeg gtaatacggt 6541 tatccacaga atcaggggat aacgcaggaa agaacatgtg agcaaaaggc cagcaaaagg 6601 ccaggaaccg taaaaaggcc gcgttgctgg cgtttttcca taggectccge cccectgacg 6661 agcatcacaa aaatcgacgc tcaagtcaga ggtggcgaaa cccgacagga ctataaagat 6721 accaggcgtt tcccectgga agetccoccteg tgcgetctec tgttecgace ctgcegetta 6781 ccggatacct gtccgecttt cteccttegyg gaagegtgge getttetcat agctcacgcet 6841 gtaggtatct cagtteggtyg taggtegttc getecaaget gggetgtgtg cacgaacccee 6901 ccgttecagec cgaccgetge gecttatceg gtaactateg tettgagtee aacccggtaa 6961 gacacgactt atcgccactg gcagcagcca ctggtaacag gattagcaga gcgaggtatg 7021 taggcggtgc tacagagttc ttgaagtggt ggcctaacta cggctacact agaagaacag 7081 tatttggtat ctgcgctctg ctgaagccag ttaccttcgg aaaaagagtt ggtagctctt 7141 gatccggcaa acaaaccacc gctggtagcg gtggtttttt tgtttgcaag cagcagatta 7201 cgcgcagaaa aaaaggatct caagaagatc ctttgatctt ttctacgggg tctgacgcte 7261 agtggaacga aaactcacgt taagggattt tggtcatgag attatcaaaa aggatcttca 7321 cctagatcct tttaaattaa aaatgaagtt ttaaatcaat ctaaagtata tatgagtaaa 7381 cttggtctga cagttaccaa tgcttaatca gtgaggcacc tatctcageg atctgtctat 7441 ttcgttcatc catagttgce tgactccecyg tecgtgtagat aactacgata cgggagggct 7501 taccatctgyg ccccagtgct gecaatgatac cgcgagaccc acgctcaccy gctccagatt 7561 tatcagcaat aaaccagcca gccggaaggg ccgagcgcag aagtggtcct gcaactttat 7621 ccgcctccat ccagtctatt aattgttgcc gggaagctag agtaagtagt tcgeccagtta 7681 atagtttgcg caacgttgtt gccattgcta caggcatcgt ggtgtcacge tcgtegtttg 7741 gtatggcttc attcagctcc ggttcccaac gatcaaggcg agttacatga tceccccatgt 7801 tgtgcaaaaa ageggttage teoctteggte ctecegategt tgtcagaagt aagttggccyg 7861 cagtgttatc actcatggtt atggcageac tgcataattc tcttactgte atgccatccyg 7921 taagatgctt ttetgtgact ggtgagtact caaccaagtc attctgagaa tagtgtatgce 7981 ggcgaccgag ttgctcttge ccggecgteaa tacgggataa taccgegeca catagcagaa 8041 ctttaaaagt gctcatcatt ggaaaacgtt ctteggggeg aaaactctca aggatcttac 8101 cgctgttgag atccagttcg atgtaaccca ctcgtgcacc caactgatct tcagcatctt 8161 ttactttcac cagcgtttct gggtgagcaa aaacaggaag gcaaaatgcc gcaaaaaagqqg 8221 gaataagggc gacacggaaa tgttgaatac tcatactctt cctttttcaa tattattgaa 8281 gcatttatca gggttattgt ctcatgagcg gatacatatt tgaatgtatt tagaaaaata 8341 aacaaatagg ggttccgcgec acatttcccc gaaaagtgcc acctgacgtc gacggatcgg 8401 gagatcgatc tcccgatcce ctagggtega ctctecagtac aatctgetct gatgccgeat 8461 agttaagcca gtatctgcte cctgcttgtg tgttggaggt cgctgagtag tgcgcgagea 8521 aaatttaagc tacaacaagg caaggcttga ccgacaattg catgaagaat ctgcttaggg 8581 ttaggcgttt tgegetgctt cgcgatgtac gggccagata tacgegttga cattgattat 8641 tgactagtta ttaatagtaa tcaattacgg ggtcattagt tcatagccca tatatggagt 8701 tccgcgttac ataacttacg gtaaatggcc cgcctggectg accgeccaac gaccccecgee 8761 cattgacgtc aataatgacg tatgttccca tagtaacgcc aatagggact tteccattgac 8821 gtcaatgggt ggagtattta cggtaaactg cccacttggc agtacatcaa gtgtatc BE4 amino acid sequence: MSSETGPVAVDPTLRRRIEPHEFEVFFDPRELRKETCLLYEINWGGRHS IWNRHTSQONTNKHV EVNFIEKFTTERYFCPNTRCSITWFLSWSPCGECSRAITEFLSRYPHVTLFIYIARLYHHAD PRNRQGLRDLISSGVTIQIMTEQESGYCWRNFVNYSPSNEAHWPRYPHLWVRLYVLELYCIT LGLPPCLNILRRKQPQLTFFTIALQSCHYQRLPPHILWATGLKSGGSSGGSSGSETPGTSES ATPESSGGSSGGSDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHS IKKNLIGA LLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKK HERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDS TDKADLRLIYLALAHMIKFRGHFLIEGDL NPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNG LFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSD AILLSDILRVNTEITKAPLSASMIKRYDEHHQODLTLLKALVRQQLPEKYKEIFFDQSKNGYA GYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGS IPHQIHLGELHAT LRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDK GASAQSFIERMTINFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKK AIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLD NEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQOLKRRRYTGWGRLSRKLINGI RDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPA IKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQ ILKEHPVENTQLONEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDS IDNKV LTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIK RQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INN YHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNI MNFFKTEITLANGEIRKRPLIETNGETGE IVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGG FSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGI TIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELAL PSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKV LSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQST TGLYETRIDLSQLGGDSGGSGGSGGSTNLSDIIEKETGKQLVIQESIIMLPEEVEEVIGNKP ESDILVHTAYDESTDENVMLLTSDAPEYKPWALVIQDSNGENKIKMLSGGSGGSGGSTNLSD IIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVMLLTSDAPEYKPW ALVIQDSNGENKIKMLSGGSPKKKRK By way of example, the adenine base editor (ABE) as used in the base editing compositions, systems and methods described herein has the nucleic acid sequence (8877 base pairs), (Addgene, Watertown, MA; Gaudelli NM, er al., Nature. 2017 Nov 23;551(7681):464- 471. doi: 10.1038 / nature24644; Koblan LW, ef al, Nat Biotechnol. 2018 Oct;36(9):843-846. doi: 10.1038 / nbt.4172.) as provided below. Polynucleotide sequences having at least 95% or greater identity to the ABE nucleic acid sequence are also encompassed. ATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTARATGGCCCGCCTGGCATTATGCCCAGTAC AT GACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGC Ld po TTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCAT TG ACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAARATGTCGTAACAACTCCGCC cc ATTGACGCARATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACC GT CAGATCCGCTAGAGATCCGCGGCCGCTAATACGACTCACTATAGGGAGAGCCGCCACCATGAAACGGA CA GCCGACGGAAGCGAGTTCGAGTCACCAARGAAGAAGCGGARAGTCTCTGAAGTCGAGTTTAGCCACGA GT ATTGGATGAGGCACGCACTGACCCTGGCARAAGCGAGCATGGGATGARAGAGRRGTCCCCGTGGGCGCC GT GCTGGTGCACAACAATAGAGTGATCGGAGAGGGATGGAARCAGGCCAATCGGCCGCCACGACCCTACCG CA CACGCAGAGATCATGGCACTGAGGCAGGGAGGCCTGGTCATGCAGAATTACCGCCTGATCGATGCCAC cc TGTATGTGACACTGGAGCCATGCGTGATGTGCGCAGGAGCAATGATCCACAGCAGGATCGGAAGAGTG GT GTTCGGAGCACGGGACGCCARGACCGGCGCAGCAGGCTCCCTGATGGATGTGCTGCACCACCCCGGCA TG AACCACCGGGTGGAGATCACAGAGGGAATCCTGGCAGACGAGTGCGCCGCCCTGCTGAGCGATTTCTT TA GRATGCGGAGACAGGAGATCRAGGCCCAGAAGAAGGCACAGAGCTCCACCGACTCTGGAGGATCTAGC GG AGGATCCTCTGGARAGCGAGACACCAGGCACARGCGAGTCCGCCACACCAGAGAGCTCCGGCGGCTCCT oc GGAGGATCCTCTGAGGTGGAGTTTTCCCACGAGTACTGGATGAGACATGCCCTGACCCTGGCCARAGAG GG CACGCGATGAGAGGGAGGTGCCTGTGGGAGCCGTGCTGGTGCTGAACAATAGAGTGATCGGCGAGGGC TG GAACAGAGCCATCGGCCTGCACGACCCAACAGCCCATGCCGARATTATGGCCCTGAGACAGGGCGGCC TG GTCATGCAGAACTACAGACTGATTGACGCCACCCTGTACGTGACATTCGAGCCTTGCGTGATGTGCGC cc GCGCCATGATCCACTCTAGGATCGGCCGCGTGGTGTTTGGCGTGAGGARCGCAAARACCGGCGCCGCA cc CTCCCTGATGGACGTGCTGCACTACCCCGGCATGAATCACCGCGTCGARATTACCGAGGGAATCCTGG CA GATGAATGTGCCGCCCTGCTGTGCTATTTCTTTCGGATGCCTAGACAGGTGTTCAATGCTCAGAAGAR GG CCCAGAGCTCCACCGACTCCGGAGGATCTAGCGGAGGCTCCTCTGGCTCTGAGACACCTGGCACAAGC GA GAGCGCAACACCTGARAGCAGCGGGGGCAGCAGCGGGGGGTCAGACAAGARGTACAGCATCGGCCTGG oC ATCGGCACCAACTCTGTGGGCTGGGCCGTGATCACCGACGAGTACAAGGTGCCCAGCAAGAAATTCAA GG TGCTGGGCAACACCGACCGGCACAGCATCAAGARGAACCTGATCGGAGCCCTGCTGTTCGACAGCGGC GA AACAGCCGAGGCCACCCGGCTGAARGAGAACCGCCAGRAAGARGATACACCAGACGGARAGAACCGGATCT cc TATCTGCAAGAGATCTTCAGCAACGAGATGGCCAAGGTGGACGACAGCTTCTTCCACAGACTGGAAGA GT CCTTCCTGGTGGAAGAGGATRAGAAGCACGAGCGGCACCCCATCTTCGGCAACATCGTGGACGAGGTG cc CTACCACGAGAAGTACCCCACCATCTACCACCTGAGARAGARACTGGTGGACAGCACCGACAAGGCCG AC CTGCGGCTGATCTATCTGGCCCTGGCCCACATGATCAAGTTCCGGGGCCACTTCCTGATCGAGGGCGA cc TGARCCCCGACAACAGCGACGTGGACAAGCTGTTCATCCAGCTGGTGCAGACCTACARACCAGCTGTTC GA GGARBRACCCCATCAACGCCAGCGGCGTGGACGCCARAGGCCATCCTGTCTGCCAGACTGAGCARGAGCA on CGGCTGGARARATCTGATCGCCCAGCTGCCCGGCGAGRAAGRAGAATGGCCTGTTCGGARRACCTGATTGC oc TGAGCCTGGGCCTGACCCCCAACTTCAAGAGCARACTTCGACCTGGCCGAGGATGCCARRACTGCAGCTG ACG CAAGGACACCTACGACGACGACCTGGACAACCTGCTGGCCCAGATCGGCGACCAGTACGCCGACCTGT TT CTGGCCGCCAAGAACCTGTCCGACGCCATCCTGCTGAGCGACATCCTGAGAGTGAACACCGAGATCAC CA AGGCCCCCCTGAGCGCCTCTATGATCAAGAGATACGACGAGCACCACCAGGACCTGACCCTGCTGARA cc TCTCGTGCGGCAGCAGCTGCCTGAGAAGTACAAAGAGATTTTCTTCGACCAGAGCAAGAACGGCTACG cc GGCTACATTGACGGCGGAGCCAGCCAGGAAGAGTTCTACAAGTTCATCAAGCCCATCCTGGARAAGAT GG ACGGCACCGAGGAACTGCTCGTGAAGCTGAACAGAGAGGACCTGCTGCGGARAGCAGCGGACCTTCGAC AD CGGCAGCATCCCCCACCAGATCCACCTGGGAGAGCTGCACGCCATTCTGCGGCGGCAGGAAGATTTTT AC CCATTCCTGAAGGACAACCGGGAAAAGATCGAGAAGATCCTGACCTTCCGCATCCCCTACTACGTGGG cc CTCTGGCCAGGGGARACAGCAGATTCGCCT GGATGACCAGARRAGAGCGAGGARACCATCACCCCCTGG AA CTTCGAGGAAGTGGTGGACRAGGGCGCTTCCGCCCAGAGCTTCATCGAGCGGATGACCAACTTCGATA AG AACCTGCCCARACGAGAAGGTGCTGCCCAAGCACAGCCTGCTGTACGAGTACTTCACCGTGTATARCGA cc TGACCAAAGTGAAATACGTGACCGAGGGAATGAGAAAGCCCGCCTTCCTGAGCGGCGAGCAGARRARG cc CATCGTGGACCTGCTGTTCARGACCAACCGGARAGTGACCGTGAAGCAGCTGAAAGAGGACTACTTCA AG AAAATCGAGTGCTTCGACTCCGTGGARATCTCCGGCGTGGAAGATCGGTTCARCGCCTCCCTGGGCAC AT ACCACGATCTGCTGARRRATTATCAAGGACAAGGACTTCCTGGACAATGAGGARAACGAGGACATTCTG GA AGATATCGTGCTGACCCTGACACTGTTTGAGGACAGAGAGATGATCGAGGAACGGCTGARRACCTATG oc CACCTGTTCGACGACARRAGTGATGAAGCAGCTGAAGCGGCGGAGATACACCGGCTGGGGCAGGCTGAG oc GGAAGCTGATCAACGGCATCCGGGACAAGCAGTCCGGCARGACAARTCCTGGATTTCCTGARAGTCCGAC GG CTTCGCCAACAGARACTTCATGCAGCTGATCCACGACGACAGCCTGACCTTTAAAGAGGACATCCAGA AR GCCCAGGTGTCCGGCCAGGGCGATAGCCTGCACGAGCACATTGCCAATCTGGCCGGCAGCCCCGCCAT TA AGAAGGGCATCCTGCAGACAGTGAAGGTGGTGGACGAGCTCGTGAAAGTGATGGGCCGGCACARGCCC GA GAACATCGTGATCGAAATGGCCAGAGAGAACCAGACCACCCAGAAGGGACAGAAGAACAGCCGCGAGA GA ATGAAGCGGATCGAAGAGGGCATCAAAGAGCTGGGCAGCCAGATCCTGARAGAACACCCCGTGGAARA Oa CCCAGCTGCAGAACGAGAAGCTGTACCTGTACTACCTGCAGAATGGGCGGGATATGTACGTGGACCAG GA ACTGGACATCAACCGGCTGTCCGACTACGATGTGGACCATATCGTGCCTCAGAGCTTTCTGAAGGACG AC TCCATCGACAACAAGGTGCTGACCAGAAGCGACAAGAACCGGGGCAAGAGCGACAACGTGCCCTCCGA AG AGGTCGTGARGAAGATGAAGAACTACTGGCGGCAGCTGCTGAACGCCARGCTGATTACCCAGAGARAG TT CGACRATCTGACCAAGGCCGAGAGAGGCGGCCTGAGCGAACTGGATAAGGCCGGCTTCATCAAGAGAC AG CTGGTGGAAACCCGGCAGATCACAAAGCACGTGGCACAGATCCTGGACTCCCGGATGAACACTAAGTA CG ACGAGAATGACAAGCTGATCCGGGRAGTGAAAGTGATCACCCTGAAGTCCARGCTGGTGTCCGATTTC cc GAAGGATTTCCAGTTTTACARAGTGCGCGAGATCAACAACTACCACCACGCCCACGACGCCTACCTGA AC GCCGTCGTGGGAACCGCCCTGATCARARAGTACCCTAAGCTGGARAGCGAGTTCGTGTACGGCGACTA CA AGGTGTACGACGTGCGGAAGATGATCGCCAAGAGCGAGCAGGARATCGGCARGGCTACCGCCAAGTAC bi fod og CTTCTACAGCAACATCATGAACTTTTTCAAGACCGAGATTACCCTGGCCAACGGCGAGATCCGGARAGC GG CCTCTGATCGAGACARACGGCGARARCCGGGGAGATCGTGTGGGATAAGGGCCGGGATTTTGCCACCGT GC GGARRGTGCTGAGCATGCCCCAAGTGAATATCGTGRRARRGACCGAGGTGCAGACAGGCGGCTTCAGC AD AGAGTCTATCCTGCCCARGAGGAACAGCGATAAGCTGATCGCCAGARAGAAGGACTGGGACCCTAAGA AG TACGGCGGCTTCGACAGCCCCACCGTGGCCTATTCTGT GCTGGTGGTGGCCARAGTGGARAAGGGCAR GT CCAAGAAACTGAAGAGTGTGAAAGAGCTGCTGGGGATCACCATCATGGAAAGAAGCAGCTTCGAGARG AR TCCCATCGACTTTCTGGAAGCCAAGGGCTACAAAGAAGTGARAAAGGACCTGATCATCAAGCTGCCTA AG TACTCCCTGTTCGAGCTGGARAACGGCCGGAAGAGAATGCTGGCCTCTGCCGGCGAACTGCAGAAGGG AD ACGAACTGGCCCTGCCCTCCAAATATGTGAACTTCCTGTACCTGGCCAGCCACTATGAGARGCTGAAG GG CTCCCCCGAGGATAATGAGCAGAAACAGCTGTTTGTGGAACAGCACARGCACTACCTGGACGAGATCA mc GAGCAGATCAGCGAGTTCTCCAAGAGAGTGATCCTGGCCGACGCTAATCTGGACARAGTGCTGTCCGC or ACAACAAGCACCGGGATAARGCCCATCAGAGAGCAGGCCGAGAATATCATCCACCTGTTTACCCTGACC AA TCTGGGAGCCCCTGCCGCCTTCAAGTACTTTGACACCACCATCGACCGGAAGAGGTACACCAGCACCA AD GAGGTGCTGGACGCCACCCTGATCCACCAGAGCATCACCGGCCTGTACGAGACACGGATCGACCTGTC Cc AGCTGGGAGGTGACTCTGGCGGCTCARAAAGAACCGCCGACGGCAGCGAATTCGAGCCCAAGARGAAG AG GAAAGTCTAACCGGTCATCATCACCATCACCATTGAGTTTAAACCCGCTGATCAGCCTCGACTGTGCC TT CTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCC AC TGTCCTTTCCTAATARRATGAGGARATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGG GT GGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGARGACAATAGCAGGCATGCTGGGGATGCGGTGGG or CTATGGCTTCTGAGGCGGARAGAACCAGCTGGGGCTCGATACCGTCGACCTCTAGCTAGAGCTTGGCG TA ATCATGGTCATAGCTGTTTCCTGTGTGARATTGTTATCCGCTCACAARTTCCACACARACATACGAGCCG GA AGCATAAAGTGTARAGCCTAGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACT cc CCGCTTTCCAGTCGGGARACCTGTCGTGCCAGCTGCATTAATGAATCGGCCARCGCGCGGGGAGAGGC cc TTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGC GA GCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGARAGAR CA TGTGAGCAARAGGCCAGCARRAGGCCAGGAACCGTAARAAGGCCGCGTTGCTGGCGTTTTTCCATAGG cr CCGCCCCCCTGACGAGCATCACARRAATCGACGCTCAAGTCAGAGGTGGCGARACCCGACAGGACTAT AD AGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGG AT ACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGT Li we GGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCT TA TCCGGTAACTATCGTCTTGAGTCCRACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGG TA ACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGT TCTTGAAGTGGTGGCCTAACTACGGC TA CACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGARRAAGAGTTGGTA cc TCTTGATCCGGCARACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCG CA GAAAARAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACACTCAGTGGARCGAARAC Cc ACGTTAAGGGATTTTGGTCATGAGATTATCARRARGGATCTTCACCTAGATCCTTTTARATTARARAT GA AGTTTTAAATCAATCTARAGTATATATGAGTARACTTGGTCTGACAGTTACCAATGCTTAATCAGTGA GC CACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACT AC GATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTC CA GATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGC CT CCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAAC GT TGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTT cc CAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCARAAAAGCGGTTAGCTCCTTCGGTCCTCC GA TCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTT AC TGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGT GT ATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTT AD AAGTGCTCATCATTGGARAACGTTCTTCGGGGCGAAAARCTCTCAAGGATCTTACCGCTGTTGAGATCC AG TTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGT GA GCARRAACAGGAAGGCAARATGCCGCARAARAGGGARATAAGGGCGACACGGARATGTTGARATACTCAT AC TCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAR TG TATTTAGAARRATARACAAATAGGGGTTCCGCGCACATTTCCCCGARRRGTGCCACCTGACGTCGACG GA TCGGGAGATCGATCTCCCGATCCCCTAGGGTCGACTCTCAGTACAATCTGCTCTGATGCCGCATAGTT AR GCCAGTATCTGCTCCCTGCTTGTGTGTTGGAGGTCGCTGAGTAGTGCGCGAGCAARATTTAAGCTACA AC BAAGGCAAGGCTTGACCGACAATTGCATGARAGRATCTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCG AT GTACGGGCCAGATATACGCGTTGACATTGATTAT TGACTAGTTATTAATAGTAATCAATTACGGGGTC AT TAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTARATGGCCCGCCTGGCTGACCG oc CRACGACCCCCGCCCATTGACGTCARATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCC AT TGACGTCAATGGETGGAGTATT TACGGTAA AC TGC CCACTTGGCAGTACATCAAGTGTATC By “base editing activity” is meant acting to chemically alter a base within a polynucleotide. In one embodiment, a first base is converted to a second base. In one embodiment, the base editing activity is cytidine deaminase activity, e.g., converting target C+G to T*A. In another embodiment, the base editing activity is adenosine or adenine deaminase activity, e.g., converting A*T to G+C. In another embodiment, the base editing activity is cytidine deaminase activity, e.g., converting target CG to T*A and adenosine or adenine deaminase activity, e.g., converting A+T to G+C. In some embodiments, base editing activity is assessed by efficiency of editing. Base editing efficiency may be measured by any suitable means, for example, by sanger sequencing or next generation sequencing. In some embodiments, base editing efficiency is measured by percentage of total sequencing reads with nucleobase conversion effected by the base editor, for example, percentage of total sequencing reads with target A.T base pair converted to a G.C base pair. In some embodiments, base editing efficiency is measured by percentage of total cells with nucleobase conversion effected by the abse editor, when base editing is performed in a population of cells. The term “base editor system” refers to a system for editing a nucleobase of a target nucleotide sequence. In various embodiments, the base editor system comprises (1) a polynucleotide programmable nucleotide binding domain (e.g., Cas9); (2) a deaminase domain (e.g., an adenosine deaminase or a cytidine deaminase) for deaminating said nucleobase; and (3) one or more guide polynucleotide (e.g., guide RNA). In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA binding domain. In some embodiments, the base editor is an adenine or adenosine base editor (ABE). In some embodiments, the base editor system is ABES. In some embodiments, a base editor system may comprise more than one base editing component. For example, a base editor system may include more than one deaminase. In some embodiments, a base editor system may include one or more adenosine deaminases. In some embodiments, a single guide polynucleotide may be utilized to target different deaminases to a target nucleic acid sequence. In some embodiments, a single pair of guide polynucleotides may be utilized to target different deaminases to a target nucleic acid sequence. The deaminase domain and the polynucleotide programmable nucleotide binding component of a base editor system may be associated with each other covalently or non- covalently, or any combination of associations and interactions thereof. For example, in some embodiments, a deaminase domain can be targeted to a target nucleotide sequence by a polynucleotide programmable nucleotide binding domain. In some embodiments, a polynucleotide programmable nucleotide binding domain can be fused or linked to a deaminase domain. In some embodiments, a polynucleotide programmable nucleotide binding domain can target a deaminase domain to a target nucleotide sequence by non-covalently interacting with or associating with the deaminase domain. For example, in some embodiments, the deaminase domain can comprise an additional heterologous portion or domain that is capable of interacting with, associating with, or capable of forming a complex with an additional heterologous portion or domain that is part of a polynucleotide programmable nucleotide binding domain. In some embodiments, the additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polypeptide. In some embodiments, the additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a guide polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a polypeptide linker. In some embodiments, the additional heterologous portion may be capable of binding to a polynucleotide linker. The additional heterologous portion may be a protein domain. In some embodiments, the additional heterologous portion may be a K Homology (KH) domain, a MS2 coat protein domain, a PP7 coat protein domain, a SfMu Com coat protein domain, a steril alpha motif, a telomerase Ku binding motif and Ku protein, a telomerase Sm7 binding motif and Sm7 protein, or an RNA recognition motif. A base editor system may further comprise a guide polynucleotide component. It should be appreciated that components of the base editor system may be associated with each other via covalent bonds, noncovalent interactions, or any combination of associations and interactions thereof. In some embodiments, a deaminase domain can be targeted to a target nucleotide sequence by a guide polynucleotide. For example, in some embodiments, the deaminase domain can comprise an additional heterologous portion or domain (e.g, polynucleotide binding domain such as an RNA or DNA binding protein) that is capable of interacting with, associating with, or capable of forming a complex with a portion or segment (e.g., a polynucleotide motif) of a guide polynucleotide. In some embodiments, the additional heterologous portion or domain (e.g., polynucleotide binding domain such as an RNA or DNA binding protein) can be fused or linked to the deaminase domain. In some embodiments, the additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polypeptide. In some embodiments, the additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a guide polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a polypeptide linker. In some embodiments, the additional heterologous portion may be capable of binding to a polynucleotide linker. The additional heterologous portion may be a protein domain. In some embodiments, the additional heterologous portion may be a K Homology (KH) domain, a MS2 coat protein domain, a PP7 coat protein domain, a SfMu Com coat protein domain, a sterile alpha motif, a telomerase Ku binding motif and Ku protein, a telomerase Sm7 binding motif and Sm7 protein, or an RNA recognition motif. In some embodiments, a base editor system can further comprise an inhibitor of base excision repair (BER) component. It should be appreciated that components of the base editor system may be associated with each other via covalent bonds, noncovalent interactions, or any combination of associations and interactions thereof. The inhibitor of BER component may comprise a BER inhibitor. In some embodiments, the inhibitor of BER can be a uracil DNA glycosylase inhibitor (UGI). In some embodiments, the inhibitor of BER can be an inosine BER inhibitor. In some embodiments, the inhibitor of BER can be targeted to the target nucleotide sequence by the polynucleotide programmable nucleotide binding domain. In some embodiments, a polynucleotide programmable nucleotide binding domain can be fused or linked to an inhibitor of BER. In some embodiments, a polynucleotide programmable nucleotide binding domain can be fused or linked to a deaminase domain and an inhibitor of BER. In some embodiments, a polynucleotide programmable nucleotide binding domain can target an inhibitor of BER to a target nucleotide sequence by non-covalently interacting with or associating with the inhibitor of BER. For example, in some embodiments, the inhibitor of BER component can comprise an additional heterologous portion or domain that is capable of interacting with, associating with, or capable of forming a complex with an additional heterologous portion or domain that is part of a polynucleotide programmable nucleotide binding domain. In some embodiments, the inhibitor of BER can be targeted to the target nucleotide sequence by the guide polynucleotide. For example, in some embodiments, the inhibitor of BER can comprise an additional heterologous portion or domain (e.g., polynucleotide binding domain such as an RNA or DNA binding protein) that is capable of interacting with, associating with, or capable of forming a complex with a portion or segment (e.g., a polynucleotide motif) of a guide polynucleotide. In some embodiments, the additional heterologous portion or domain of the guide polynucleotide (e.g., polynucleotide binding domain such as an RNA or DNA binding protein) can be fused or linked to the inhibitor of BER. In some embodiments, the additional heterologous portion may be capable of binding to, interacting with, associating with, or forming a complex with a polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a guide polynucleotide. In some embodiments, the additional heterologous portion may be capable of binding to a polypeptide linker. In some embodiments, the additional heterologous portion may be capable of binding to a polynucleotide linker. The additional heterologous portion may be a protein domain. In some embodiments, the additional heterologous portion may be a K Homology (KH) domain, a MS2 coat protein domain, a PP7 coat protein domain, a SfMu Com coat protein domain, a sterile alpha motif, a telomerase Ku binding motif and Ku protein, a telomerase Sm7 binding motif and Sm7 protein, or an RNA recognition motif. The term “Cas9” or “Cas9 domain” refers to an RNA guided nuclease comprising a Cas9 protein, or a fragment thereof (e.g., a protein comprising an active, inactive, or partially active DNA cleavage domain of Cas9, and / or the gRNA binding domain of Cas9). A Cas9 nuclease is also referred to sometimes as a Casnl nuclease or a CRISPR (clustered regularly interspaced short palindromic repeat) associated nuclease. CRISPR is an adaptive immune system that provides protection against mobile genetic elements (viruses, transposable elements and conjugative plasmids). CRISPR clusters contain spacers, sequences complementary to antecedent mobile elements, and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA). In type II CRISPR systems correct processing of pre-crRNA requires a trans-encoded small RNA (tracrRNA), endogenous ribonuclease 3 (mc) and a Cas9 protein. The tractRNA serves as a guide for ribonuclease 3-aided processing of pre-crRNA. Subsequently, Cas9 / crRNA / tracrRNA endonucleolytically cleaves linear or circular dsDNA target complementary to the spacer. The target strand not complementary to crRNA is first cut endonucleolytically, then trimmed 3'-5' exonucleolytically. In nature, DNA-binding and cleavage typically requires protein and both RNAs. However, single guide RNAs (“sgRNA”, or simply “gNRA”) can be engineered 50 as to incorporate aspects of both the crRNA and tracrRNA into a single RNA species. See, e.g., Jinek M., et al., Science 337:816-821(2012), the entire contents of which is hereby incorporated by reference. Cas9 recognizes a short motif in the CRISPR repeat sequences (the PAM or protospacer adjacent motif) to help distinguish self versus non-self. Cas9 nuclease sequences and structures are well known to those of skill in the art (see, e.g., “Complete genome sequence of an M1 strain of Streptococcus pyogenes.” Ferretti ef al., Proc. Natl. Acad. Sci. U.S.A. 98:4658-4663(2001); “CRISPR RNA maturation by trans- encoded small RNA and host factor RNase IIL.” Deltcheva E., et al., Nature 471:602- 607(2011); and “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.” Jinek M., et al., Science 337:816-821(2012), the entire contents of each of which are incorporated herein by reference). Cas9 orthologs have been described in various species, including, but not limited to, S. pyogenes and S. thermophilus. Additional suitable Cas9 nucleases and sequences will be apparent to those of skill in the art based on this disclosure, and such Cas9 nucleases and sequences include Cas9 sequences from the organisms and loci disclosed in Chylinski, Rhun, and Charpentier, “The tractRNA and Cas9 families of type II CRISPR-Cas immunity systems” (2013) RNA Biology 10:5, 726-737; the entire contents of which are incorporated herein by reference. An exemplary Cas9, is Streptococcus pyogenes Cas9 (spCas9), the amino acid sequence of which is provided below: MDKKYSIGLDIGTNSVGWAVITDDYKVPSKKFKVLGNTDRHS IKKNLIGALLFGSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLADSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFI QLVQIYNQLFEENPINASRVDAKAILSARLSKSRRLENLIAQLPGEKRNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNS EITKAPLSASMIKRYDEHHQDLTLLKALVRQQOLPEKYKEIFFDQSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VIVKQLKEDYFKKIECFDSVEISGVEDRFNASLGAYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDRGMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGHSLHEQIANLAGSPATIKKGILOTVKIV DELVKVMGHKPENTVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQLQ NEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFIKDDS IDNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFTKROIVETRQITKHV AQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAVV GTALIKKYPKIESEFVYGDYKVYDVRKMIAKSFEQORIGKATAKYFFYSNIMNFFKTETITLANG EIRKRPLIETNGETGE IVWDKGRDEFATVRKVLESMPOVNIVKKTEVOTGGFSKESILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH YEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL GCL (single underline: HNH domain; double underline: RuvC domain) A nuclease-inactivated Cas9 protein may interchangeably be referred to as a “dCas9” protein (for nuclease-“dead” Cas9) or catalytically inactive Cas9. Methods for generating a Cas9 protein (or a fragment thereof) having an inactive DNA cleavage domain are known (See, e.g., Jinek et al., Science. 337:816-821(2012); Qi et al., “Repurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene Expression” (2013) Cell. 28;152(5):1173-83, the entire contents of each of which are incorporated herein by reference). For example, the DNA cleavage domain of Cas9 is known to include two subdomains, the HNH nuclease subdomain and the RuvCl1 subdomain. The HNH subdomain cleaves the strand complementary to the gRNA, whereas the RuvC1 subdomain cleaves the non-complementary strand. Mutations within these subdomains can silence the nuclease activity of Cas9. For example, the mutations D10A and H840A completely inactivate the nuclease activity of S. pyogenes Cas9 (Jinek et al, Science. 337:816-821(2012); Qi et al, Cell. 28;152(5):1173-83 (2013)). In some embodiments, a Cas9 nuclease has an inactive (e.g., an inactivated) DNA cleavage domain, that is, the Cas9 is a nickase, referred to as an “nCas9” protein (for “nickase” Cas9). In some embodiments, proteins comprising fragments of Cas9 are provided. For example, in some embodiments, a protein comprises one of two Cas9 domains: (1) the gRNA binding domain of Cas9; or (2) the DNA cleavage domain of Cas9. In some embodiments, proteins comprising Cas9 or fragments thereof are referred to as “Cas9 variants.” A Cas9 variant shares homology to Cas9, or a fragment thereof. For example, a Cas9 variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to wild-type Cas9. In some embodiments, the Cas variant may have 1,2, 3,4,5,6,7,8,9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more amino acid changes compared to wild-type Cas9. In some embodiments, the Cas9 variant comprises a fragment of Cas9 (e.g., a gRNA binding domain or a DNA-cleavage domain), such that the fragment is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to the corresponding fragment of wild-type Cas9. In some embodiments, the fragment is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% identical, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the amino acid length of a corresponding wild-type Cas9. In some embodiments, the fragment is at least 100 amino acids in length. In some embodiments, the fragment is at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, or at least 1300 amino acids in length. In some embodiments, wild-type Cas9 corresponds to Cas9 from Streptococcus pyogenes (NCBI Reference Sequence: NC_017053.1, nucleotide and amino acid sequences as follows). ATGGATAAGAAATACTCAATAGGCTTAGATATCGGCACAAATAGCGTCGGATGGGCGGTGAT CACTGATGATTATAAGGTTCCGTCTARARAGTTCAAGGTTCTGGGAAATACAGACCGCCACA GTATCAAAAAAAATCTTATAGGGGCTCTTTTATTTGGCAGTGGAGAGACAGCGGAAGCGACT CCTCTCARACCCACAGC TCG I ACGAACG TI ATAC AC CTCEGARG AATCC TATTTCTTATCTACA GGAGATTTTTTCAAATGAGATGGCGAAAGTAGATGATAGTTTCTTTCATCGACTTGAAGAGT CTTTTTTGGTGGAAGAAGACAAGAAGCATGAACGTCATCCTATTTTTGGAAATATAGTAGAT GAAGTTGCTTATCATGAGAAATATCCAACTATCTATCATCTGCGARAAARATTGGCAGATTC TACTGATAAAGCGGATTTGCGCTTAATCTATTTGGCCTTAGCGCATATGATTAAGTTTCGTG GICATTTTTTGATTGAGGGAGATTTAAATCCTGATAATAGTGATGTGGACAAACTATTTATC CAGTTGGTACAAATCTACAATCAATTATTTGAAGAAAACCCTATTAACGCAAGTAGAGTAGA TGCTAAAGCGATTCTTTCTGCACGATTGAGTAAATCAAGACGATTAGARAATCTCATTGCTC AGCTCCCCGGTGAGAAGAGAAATGGCTTGTTTGGGAATCTCATTGCTTTGTCATTGGGATTG ACCCCTAATTTTAAATCAAATTTTGATTTGGCAGAAGATGCTAARATTACAGCTTTCAAAAGA TACTTACGATGATGATTTAGATAATTTATTGGCGCAAATTGGAGATCAATATGCTGATTTGT TTTTGGCAGCTAAGAATTTATCAGATGCTATTTTACTTTCAGATATCCTAAGAGTAAATAGT GAAATAACTAAGGCTCCCCTATCAGCTTCAATGATTAAGCGCTACGATGAARCATCATCAAGA CTTGACTCTTTTAAAAGCTTTAGTTCGACAACAACTTCCAGAAAAGTATAARAGARAATCTTTT TTGATCAATCAAAAAACGGATATGCAGGTTATATTGATGGGGGAGCTAGCCAAGAAGAATTT TATAAATTTATCARACCAATTTTAGAAARAATGGATGGTACTGAGGAATTATTGGTGAAACT AAATCGTGAAGATTTGCTGCGCAAGCAACGGACCTTTGACAACGGCTCTATTCCCCATCARA TTCACTTGGGTGAGCTGCATGCTATTTTGAGAAGACAAGAAGACTTTTATCCATTTTTAAAA GACAATCGTGAGAAGATTGAARARATCTTGACTTTTCGAATTCCTTATTATGTTGGTCCATT GGCGCGTGGCAATAGTCGTTTTGCATGGATGACTCGGAAGTCTGAAGAAACAATTACCCCAT GGAATTTTGAAGAAGTTGTCGATAAAGGTGCTTCAGCTCAATCATTTATTGARCGCATGACA AACTTTGATAAARATCTTCCAAATGARAAAGTACTACCAAAACATAGTTTGCTTTATGAGTA TTTTACGGTTTATAACGAATTGACARAGGTCARATATGT TACTGAGGGAATGCGAARACCAG CATTTCTTTCAGGTGAACAGARGAAAGCCATTGTTGATTTACTCTTCAAAACAAATCGAARA GTAACCGTTAAGCAATTAAAAGAAGATTATTTCAAAAARATAGAATGTTTTGATAGTGTTGA AATTTCAGGAGTTGAAGATAGATTTAATGCTTCATTAGGCGCCTACCATGATTTGCTAAARA TTATTAAAGATAARGATTTTTTGGATAATGAAGAAAATGAAGATATCTTAGAGGATATTGTT TTAACATTGACCTTATTTGAAGATAGGGGGATGAT TGAGGAARGACTTARAACATATGCTCA CCTCTTTGATGATAAGGTGATGAAACAGCTTAAACGTCGCCGTTATACTGGTTGGGGACGTT TGTCTCGAAAATTGATTAATGGTAT TAGGGATARGCAATCTGGCAARAACAATATTAGATTTT TTGAAATCAGATGGTTTTGCCAATCGCAATTTTATGCAGCTGATCCATGATGATAGTTTGAC ATTTAAAGAAGATATTCAAAAAGCACAGGTGTCTGGACAAGGCCATAGTTTACATGAACAGA TTGCTAACTTAGCTGGCAGTCCTGCTATTAAAAAAGGTATTTTACAGACTGTAAAAATTGTT GATGAACTGGTCARAGTAATGGGGCATAAGCCAGAAARATATCGTTATTGARATGGCACGTGA AAATCAGACAACTCAAAAGGGCCAGAAAAATTCGCGAGAGCGTATGAAACGAATCGAAGAAG GTATCARAAGAATTAGGAAGTCAGATTCTTAAAGAGCATCCTGTTGAAAATACTCAATTGCAA AATGAAAAGCTCTATCTCTATTATCTACAAAATGGAAGAGACATGTATGTGGACCAAGAATT AGATATTAATCGTTTAAGTGATTATGATGTCGATCACATTGTTCCACAAAGTTTCATTAAAG ACGATTCAATAGACAATAAGGTACTAACGCGTTCTGATAAAAATCGTGGTARATCGGATAAC GTTCCAAGTGAAGAAGTAGTCAAAAAGATGARARACTATTGGAGACAACTTCTAARCGCCAA GTTAATCACTCAACGTAAGTTTGATAATTTAACGAAAGCTGAACGTGGAGGTTTGAGTGAAC TTGATAAAGCTGGTTTTATCAAACGCCAATTGGTTGARACTCGCCAAATCACTAAGCATGTG GCACAAATTTTGGATAGTCGCATGAATACTARATACGATGAARATGATAAACTTATTCGAGA GGTTAAAGTGATTACCTTAAAATCTAAATTAGTTTCTGACTTCCGAAAAGATTTCCAATTCT ATAAAGTACGTGAGATTAACAATTACCATCATGCCCATGATGCGTATCTAAATGCCGTCGTT GGAACTGCTTTGATTAAGAAATATCCAAAACTTGAATCGGAGTTTGTCTATGGTGATTATAA AGTTTATGATGTTCGTAAAATGATTGCTAAGTCTGAGCAAGARATAGGCARAGCARCCGCAA AATATTTCTTTTACTCTAATATCATGAACTTCTTCARAACAGAAATTACACTTGCAAATGGA GAGATTCGCAAACGCCCTCTAATCGARACTAATGGGGARACTGGAGARATTGTCTGGGATAA AGGGCGAGATTTTGCCACAGTGCGCARAGTATTGTCCATGCCCCAAGTCAATATTGTCAAGA AAACAGAAGTACAGACAGGCGGATTCTCCAAGGAGTCAATTTTACCAARAAGARATTCGGAC AAGCTTATTGCTCGTAARAAAGACTGGGATCCAAAARAATATGGTGGTTTTGATAGTCCAAC GGTAGCTTATTCAGTCCTAGTGGTTGCTAAGGTGGAARAAGGGARAATCGAAGAAGTTAARAT CCGTTARAGAGTTACTAGGGATCACAATTATGGAARGAAGTTCCTTTGARAAAAATCCGATT GACTTTTTAGAAGCTARAGGATATAAGGAAGT TAAAARAGACTTAATCATTARACTACCTAA ATATAGTCTTTTTGAGTTAGAARACGGTCGTAAACGGATGCTGGCTAGTGCCGGAGAATTAC AAAAAGGAAATGAGCTGGCTCTGCCAAGCAAATATGTGAATTTTTTATATTTAGCTAGTCAT TATGAAAAGT TGAAGGGTAGTCCAGAAGATAACGAACAAAAACAATTGTTTGTGGAGCAGCA TAAGCATTATTTAGATGAGATTATTGAGCAAATCAGTGAATTTTCTAAGCGTGTTATTTTAG CAGATGCCAATTTAGATARAGTTCTTAGTGCATATAACAARCATAGAGACARACCAATACGT GAACAAGCAGARAATATTATTCATTTATTTACGTTGACGAATCTTGGAGCTCCCGCTGCTTT TAAATATTTTGATACAACARATTGATCGTARACGATATACGTCTACAARAGAAGTTTTAGATG CCACTCTTATCCATCAATCCATCACTGGTCTTTATGAAACACGCATTGATTTGAGTCAGCTA GCACGCTCACTGA: MDKKYSIGLDIGTNSVGWAVITDDYKVPSKKFKVLGNTDRHSIKKNLIGALLFGSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLADS TDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEI QLVQIYNQLFEENPINASRVDAKAILSARLSKSRRLENLIAQLPGEKRNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNS EITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGAYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDRGMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGHSLHEQIANTLAGSPATKKGILQTVKIV DELVKVMGHKPENIVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQLQ NEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFIKDDS IDNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKL ITQRKFDNLTKAERGGLSELDKAGE IKROLVETRQITKHV AQTTL.DSRMNTKYDENDKL IREVKVITLKSKIVSDFRKDFQFYKVRE INNYHHAHDAYTL.NAVV GTALIKKYPKIESEFVYGDYKVYDVRKMIAKSEQE IGKATAKYFFYSNIMNEFFKTE ITLANG EIRKRPLIETNGETGEIVWDKGRDFATVRRVI.SMPOVNIVKKTEVOTGGFSKESILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH YEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL GGD (single underline: HNH domain; double underline: RuvC domain) In some embodiments, wild-type Cas9 corresponds to, or comprises the following nucleotide and / or amino acid sequences: ATGGATAAAAAGTATTCTATTGGTTTAGACATCGGCACTAATTCCGTTGGATGGGCTGTCAT AACCGATGAATACAAAGTACCTTCAAAGAAATTTAAGGTGTTGGGGAACACAGACCGTCATT CGATTAAARAGAATCTTATCGGTGCCCTCCTATTCGATAGTGGCGARACGGCAGAGGCGACT CGCCTGAAACGAACCGCTCGGAGAAGGTATACACGTCGCAAGAACCGAATATGTTACTTACA AGAAATTTTTAGCAATGAGATGGCCAAAGTTGACGATTCTTTCTTTCACCGTTTGGAAGAGT CCTTCCTTGTCGAAGAGGACAAGAAACATGAACGGCACCCCATCTTTGGARACATAGTAGAT GAGGTGGCATATCATGAARAGTACCCAACGATTTATCACCTCAGARARARGCTAGTTGACTC AACTGATAAAGCGGACCTGAGGTTAATCTACTTGGCTCTTGCCCATATGATAAAGTTCCGTG GGCACTTTCTCATTGAGGGTGATCTARATCCGGACRACTCGGATGTCGACARACTGTTCATC CAGTTAGTACAAACCTATAATCAGTTGTTTGAAGAGAACCCTATAAATGCAAGTGGCGTGGA TGCGAAGGCTATTCTTAGCGCCCGCCTCTCTAAATCCCGACGGCTAGARAACCTGATCGCAC AAT TACCCGGAGAGARAGARARAATGGGTIGT TCGGTARCCTTATAGCGCTCTCACTAGGCCTG ACACCAAATTTTAAGTCGAACTTCGACTTAGCTGAAGATGCCAARATTGCAGCTTAGTAAGGA CACGTACGATGACGATCTCGACAATCTACTGGCACAAATTGGAGATCAGTATGCGGACTTAT TTTTGGCTGCCAARAACCTTAGCGATGCAATCCTCCTATCTGACATACTGAGAGTTAATACT GAGATTACCAAGGCGCCGTTATCCGCTTCAATGATCAAAAGGTACGATGAACATCACCAAGA CTTGACACTTCTCAAGGCCCTAGTCCGTCAGCAACTGCCTGAGAAATATAAGGARATATTCT TTGATCAGTCGAAAAACGGGTACGCAGGTTATATTGACGGCGGAGCGAGTCAAGAGGAATTC TACAAGTTTATCARACCCATATTAGAGARAGATGGATGGGACGGAAGAGTTGCTTGTAAAACT CAATCGCGAAGATCTACTGCGAAAGCAGCGGACTTTCGACAACGGTAGCATTCCACATCARA TCCACTTAGGCGAATTGCATGCTATACTTAGAAGGCAGGAGGATTTTTATCCGTTCCTCAAA GACAATCGTGAAAAGATTGAGARARATCCTAACCTTTCGCATACCTTACTATGTGGGACCCCT GGCCCGAGGGAACTCTCGGTTCGCATGGATGACAAGAAAGTCCGAAGAAACGATTACTCCAT GGAATTTTGAGGAAGTTGTCGATAAAGGTGCGTCAGCTCAATCGTTCATCGAGAGGATGACC AACTTTGACAAGAATTTACCGAACGARAAAGTATTGCCTAAGCACAGTTTACTTTACGAGTA TTTCACAGTGTACAATGAACTCACGAAAGT TAARGTATGTCACTGAGGGCATGCGTARACCCG CCTTTCTAAGCGGAGAACAGARGAAAGCAATAGTAGATCTGTTATTCAAGACCAACCGCARA GTGACAGTTAAGCAATTGAAAGAGGACTACTTTAAGARAATTGAATGCTTCGATTCTGTCGA GATCTCCGGGGTAGAAGATCGATTTAATGCGTCACTTGGTACGTATCATGACCTCCTAAAGA TAATTAAAGATAAGGACTTCCTGGATAACGAAGAGAATGAAGATATCTTAGAAGATATAGTG TTGACTCTTACCCTCTTTGAAGATCGGGAAATGAT TGAGGAARGACTAAAAACATACGCTCA CCTGTTCGACGATAAGGTTATGARACAGTTARAAGAGGCGTCGCTATACGGGCTGGGGACGAT TGTCGCGGAAACTTATCAACGGGATAAGAGACARGCAARGTGGTAAAACTATTCTCGATTTT CTARAGAGCGACGGCTTCGCCAATAGGAACTTTATGCAGCTGATCCATGATGACTCTTTAAC CTTCAARAGAGGATATACAAAAGGCACAGGTTTCCGGACAAGGGGACTCATTGCACGAACATA TTGCGAATCTTGCTGGTTCGCCAGCCATCAAARAGGGCATACTCCAGACAGTCAAAGTAGTG GATGAGCTAGTTAAGGTCATGGGACGTCACARACCGGAAARCATTGTAATCGAGATGGCACG CGAAAATCAAACGACTCAGAAGGGGCAAAARAACAGTCGAGAGCGGATGARGAGAATAGAAG AGGGTATTARAGAACTGGGCAGCCAGATCTTARAGGAGCATCCTGTGGARAATACCCAATTG CAGAACGAGAAACTTTACCTCTATTACCTACAAAATGGAAGGGACATGTATGTTGATCAGGA ACTGGACATAAACCGTTTATCTGATTACGACGTCGATCACATTGTACCCCAATCCTTTTTGA AGGACGATTCAATCGACAATAARGTGCTTACACGCTCGGATAAGAACCGAGGGAAAAGTGAC AATGTTCCAAGCGAGGARGTCGTAARAGAAARATGAAGAACTATTGGCGGCAGCTCCTAAATGC GAAACTGATAACGCAAAGAAAGTTCGATAACTTAACTAAAGCTGAGAGGGGTGGCTTGTCTG AACTTGACAAGGCCGGATTTATTARACGTCAGCTCGTGGAARCCCGCCARATCACARAGCAT GTTGCACAGATACTAGAT TCCCGAATGAATACGAAATACGACGAGAACGATAAGCTGATTCG GGAAGTCAAAGTAATCACTTTAAAGTCAAAATTGGTGTCGGACTTCAGAAAGGATTTTCAAT TCTATAAAGTTAGGGAGATARATAACTACCACCATGCGCACGACGCTTATCTTAATGCCGTC GTAGGGACCGCACTCATTAAGAAATACCCGAAGCTAGARAGTGAGTTTGTGTATGGTGATTA CAAAGTTTATGACGTCCGTAAGATGATCGCGARAAGCGAACAGGAGATAGGCAAGGCTACAG CCAAATACTTCTTTTATTCTAACATTATGAATTTCTTTAAGACGGAAATCACTCTGGCARAC GGAGAGATACGCARACGACCTTTAATTGAAACCAATGGGGAGACAGGTGARATCGTATGGGA TAAGGGCCGGGACTTCGCGACGGTGAGAAAAGTTTTGTCCATGCCCCAAGTCAACATAGTAA AGAARACTGAGGTGCAGACCGGAGGGTTTTCAAAGGAATCGATTCTTCCAARAAGGAATAGT GATAAGCTCATCGCTCGTAAARAGGACTGGGACCCGAAAARGTACGGTGGCTTCGATAGCCC TACAGTTGCCTATTCTGTCCTAGTAGTGGCAARAGTTGAGAAGGGAARATCCAAGAAACTGA AGTCAGTCAAAGAATTATTGGGGATAACGATTATGGAGCGCTCGTCTTTTGAAAAGAACCCC ATCGACTTCCTTGAGGCGARAGGT TACAAGGAAGTAAARAAGGATCTCATAATTAAACTACC AAAGTATAGTCTGTTTGAGT TAGAAAATGGCCGAAARCGGATGTTGGCTAGCGCCGGAGAGC TTCAARAGGGGAACGAACTCGCACTACCGTCTARATACGTGAATTTCCTGTATTTAGCGTCC CATTACGAGAAGTTGARAGGTTCACCTGAAGATAACGAACAGAAGCAACTTTTTGTTGAGCA GCACAAACATTATCTCGACGARATCATAGAGCAAATTTCGGAATTCAGTAAGAGAGTCATCC TAGCTGATGCCAATCTGGACAAAGTATTAAGCGCATACAACARGCACAGGGATAAACCCATA CGTGAGCAGGCGGAAAATATTATCCATTTGTTTACTCTTACCAACCTCGGCGCTCCAGCCGC ATTCAAGTATTTTGACACAACGATAGATCGCARACGATACACTTCTACCAAGGAGGTGCTAG ACGCGACACTGATTCACCAATCCATCACGGGATTATATGAAACTCGGATAGATTTGTCACAG CTTGGGGGTGACGGATCCCCCAAGAAGAAGAGGAAAGTCTCGAGCGACTACARAGACCATGA CCC TCA TAT ARNG TCATGACATC GAT TAC A GG A IGA CAT AC AA GGOTCUAGEN. MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVIGNTDRHSIKKNL IGALLFDSGETAREAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLET QLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNT EITKAPLSASMIKRYDEHHQDLTLLKALVRQQOLPEKYKEIFFDQSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDREMIEERLKTYAHLFDDKVMKOLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGS PATKKGILQTVKVV DELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQL ONEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDS IDNKVLTRSDKNRGKSD NVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQIVETRQITKH VAQILDSRMNTKYDENDKL IREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAV VGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQE IGKATAKYFFYSNIMNFFKTEITLAN GEIRKRPLIETNGETGE IVWDKGRDFATVRKVLSMPOVNIVKKTEVOTGGFSKESILPKRNS DKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNP IDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLAS HYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPI REQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQ 1.Ggeh (single underline: HNH domain; double underline: RuvC domain) In some embodiments, wild-type Cas9 corresponds to Cas9 from Streptococcus pyogenes (NCBI Reference Sequence: NC_002737.2 (nucleotide sequence as follows); and Uniprot Reference Sequence: Q99ZW?2 (amino acid sequence as follows). ATGGATAAGAAATACTCAATAGGCTTAGATATCGGCACARATAGCGTCGGATGGGCGGTGAT CACTGATGAATATAAGGTTCCGTCTARAAAGTTCAAGGTTCTGGGAAATACAGACCGCCACA GTATCAAARAARATCTTATAGGGGCTCTTTTATTTGACAGTGGAGAGACAGCGGAAGCGACT CGTCTCAAACGGACAGCTCGTAGAAGGTATACACGTCGGARAGAATCGTATTTGTTATCTACA GGAGATTTTTTCARATGAGATGGCGARAGTAGATGATAGTTTCTTTCATCGACTTGAAGAGT CTTTTTTGGTGGAAGAAGACAAGAAGCATGAACGTCATCCTATTTTTGGARATATAGTAGAT GAAGTTGCTTATCATGAGAAATATCCAACTATCTATCATCTGCGARARARATTGGTAGATTC TACTGATARAGCGGATTTGCGCTTAATCTATTTGGCCTTAGCGCATATGATTAAGTTTCGTG GTCATTTTTTGATTGAGGGAGATTTARATCCTGATAATAGTGATGTGGACARACTATTTATC CAGTTGGTACARACCTACAATCAATTATTTGAAGAAAACCCTATTAACGCAAGTGGAGTAGA TGCTAAAGCGATTCTTTCTGCACGATTGAGTAAATCAAGACGATTAGARAATCTCATTGCTC AGCTCCCCGGTGAGAAGAARAATGGCTTATTTGGGAATCTCATTGCTTTGTCATTGGGTTTG ACCCCTAATTTTAAATCAAATTTTGATTTGGCAGAAGATGCTAAATTACAGCTTTCAAAAGA TACTTACGATGATGATTTAGATAATTTATTGGCGCAAATTGGAGATCAATATGCTGATTTGT TTTTGGCAGCTAAGAATTTATCAGATGCTATTTTACTTTCAGATATCCTAAGAGTAAATACT GAAATAACTAAGGCTCCCCTATCAGCTTCAATGATTAAACGCTACGATGARCATCATCAAGA CTTGACTCTTTTAAAAGCTTTAGTTCGACAACAACTTCCAGAAAAGTATAAAGAAATCTTTT TTCATCAATCAAARAAMCGECATATCGC AGG IT TATATTGATGGGGGAGC TAGC CAR AAGAATTT TATAAATTTATCARACCAATTTTAGAAARAATGGATGGTACTGAGGAATTATTGGTGAAACT AAATCGTGAAGATTTGCTGCGCAAGCAACGGACCTTTGACAACGGCTCTATTCCCCATCARA TTCACTTGGGTGAGCTGCATGCTATTTTGAGAAGACARGAAGACTTTTATCCATTTTTAAAA GACAATCGTGAGAAGATTGAAAAAATCTTGACTTTTCGAATTCCTTATTATGTTGGTCCATT GGCGCGTGGCAATAGTCGTTTTGCATGGATGACTCGGAAGTCTGAAGAAACAATTACCCCAT GGAATTTTGAAGAAGTTGTCGATAAAGGTGCTTCAGCTCAATCATTTATTGAACGCATGACA AACTTTGATAAARATCTTCCAAATGARAAAGTACTACCAAAACATAGTTTGCTTTATGAGTA TTTTACGGTTTATAACGAATTGACAARAGGTCARATATGT TACTGAAGGAATGCGAARACCAG CATTTCTTTCAGGTGAACAGARGAAAGCCATTGTTGATTTACTCTTCAAARCAAATCGAARA GTAACCGTTAAGCAATTARAAGAAGATTATTTCAAAARAATAGAATGTTTTGATAGTGTTGA AATTTCAGGAGTTGAAGATAGATTTAATGCTTCATTAGGTACCTACCATGATTTGCTAAARA TTATTAAAGATAAAGATTTTTTGGATAATGAAGAARATGAAGATATCTTAGAGGATATTGTT TTAACATTGACCTTATTTGAAGATAGGGAGATGAT TGAGGAARGACTTAAAACATATGCTCA CCTCTTTGATGATAAGGTGATGARACAGCTTARACGTCGCCGTTATACTGGTTGGGGACGTT TGTCTCGARAATTGATTAATGGTATTAGGGATARGCAATCTGGCAAAACAATATTAGATTTT TTGAAATCAGATGGTTTTGCCAATCGCAATTTTATGCAGCTGATCCATGATGATAGTTTGAC ATTTAAAGAAGACATTCAAAAAGCACAAGTGTCTGGACAAGGCGATAGTTTACATGAACATA TTGCARATTTAGCTGGTAGCCCTGCTAT TARAARAGGTATTTTACAGACTGTARRAGTTGTT GATGAATTGGTCAAAGTAATGGGGCGGCATAAGCCAGAAAATATCGTTATTGAAATGGCACG TGAAAATCAGACARCTCARAAGGGCCAGARAAATTCGCGAGAGCGTATGAARCGAATCGAAG AAGGTATCAAAGAATTAGGAAGTCAGATTCTTAAAGAGCATCCTGTTGAAAATACTCAATTG CAARATGARAAGCTCTATCTCTATTATCTCCAARATGGAAGAGACATGTATGTGGACCAAGA ATTAGATATTAATCGTTTAAGTGATTATGATGTCGATCACATTGTTCCACAAAGTTTCCTTA AAGACGATTCAATAGACAATAAGGTCTTAACGCGTTCTGATAAAAATCGTGGTAAATCGGAT AACGTTCCAAGTGAAGAAGTAGTCAAARAGATGARARACTATTGGAGACAACTTCTAAACGC CAAGTTAATCACTCAACGTAAGTTTGATAATTTAACGAAAGCTGARCGTGGAGGTTTGAGTG AACTTGATARAGCTGGTTTTATCARACGCCAATTGGTTGAARCTCGCCARATCACTAAGCAT GTGGCACAAATTTTGGATAGTCGCATGAATACTAAATACGATGAARATGATAAACTTATTCG AGAGGTTAAAGTGATTACCTTARAATCTARATTAGTTTCTGACTTCCGARARGATTTCCAAT TCTATAAAGTACGTGAGATTAACAATTACCATCATGCCCATGATGCGTATCTARATGCCGTC GTTGGAACTGCTTTGATTAAGAAATATCCAARACTTGAATCGGAGTTTGTCTATGGTGATTA TAAAGTTTATGATGTTCGTAAAATGATTGCTAAGTCTGAGCARGAAATAGGCAAAGCAACCG CAAAATATTTCTTTTACTCTAATATCATGAARCTTCTTCAARACAGAAATTACACTTGCARAT GGAGAGATTCGCAAACGC CC IC TAA TCGAAAC TAA TGGGGAAACTGGAGAAATTGTCTGGGA TAAAGGGCGAGATTTTGCCACAGTGCGCAAAGTATTGTCCATGCCCCAAGTCAATATTGTCA AGAARACAGAAGTACAGACAGGCGGATTCTCCAAGGAGTCAATTTTACCAAAAAGARATTCG GACAAGCTTATTGCTCGTAAARAAGACTGGGATCCAAAAARATATGGTGGTTTTGATAGTCC AACGGTAGCTTATTCAGTCCTAGTGGTTGCTAAGGTGGAAAAAGGGARATCGAAGAAGTTAA AATCCGTTAAAGAGTTACTAGGGATCACAATTATGGARAGAAGTTCCTTTGAAAAARATCCG ATTGACTTTTTAGAAGCTARAGGATATAAGGAAGTTAAAAAAGACTTAATCATTAAACTACC TAAATATAGTCTTTTTGAGT TAGAAAACGGTCGTAAACGGATGCTGGCTAGTGCCGGAGAAT TACAARAAGGAAATGAGCTGGCTCTGCCAAGCARATATGTGAATTTTTTATATTTAGCTAGT CATTATGAAAAGT TGAAGGGTAGTCCAGAAGATAACGAACAAAAACAATTGTTTGTGGAGCA GCATAAGCATTATTTAGATGAGATTATTGAGCAAATCAGTGAATTTTCTAAGCGTGTTATTT TAGCAGATGCCAATTTAGATAAAGTTCTTAGTGCATATAACARACATAGAGACAAACCAATA CGTGAACAAGCAGAAAATATTATTCATTTATTTACGT TGACGRATCTTGGAGCTCCCGCTGC TTTTAAATATTTTGATACAACAATTGATCGTARACGATATACGTCTACAAAAGAAGTTTTAG ATGCCACTCTTATCCATCAATCCATCACTGGTCTTTATGAAACACGCATTGATTTGAGTCAG CTAGGAGCGTGACTGA MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHS IKKNL IGALLFDSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLET QLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNT EITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VIVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGS PATKKGILOTVKVV DELVKVMGRHKPENIVIEMARENQTTOQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQL ONEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDS IDNKVLTRSDKNRGKSD NVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQIVETRQITKH VAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAV VGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQE IGKATAKYFFYSNIMNFFKTEITLAN GEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNS DKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNP IDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLAS HYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPI REQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQ GGD (SEQ ID NO: 1) (single underline: HNH domain; double underline: RuvC domain) In some embodiments, Cas9 refers to Cas9 from: Corynebacterium ulcerans (NCBI Refs: NC_015683.1, NC_017317.1); Corynebacterium diphtheria (NCBI Refs: NC_016782.1, NC_016786.1); Spiroplasma syrphidicola (NCBI Ref: NC_021284.1); Prevotella intermedia (NCBI Ref: NC_017861.1); Spiroplasma taiwanense (NCBI Ref: NC_021846.1); Streptococcus iniae (NCBI Ref: NC_021314.1); Belliella baltica (NCBI Ref: NC_018010.1); Psychroflexus torquisI (NCBI Ref: NC_018721.1); Streptococcus thermophilus (NCBI Ref: YP_820832.1), Listeria innocua (NCBI Ref: NP_472073.1), Campylobacter jejuni (NCBI Ref: YP_002344900.1) or Neisseria meningitidis (NCBI Ref: YP 002342100.1) or to a Cas9 from any other organism. In some embodiments, dCas9 corresponds to, or comprises in part or in whole, a Cas9 amino acid sequence having one or more mutations that inactivate the Cas9 nuclease activity. For example, in some embodiments, a dCas9 domain comprises D10A and an H840A mutation as numbered in SEQ ID NO: 1 or corresponding mutations in another Cas9. In some embodiments, the dCas9 comprises the amino acid sequence of dCas9 (D10A and HS40A): MDKKYSIGLAIGTNSVGWAVITDEYRVPSKKFKVLGNTDRHSTKKNTL IGATLFDSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFI QLVQTYNQLFEENP INASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNT EITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDOSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRY TGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVV DELVKVMGRHKPENIVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQL ONEKLYLYYLONGRDMYVDQELDINRLSDYDVDAIVPQSFLKDDS IDNKVLTRSDKNRGKSD NVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQIVETRQITKH VAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAV VGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQE IGKATAKYFFYSNIMNFEFKTEITLAN GEIRKRPLIETNGETGE IVWDKGRDFATVRKVL.SMPQVNIVKKTEVQTGGFSKESILPKRNS DKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNP IDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLAS HYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPI REQAENITHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQ LGGD (single underline: HNH domain; double underline: RuvC domain). In some embodiments, the Cas9 domain comprises a D10A mutation, while the residue at position 840 remains a histidine in the amino acid sequence provided above, or at corresponding positions in any of the amino acid sequences provided herein. In other embodiments, dCas9 variants having mutations other than D10A and H840A are provided, which, e.g., result in nuclease inactivated Cas9 (dCas9). Such mutations, by way of example, include other amino acid substitutions at D10 and H840, or other substitutions within the nuclease domains of Cas9 (e.g., substitutions in the HNH nuclease subdomain and / or the RuvC1 subdomain). In some embodiments, variants or homologues of dCas9 are provided which are at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical. In some embodiments, variants of dCas9 are provided having amino acid sequences which are shorter, or longer, by about 5 amino acids, by about 10 amino acids, by about 15 amino acids, by about 20 amino acids, by about 25 amino acids, by about 30 amino acids, by about 40 amino acids, by about 50 amino acids, by about 75 amino acids, by about 100 amino acids or more. In some embodiments, Cas9 fusion proteins as provided herein comprise the full- length amino acid sequence of a Cas9 protein, e.g., one of the Cas9 sequences provided herein. In other embodiments, however, fusion proteins as provided herein do not comprise a full-length Cas9 sequence, but only one or more fragments thereof. Exemplary amino acid sequences of suitable Cas9 domains and Cas9 fragments are provided herein, and additional suitable sequences of Cas9 domains and fragments will be apparent to those of skill in the art. It should be appreciated that additional Cas9 proteins (e.g., a nuclease dead Cas9 (dCas9), a Cas9 nickase (nCas9), or a nuclease active Cas9), including variants and homologs thereof, are within the scope of this disclosure. Exemplary Cas9 proteins include, without limitation, those provided below. In some embodiments, the Cas9 protein is a nuclease dead Cas9 (dCas9). In some embodiments, the Cas9 protein is a Cas9 nickase (nCas9). In some embodiments, the Cas9 protein is a nuclease active Cas9. Exemplary catalytically inactive Cas9 (dCas9): DKKYSIGLAIGINSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATR LKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDE VAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEFIQ LVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLT PNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAARKNLSDAILLSDILRVNTE ITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFY KFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKD NREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTN FDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKV TVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKI IKDKDFLDNEENEDILEDIVL TLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRY TGWGRLSRKLINGIRDKQSGKTILDEFL KSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPATIKKGILQTVKVVD ELVKVMGRHKPENIVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQLQ NEKLYLYYLONGRDMYVDQELDINRLSDYDVDAIVPQSFLKDDS IDNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGEF IKRQLVETRQITKHV AQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVV GTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANG EIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH YEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL CCD Exemplary catalytically Cas9 nickase (nCas9): DKKYSIGLAIGINSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATR LKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDE VAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQ LVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLT PNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLARKNLSDAILLSDILRVNTE ITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFY KFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKD NREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTN FDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKV TVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVL TLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRY TGWGRLSRKLINGIRDKQSGKTILDFL KSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVD ELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQ NEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGF IKRQLVETRQITKHV AQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAVV GTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANG EIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH YEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL GGD Exemplary catalytically active Cas9: DKKYSIGLDIGINSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATR LKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDE VAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEFIQ LVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLT PNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLARKNLSDAILLSDILRVNTE ITKAPLSASMIKRYDEHHQDLTLLKALVRQQOLPEKYKEIFFDQSKNGYAGYIDGGASQEEFY KFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKD NREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTN FDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKV TVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVL TLTLFEDREMIEERLKTYAHLFDDKVMKQOLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFL KSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVD ELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQ NEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHV AQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAVV GTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANG EIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH YEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL CGD. In some embodiments, Cas9 refers to a Cas9 from archaea (e.g, nanoarchaea), which constitute a domain and kingdom of single-celled prokaryotic microbes. In some embodiments, Cas9 refers to CasX or CasY, which have been described in, for example, Burstein ef al., "New CRISPR-Cas systems from uncultivated microbes." Cell Res. 2017 Feb 21. doi: 10.1038 / cr.2017.21, the entire contents of which is hereby incorporated by reference. Using genome-resolved metagenomics, a number of CRISPR-Cas systems were identified, including the first reported Cas9 in the archaeal domain of life. This divergent Cas9 protein was found in little- studied nanoarchaea as part of an active CRISPR-Cas system. In bacteria, two previously unknown systems were discovered, CRISPR-CasX and CRISPR-CasY, which are among the most compact systems yet discovered. In some embodiments, Cas9 refers to CasX, or a variant of CasX. In some embodiments, Cas9 refers to a CasY, or a variant of CasY. It should be appreciated that other RNA-guided DNA binding proteins may be used as a nucleic acid programmable DNA binding protein (napDNAbp), and are within the scope of this disclosure. In particular embodiments, napDNAbps useful in the methods of the invention include circular permutants, which are known in the art and described, for example, by Oakes etal., Cell 176, 254-267, 2019. An exemplary circular permutant follows where the bold sequence indicates sequence derived from Cas, the italics sequence denotes a linker sequence, and the underlined sequence denotes a bipartite nuclear localization sequence, CP5 (with MSP “NGC=Pam Variant with mutations Regular Cas9 likes NGG” PID=Protein Interacting Domain and “D10A” nickase): EIGKATAKYFFYSNIMNFFKTE I TLANGE IRKRPLIE TNGE TGE IVWDKGRDFATVRKVLSM PQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWD PKKYGGFMQPTVAYSVLVVAKVEK GKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLI IKLPKYSLFELENGRKRM LASAKFLOKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISE FSKRVILADANLDKVLSAYNKHRDKPIREQAENIITHLFTLTNLGAPRAFKYFDTTIARKEYR STKEVLDATLIHQSITGLYE TRIDLSQLGGDGGSGGSGGSGGSGGSGGSGGMDKKYSIGLAT GTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGE TAEATRLKRTARRRYT RRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTI YHLRKKLVDS TDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEFIQLVQTYNQLFE ENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLA EDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTE ITKAPLSASM IKRYDEHHQDLTLLKALVRQQLPEKYKE IFFDQSKNGYAGY IDGGASQEEFYKFIKPILEKM DGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGE LHAILRRQEDFYPFLKDNREKIEKILT FRIPYYVGPLARGNSRFAWMTRKSEE TI TPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKV LPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYF KKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREM IEERLKTYAHLFDDKVMKQLKRRRY TGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNF MQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDE LVKVMGRHK PENIVIEMARENQTTQKGOKNSRERMKRIEEGIKE LGSQILKEHPVENTQLONEKLYLYYLQ NGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKM KNYWRQLLNAKLI TQRKFDNLTKAERGGLSE LDKAGF IKRQLVE TRQI TKHVAQILDSRMNT KYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYILNAVVGTALIKKYPK LESEFVYGDYKVYDVRKMIAKSEQEGADKRTADGSEFESPKKKRKV* Non-limiting examples of a polynucleotide programmable nucleotide binding domain which can be incorporated into a base editor include a CRISPR protein-derived domain, a restriction nuclease, a meganuclease, TAL nuclease (TALEN), and a zinc finger nuclease (ZEN). In some embodiments, the nucleic acid programmable DNA binding protein (napDNAbp) of any of the fusion proteins provided herein may be a CasX or CasY protein. In some embodiments, the napDNADbp is a CasX protein. In some embodiments, the napDNAbp is a CasY protein. In some embodiments, the napDNAbp comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at ease 99.5% identical to a naturally-occurring CasX or CasY protein. In some embodiments, the napDNADbp is a naturally-occurring CasX or CasY protein. In some embodiments, the napDNAbp comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at ease 99.5% identical to any CasX or CasY protein described herein. It should be appreciated that Cas12b / C2cl1, CasX and CasY from other bacterial species may also be used in accordance with the present disclosure. Cas12b / C2c1 (uniprot.org / uniprot / TOD7A2#2) sp|TOD7A2|C2C1_ALIAG CRISPR-associated endo- nuclease C2cl OS = Alicyclobacillus acido- terrestris (strain ATCC 49025 / DSM 3922 / CIP 106132 / NCIMB 13137 / GD3B) GN=c2c1 PE=1 SV=1 MAVKSIKVKLRLDDMPEIRAGLWKLHKEVNAGVRYYTEWLSLLRQENLYRRSPNGDGEQECD KTAEECKAELLERLRARQVENGHRGPAGSDDELLQLARQLYELLVPQAIGAKGDAQQIARKE LSPLADKDAVGGLGIAKAGNKPRWVRMREAGEPGWEEEKEKAETRKSADRTADVLRALADFG LKPLMRVYTDSEMSSVEWKPLRKGQAVRTWDRDMFQQATIERMMSWESWNQRVGQEYAKLVEQ KNRFEQKNFVGQEHLVHLVNQLOQDMKEASPGLESKEQTAHYVTGRALRGSDKVFEKWGKLA PDAPFDLYDAEIKNVQRRNTRRFGSHDLFAKLAEPEYQALWREDASFLTRYAVYNSILRKLN HAKMFATFTLPDATAHPIWTRFDKLGGNLHQYTFLFNEFGERRHAIRFHKLLKVENGVAREV DDVTVPISMSEQLDNLLPRDPNEPIALYFRDYGAEQHFTGEFGGAKIQCRRDQLAHMHRRRG ARDVYLNVSVRVQSQSEARGERRPPYAARVFRLVGDNHRAFVHFDKLSDYLAEHPDDGKLGSE GLLSGLRVMSVDLGLRTSASISVFRVARKDELKPNSKGRVPFFFPIKGNDNLVAVHERSQLL KLPGETESKDLRATIREERQRTLRQLRTQLAYLRLLVRCGSEDVGRRERSWAKLIEQPVDAAN HMTPDWREAFENELQKLKSLHGICSDKEWMDAVYESVRRVWRHMGKQVRDWRKDVRSGERPK IRGYAKDVVGGNSIEQIEYLERQYKFLKSWSFFGKVSGQVIRAEKGSRFAITLREHIDHAKE DRLKKLADRIIMEALGYVYALDERGKGKWVAKYPPCQLILLEELSEYQFNNDRPPSENNQLM QWSHRGVFQELINQAQVHDLLVGTMYAAFSSRFDARTGAPGIRCRRVPARCTQEHNPEPFPW WLNKFVVEHTLDACPLRADDLIPTGEGEIFVSPFSAEEGDFHQIHADLNARQNLQQORLWSDF DISQIRLRCDWGEVDGELVLIPRLTGKRTADSYSNKVEYTNTGVTYYERERGKKRRKVFAQE KLSEEEAELLVEADEAREKSVVLMRDPSGIINRGNWTRQKEFWSMV NQRIEGYLVKQIRSR VPLQODSACENTGDI CasX (uniprot.org / uniprot / FONNS87; uniprot.org / uniprot / FONH53) >tr[FONN87|[FONN87_SULIH CRISPR-associated Casx protein OS = Sulfolobus islandicus (strain HVE10 / 4) GN = SiH 0402 PE=4 SV=1 MEVPLYNIFGDNYIIQVATEAENSTIYNNKVEIDDEELRNVLNLAYKIAKNNEDAAAERRGK AKKKKGEEGETTTSNIILPLSGNDKNPWTETLKCYNFPTTVALSEVFKNFSQVKECEEVSAP SFVKPEFYEFGRSPGMVERTRRVKLEVEPHYLIIAAAGWVLTRLGKAKVSEGDYVGVNVETP TRGILYSLIQONVNGIVPGIKPETAFGLWIARKVVSSVINPNVSVVRIYTISDAVGONPTTIN GGFSIDLTKLLEKRYLLSERLEAIARNALSISSNMRERYIVLANYIYEYLTG SKRLEDLLY FANRDLIMNLNSDDGKVRDLKLISAYVNGELIRGEG >tr[FONHS3[FONH53_SULIR CRISPR associated protein, Casx OS = Sulfolobus islandicus (strain REY15A) GN=SiRe 0771 PE=4 SV=1 MEVPLYNIFGDNYIIQVATEAENSTIYNNKVEIDDEELRNVLNLAYKIAKNNEDAAAERRGK AKKKKGEEGETTTSNIILPLSGNDKNPWTETLKCYNFPTTVALSEVFKNFSQVKECEEVSAP SFVKPEFYKFGRSPGMVERTRRVKLEVEPHYLIMARAGWVLTRLGKAKVSEGDYVGVNVETP TRGILYSLIQNVNGIVPGIKPETAFGLWIARKVVSSVINPNVSVVSIYTISDAVGONPTTIN GGFSIDLTKLLEKRDLLSERLEATARNALSISSNMRERYIVLANYIYEYLTGSKRLEDLLYF ANRDLIMNLNSDDGKVRDLKLISAYVNGELIRGEG Deltaproteobacteria CasX MEKRINKIRKKLSADNATKPVSRSGPMKTLLVRVMTDDLKKRLEKRRKKPEVMPQVISNNAA NNLRMLLDDYTKMKEAILQVYWQEFKDDHVGLMCKFAQPASKKIDONKLKPEMDEKGNLTTA GFACSQCGQPLFVYKLEQVSEKGKAYTNYFGRCNVAEHEKLILLAQLKPVKDSDEAVTYSLG KFGQRALDFYSIHVTKESTHPVKPLAQIAGNRYASGPVGKALSDACMGTIASFLSKYQDIIT EHQKVVKGNQKRLESLRELAGKENLEYPSVTLPPQPHTKEGVDAYNEVIARVRMWVNLNLWQ KLKLSRDDAKPLLRLKGFPSFPVVERRENEVDWWNT INEVKKL IDAKRDMGRVEWSGVTAEK RNTILEGYNYLPNENDHKKREGSLENPKKPAKRQFGDLLLYLEKKYAGDWGKVFDEAWERID KKIAGLTSHIEREEARNAEDAQSKAVLTDWLRAKASFVLERLKEMDEKEFYACEIQLQKWYG DLRGNPFAVEAENRVVDISGFSIGSDGHS IQYRNLLAWKYLENGKREFYLLMNYGKKGRIRF TDGTDIKKSGKWQGLLYGGGKAKVIDLTFDPDDEQLIILPLAFGTRQGREFIWNDLLSLETG LIKLANGRVIEKTIYNKKIGRDEPALFVALTFERREVVDPSNIKPVNLIGVARGENIPAVIA LTDPEGCPLPEFKDSSGGPTDILRIGEGYKEKQRAIQAAKEVEQRRAGGY SRKFASKSRNLA DDMVRNSARDLFYHAVTHDAVLVFANLSRGFGRQGKRTFMTERQY TKMEDWLTAKLAYEGLT SKTYLSKTLAQYTSKTCSNCGFTITYADMDVMLVRLKKTSDGWATTLNNKELKAEYQITYYN RYKRQTVEKELSAELDRLSEESGNNDISKWTKGRRDEALFLLKKRFSHRPVQEQFVCLDCGH EVHAAEQAALNIARSWLEFLNSNSTEFKSYKSGKOPEVGAWQAFYKRRLKEVWKPNA CasY (ncbi.nlm.nih.gov / protein / APG80656.1) >APG80656.1 CRISPR-associated protein CasY [uncultured Parcubacteria group bacterium] MSKRHPRISGVKGYRLHAQRLEYTGKSGAMRTIKYPLYSSPSGGRTVPREIVSAINDDYVGL YGLSNFDDLYNAEKRNEEKVYSVLDFWYDCVQYGAVFSYTAPGLLKNVAEVRGGSYELTKTL KGSHLYDELQIDKVIKFLNKKEISRANGSLDKLKKDI IDCFKAEYRERHKDQCNKLADDIKN AKKDAGASLGERQKKLFRDFFGISEQSENDKPSFTNPLNLTCCLLPFDTVNNNRNRGEVLEN KLKEYAQKLDKNEGSLEMWEYIGIGNSGTAFSNFLGEGFLGRLRENKITELKKAMMDI TDAW RGQEQEEELEKRLRILAALTIKLREPKFDNHWGGYRSDINGKLSSWLONYINQTVKIKEDLK GHKKDLKKAKEMINRFGESDTKEEAVVSSLLESIEKIVPDDSADDEKPDIPATAIYRRFLSD GRLTLNRFVQREDVQEALIKERLEAEKKKKPKKRKKKSDAEDEKET IDFKELFPHLAKPLKL VPNFYGDSKRELYKKYKNAAIYTDALWKAVEKIYKSAFSSSLKNSFFDTDFDKDFFIKRLQOK IFSVYRRENTDKWKPIVKNSFAPYCDIVSLAENEVLYKPKQSRSRKSAAIDKNRVRLPSTEN IAKAGIALARELSVAGFDWKDLLKKEEHEEYIDLIELHKTALALLLAVTETQLDISALDFVE NGTVKDFMKTRDGNLVLEGRFLEMFSQS IVFSELRGLAGLMSRKEF ITRSAIQTMNGKQAEL LYIPHEFQSAKITTPKEMSRAFLDLAPAEFATSLEPESLSEKSLLKLKQMRYYPHYFGYELT RTGQGIDGGVAENALRLEKSPVKKREIKCKQYKTLGRGONKIVLYVRSSYYQTQFLEWFLHR PKNVQTDVAVSGSFLIDEKKVKTRWNYDALTVALEPVSGSERVFVSQPFTIFPEKSAEEEGQ RYLGIDIGEYGIAYTALEITGDSAKILDONFISDPQLKTLREEVKGLKLDQRRGTFAMPSTK IARIRESLVHSLRNRIHHLALKHKAKIVYELEVSRFEEGKQKIKKVYATLKKADVYSEIDAD KNLQTTVWGKLAVASEISASYTSQFCGACKKLWRAEMQVDETITTQELIGTVRVIKGGTLID AIKDFMRPPIFDENDTPFPKYRDFCDKHHISKKMRGNSCLFICPFCRANADADIQASQTIAL LRYVKEEKKVEDYFERFRKLKNIKVLGOMKKI The term “Cas12” or “Cas12 domain” refers to an RNA guided nuclease comprising a Casl2 protein or a fragment thereof (e.g., a protein comprising an active, inactive, or partially active DNA cleavage domain of Cas12, and / or the gRNA binding domain of Cas12). Cas12 belongs to the class 2, Type V CRISPR / Cas system. A Casl2 nuclease is also referred to sometimes as a CRISPR (clustered regularly interspaced short palindromic repeat) associated nuclease. The sequence of an exemplary Bacillus hisashii Cas 12b (BhCas12b) Cas 12 domain is provided below: MAPKKKRKVGIHGVPAAATRSFILKIEPNEEVKKGLWKTHEVLNHGIAYYMNILKLIRQEAT YEHHEQDPKNPKKVSKAEIQAELWDFVLKMQOKCNSFTHEVDKDEVFNILRELYEELVPSSVE KKGEANQLSNKFLYPLVDPNSQSGKGTASSGRKPRWYNLKIAGDPSWEEEKKKWEEDKKKDP LAKILGKLAEYGLIPLFIPYTDSNEPIVKEIKWMEKSRNQOSVRRLDKDMFIQALERFLSWES WNLKVKEEYEKVEKEYKTLEERIKEDIQALKALEQYEKERQEQLLRDTLNTNEYRLSKRGLR GWREIIQKWLKMDENEPSEKYLEVFKDYQRKHPREAGDYSVYEFLSKKENHFIWRNHPEYPY LYATFCEIDKKKKDAKQQATFTLADPINHPLWVRFEERSGSNLNKYRILTEQLHTEKLKKKL TVQLDRLIYPTESGGWEEKGKVDIVLLPSRQFYNQIFLDIEEKGKHAFTYKDESIKFPLKGT LGGARVQFDRDHLRRYPHKVESGNVGRIYFNMTVNIEPTESPVSKSLKIHRDDFPKVVNFKP KELTEWIKDSKGKKLKSGIESLEIGLRVMSIDLGQRQAAAASIFEVVDQKPDIEGKLFFPIK GTELYAVHRASFNIKLPGETLVKSREVLRKAREDNLKLMNQKLNFLRNVLHFQQFEDITERE KRVTKWISRQENSDVPLVYQDELIQIRELMYKPYKDWVAFLKQLHKRLEVEIGKEVKHWRKS LSDGRKGLYGISLKNIDEIDRTRKFLLRWSLRPTEPGEVRRLEPGQRFAIDQLNHLNALKED RLKKMANT I IMHALGYCYDVRKKKWQAKNPACQIILFEDLSNYNPYEERSRFENSKLMKWSR REIPRQVALQGEIYGLQVGEVGAQFSSRFHAKTGSPGIRCSVVTKEKLODNRFFKNLQREGR LTLDKIAVLKEGDLYPDKGGEKFISLSKDRKCVTTHADINAAQNLOQKRFWTRTHGFYKVYCK AYQVDGQTVYIPESKDQKQKIIEEFGEGYFILKDGVYEWVNAGKLKIKKGSSKQSSSELVDS DILKDSFDLASELKGEKLMLYRDPSGNVFPSDKWMAAGVFFGKLERILISKLTNQYSISTIE DDSSKQOSMKRPAATKKAGQAKKKK . Amino acid sequences having at least 85% or greater identity to the BhCas12b amino acid sequence are also useful in the methods of the invention. By “cytidine deaminase” is meant a polypeptide or fragment thereof capable of catalyzing a deamination reaction that converts an amino group to a carbonyl group. In one embodiment, the cytidine deaminase converts cytosine to uracil or 5-methylcytosine to thymine. PmCDA1, which is derived from Petromyzon marinus (Petromyzon marinus cytosine deaminase 1, “PmCDA1”), AID (Activation-induced cytidine deaminase; AICDA), which is derived from a mammal (e.g., human, swine, bovine, horse, monkey etc.), and APOBEC are exemplary cytidine deaminases. The term “conservative amino acid substitution” or “conservative mutation” refers to the replacement of one amino acid by another amino acid with a common property. A functional way to define common properties between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (Schulz, G. E. and Schirmer, R. H., Principles of Protein Structure, Springer-Verlag, New York (1979)). According to such analyses, groups of amino acids can be defined where amino acids within a group exchange preferentially with each other, and therefore resemble each other most in their impact on the overall protein structure (Schulz, G. E. and Schirmer, R. H,, supra). Non-limiting examples of conservative mutations include amino acid substitutions of amino acids, for example, lysine for arginine and vice versa such that a positive charge can be maintained; glutamic acid for aspartic acid and vice versa such that a negative charge can be maintained; serine for threonine such that a free -OH can be maintained; and glutamine for asparagine such that a free -NH2 can be maintained. The term “coding sequence” or “protein coding sequence” as used interchangeably herein refers to a segment of a polynucleotide that codes for a protein. The region or sequence is bounded nearer the 5° end by a start codon and nearer the 3’ end with a stop codon. Coding sequences can also be referred to as open reading frames. The term “deaminase” or “deaminase domain,” as used herein, refers to a protein or enzyme that catalyzes a deamination reaction. In some embodiments, the deaminase is an adenosine deaminase, which catalyzes the hydrolytic deamination of adenine to hypoxanthine. In some embodiments, the deaminase is an adenosine deaminase, which catalyzes the hydrolytic deamination of adenosine or adenine (A) to inosine (I). In some embodiments, the deaminase or deaminase domain is an adenosine deaminase catalyzing the hydrolytic deamination of adenosine or deoxyadenosine to inosine or deoxyinosine, respectively. In some embodiments, the adenosine deaminase catalyzes the hydrolytic deamination of adenosine in deoxyribonucleic acid (DNA). The adenosine deaminases (e.g., engineered adenosine deaminases, evolved adenosine deaminases) provided herein can be from any organism, such as a bacterium. In some embodiments, the adenosine deaminase is from a bacterium, such as Escherichia coli, Staphylococcus aureus, Salmonella typhimurium, Shewanella putrefaciens, Haemophilus influenzae, or Caulobacter crescentus. In some embodiments, the adenosine deaminase is a TadA deaminase. In some embodiments, the TadA deaminase is TadA variant. In some embodiments, the TadA variant is a TadA*8. In some embodiments, the deaminase or deaminase domain is a variant of a naturally occurring deaminase from an organism, such as a human, chimpanzee, gorilla, monkey, cow, dog, rat, or mouse. In some embodiments, the deaminase or deaminase domain does not occur in nature. For example, in some embodiments, the deaminase or deaminase domain is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9% identical to a naturally occurring deaminase. For example, deaminase domains are described in International PCT Application Nos, PCT / 2017 / 045381 (WO 2018 / 027078) and PCT / US2016 / 058344 (WO 2017 / 070632), each of which is incorporated herein by reference for its entirety. Also, see Komor, A.C, etal., “Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage” Nature 533, 420-424 (2016); Gaudelli, N.M,, ef al., “Programmable base editing of A+T to G+C in genomic DNA without DNA cleavage” Nature 551, 464-471 (2017); Komor, A.C, etal, “Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity” Science Advances 3:eaa04774 (2017) ), and Rees, HA , ez al., “Base editing: precision chemistry on the genome and transcriptome of living cells.” Nat Rev Genet. 2018 Dec;19(12):770-788. doi: 10.1038 / s41576-018-0059-1, the entire contents of which are hereby incorporated by reference. “Detect” refers to identifying the presence, absence or amount of the analyte to be detected. In one embodiment, a sequence alteration in a polynucleotide or polypeptide is detected. In another embodiment, the presence of indels is detected. By "detectable label” is meant a composition that when linked to a molecule of interest renders the latter detectable, via spectroscopic, photochemical, biochemical, immunochemical, or chemical means. For example, useful labels include radioactive isotopes, magnetic beads, metallic beads, colloidal particles, fluorescent dyes, electron-dense reagents, enzymes (for example, as commonly used in an enzyme linked immunosorbent assay (ELISA)), biotin, digoxigenin, or haptens. By “disease” is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. The term “effective amount,” as used herein, refers to an amount of a biologically active agent that is sufficient to elicit a desired biological response. The effective amount of an active agent(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an “effective” amount. In one embodiment, an effective amount is the amount of a base editor of the invention (e.g., a fusion protein comprising a programable DNA binding protein, a nucleobase editor and gRNA) sufficient to introduce an alteration in a gene of interest in a cell (e.g., a cell in vitro or in vivo). In some embodiments, an effective amount of a fusion protein provided herein, e.g., of a nucleobase editor comprising a nCas9 domain and a deaminase domain (e.g., adenosine deaminase or cytidine deaminase) may refer to the amount of the fusion protein that is sufficient to induce editing of a target site specifically bound and edited by the nucleobase editor. In one embodiment, an effective amount is the amount of a base editor required to achieve a therapeutic effect (e.g., to reduce or control a disease or a symptom or condition thereof). Such therapeutic effect need not be sufficient to alter a gene of interest in all cells of a subject, tissue or organ, but only to alter a gene of interest in about 1%, 5%, 10%, 25%, 50%, 75% or more of the cells present in a subject, tissue or organ. In some embodiments, an effective amount of a fusion protein provided herein, e.g., of a nucleobase editor comprising a nCas9 domain and a deaminase domain (e.g., adenosine deaminase or cytidine deaminase) refers to the amount of the fusion protein that is sufficient to induce editing of a target site specifically bound and edited by the nucleobase editors described herein. As will be appreciated by the skilled artisan, the effective amount of an agent, e.g., a fusion protein, a nuclease, a hybrid protein, a protein dimer, a complex of a protein (or protein dimer) and a polynucleotide, or a polynucleotide, may vary depending on various factors as, for example, on the desired biological response, e.g., on the specific allele, genome, or target site to be edited, on the cell or tissue being targeted, and / or on the agent being used. By "fragment" is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide. A fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids. By “guide RNA” or “gRNA” is meant a polynucleotide which can be specific for a target sequence and can form a complex with a polynucleotide programmable nucleotide binding domain protein (e.g., Cas9 or Cpfl). In an embodiment, the guide polynucleotide is a guide RNA (gRNA). gRNAs can exist as a complex of two or more RNAs, or as a single RNA molecule. gRNAs that exist as a single RNA molecule may be referred to as single-guide RNAs (sgRNAs), though “gRNA”™ is used interchangeably to refer to guide RNAs that exist as either single molecules or as a complex of two or more molecules. Typically, gRNAs that exist as single RNA species comprise two domains: (1) a domain that shares homology to a target nucleic acid (e.g., and directs binding of a Cas9 complex to the target); and (2) a domain that binds a Cas9 protein. In some embodiments, domain (2) corresponds to a sequence known as atractRNA, and comprises a stem-loop structure. For example, in some embodiments, domain (2) is identical or homologous to a tractfRNA as provided in Jinek er al., Science 337:816- 821(2012), the entire contents of which is incorporated herein by reference. Other examples of gRNAs (e.g., those including domain 2) can be found in U.S. Provisional Patent Application, U.S.S.N. 61 / 874,682, filed September 6, 2013, entitled "Switchable Cas9 Nucleases and Uses Thereof," and U.S. Provisional Patent Application, U.S.S.N. 61 / 874,746, filed September 6, 2013, entitled "Delivery System For Functional Nucleases," the entire contents of each are hereby incorporated by reference in their entirety. In some embodiments, a gRNA comprises two or more of domains (1) and (2), and may be referred to as an “extended gRNA.” An extended gRNA will bind two or more Cas9 proteins and bind a target nucleic acid at two or more distinct regions, as described herein. The gRNA comprises a nucleotide sequence that complements a target site, which mediates binding of the nuclease / RNA complex to said target site, providing the sequence specificity of the nuclease:RNA complex. “Hybridization” means hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. For example, adenine and thymine are complementary nucleobases that pair through the formation of hydrogen bonds. The term "inhibitor of base repair" or "IBR" refers to a protein that is capable in inhibiting the activity of a nucleic acid repair enzyme, for example a base excision repair (BER) enzyme. In some embodiments, the IBR is an inhibitor of inosine base excision repair. Exemplary inhibitors of base repair include inhibitors of APE1, Endo III, Endo IV, Endo V, Endo VIII, Fpg, hOGGI, hNEILL, T7 Endol, T4PDG, UDG, hSMUGI, and hAAG. In some embodiments, the IBR is an inhibitor of Endo V or hAAG. In some embodiments, the IBR is a catalytically inactive EndoV or a catalytically inactive hAAG. In some embodiments, the base repair inhibitor is an inhibitor of Endo V or hAAG. In some embodiments, the base repair inhibitor is a catalytically inactive EndoV or a catalytically inactive hAAG. In some embodiments, the base repair inhibitor is uracil glycosylase inhibitor (UGI). UGI refers to a protein that is capable of inhibiting a uracil-DNA glycosylase base-excision repair enzyme. In some embodiments, a UGI domain comprises a wild-type UGI or a fragment of a wild-type UGL In some embodiments, the UGI proteins provided herein include fragments of UGI and proteins homologous to a UGI or a UGI fragment. In some embodiments, the base repair inhibitor is an inhibitor of inosine base excision repair. In some embodiments, the base repair inhibitor is a “catalytically inactive inosine specific nuclease” or “dead inosine specific nuclease. Without wishing to be bound by any particular theory, catalytically inactive inosine glycosylases (e.g., alkyl adenine glycosylase (AAG)) can bind inosine, but cannot create an abasic site or remove the inosine, thereby sterically blocking the newly formed inosine moiety from DNA damage / repair mechanisms. In some embodiments, the catalytically inactive inosine specific nuclease can be capable of binding an inosine in a nucleic acid but does not cleave the nucleic acid. Non-limiting exemplary catalytically inactive inosine specific nucleases include catalytically inactive alkyl adenosine glycosylase (AAG nuclease), for example, from a human, and catalytically inactive endonuclease V (EndoV nuclease), for example, from E. coli. In some embodiments, the catalytically inactive AAG nuclease comprises an E125Q mutation or a corresponding mutation in another AAG nuclease. By “increases” is meant a positive alteration of at least 10%, 25%, 50%, 75%, or 100%. An "intein" is a fragment of a protein that is able to excise itself and join the remaining fragments (the exteins) with a peptide bond in a process known as protein splicing. Inteins are also referred to as "protein introns.” The process of an intein excising itself and joining the remaining portions of the protein is herein termed "protein splicing" or "intein- mediated protein splicing." In some embodiments, an intein of a precursor protein (an intein containing protein prior to intein-mediated protein splicing) comes from two genes. Such intein is referred to herein as a split intein (e.g., split intein-N and split intein-C). For example, in cyanobacteria, DnaE, the catalytic subunit a of DNA polymerase III, is encoded by two separate genes, dnaE-n and dnaE-c. The intein encoded by the dnaE-n gene may be herein referred as "intein-N." The intein encoded by the dnaE-c gene may be herein referred as "intein-C." Other intein systems may also be used. For example, a synthetic intein based on the dnaE intein, the Cfa-N (e.g, split intein-N) and Cfa-C (e.g., split intein-C) intein pair, has been described (e.g., in Stevens et al., J Am Chem Soc. 2016 Feb. 24; 138(7):2162-5, incorporated herein by reference). Non-limiting examples of intein pairs that may be used in accordance with the present disclosure include: Cfa DnaE intein, Ssp GyrB intein, Ssp DnaX intein, Ter DnaE3 intein, Ter ThyX intein, Rma DnaB intein and Cne Prp8 intein (e.g., as described in U.S. Patent No. 8,394,604, incorporated herein by reference. Exemplary nucleotide and amino acid sequences of inteins are provided. DnaFE Intein-N DNA: TGCCTGTCATACGAAACCGAGATACTGACAGTAGAATATGGCCTTCTGCCAATCGGGAAGAT TGTGGAGAAACGGATAGAATGCACAGTTTACTCTGTCGATAARCAATGGTAACATTTATACTC AGCCAGTTGCCCAGTGGCACGACCGGGGAGAGCAGGAAGTATTCGAATACTGTCTGGAGGAT GGAAGTCTCATTAGGGCCACTAAGGACCACAAATTTATGACAGTCGATGGCCAGATGCTGCC TATAGACGAAATCTTTGAGCGAGAGTTGGACCTCATGCGAGTTGACAACCTTCCTAAT DnaE Intein-N Protein: CLSYETEILTVEYGLLPIGKIVEKRIECTVYSVDNNGNIYTQPVAQWHDR GEQEVFEYCLEDGSLIRATKDHKFMTVDGCMLPIDEIFERELDLMRVDNLPN DnaE Intein-C DNA: ATGATCAAGATAGCTACAAGGAAGTATCTTGGCAAACAARAACGTTTATGA TATTGGAGTCGAARGAGATCACARCTTTGCTCTGAAGAACGGATTCATAGCTTCTAAT Intein-C: MIKIATRKYLGKQNVYDIGVERDHNFALKNGFIASN Cfa-N DNA: TGCCTGTCTTATGATACCGAGATACTTACCGTTGAATATGGCTTCTTGCCTATTGGAAAGAT TGTCGAAGAGAGAATTGAATGCACAGTATATACTGTAGACAAGAATGGTTTCGTTTACACAC AGCCCATTGCTCAATGGCACAATCGCGGCGAACAAGAAGTATTTGAGTACTGTCTCGAGGAT GGAAGCATCATACGAGCAACTAAAGATCATAAATTCATGACCACTGACGGGCAGATGTTGCC AATAGATGAGATATTCGAGCGGGGCTTGGATCTCAAACAAGTGGATGGATTGCCA Cfa-N Protein: CLSYDTEILTVEYGFLPIGKIVEERIECTVYTVDKNGEVYTQPIAQWHNRGEQEVFEYCLED GSIIRATKDHKFMTTDGCMLPIDEIFERGLDLKOVDGLP Cfa-C DNA: ATGAAGAGGACTGCCGATGGATCAGAGTTTGAATCTCCCAAGAAGARGAGGAAAGTAAAGAT AATATCTCGAAARAGTCTTGGTACCCAARATGTCTATGATATTGGAGTGGAGARAGATCACA ACT TCCTITO I CARGBA CGO TC TOG TAGUC AGO ARN, Cfa-C Protein: MKRTADGSEFESPKKKRKVKIISRKSLGTONVYDIGVEKDHNFLLKNGLVASN Intein-N and intein-C may be fused to the N-terminal portion of the split Cas9 and the C-terminal portion of the split Cas9, respectively, for the joining of the N-terminal portion of the split Cas9 and the C-terminal portion of the split Cas9. For example, in some embodiments, an intein-N is fused to the C-terminus of the N-terminal portion of the split Cas9, i.e., to form a structure of N--[N-terminal portion of the split Cas9]-[intein-N]--C. In some embodiments, an intein-C is fused to the N-terminus of the C-terminal portion of the split Cas9, i.e., to form a structure of N-[intein-C]--[C-terminal portion of the split Cas9]-C. The mechanism of intein-mediated protein splicing for joining the proteins the inteins are fused to (e.g., split Cas9) is known in the art, e.g., as described in Shah et al., Chem Sci. 2014; 5(1):446-461, incorporated herein by reference. Methods for designing and using inteins are known in the art and described, for example by W02014004336, W02017132580, US20150344549, and US20180127780, each of which is incorporated herein by reference in their entirety. The terms "isolated," "purified," or "biologically pure" refer to material that is free to varying degrees from components which normally accompany it as found in its native state. "Isolate" denotes a degree of separation from original source or surroundings. "Purify" denotes a degree of separation that is higher than isolation. A "purified" or "biologically pure" protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of this invention is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high-performance liquid chromatography. The term "purified" can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. For a protein that can be subjected to modifications, for example, phosphorylation or glycosylation, different modifications may give rise to different isolated proteins, which can be separately purified. By "isolated polynucleotide" is meant a nucleic acid (e.g., a DNA) that is free of the genes which, in the naturally-occurring genome of the organism from which the nucleic acid molecule of the invention is derived, flank the gene. The term therefore includes, for example, a recombinant DNA that is incorporated into a vector; into an autonomously replicating plasmid or virus; or into the genomic DNA of a prokaryote or eukaryote; or that exists as a separate molecule (for example, a cDNA or a genomic or cDNA fragment produced by PCR or restriction endonuclease digestion) independent of other sequences. In addition, the term includes an RNA molecule that is transcribed from a DNA molecule, as well as a recombinant DNA that is part of a hybrid gene encoding additional polypeptide sequence. By an "isolated polypeptide" is meant a polypeptide of the invention that has been separated from components that naturally accompany it. Typically, the polypeptide is isolated when it is at least 60%, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, a polypeptide of the invention. An isolated polypeptide of the invention may be obtained, for example, by extraction from a natural source, by expression of a recombinant nucleic acid encoding such a polypeptide; or by chemically synthesizing the protein. Purity can be measured by any appropriate method, for example, column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis. The term “linker”, as used herein, can refer to a covalent linker (e.g., covalent bond), a non-covalent linker, a chemical group, or a molecule linking two molecules or moieties, e.g., two components of a protein complex or a ribonucleocomplex, or two domains of a fusion protein, such as, for example, a polynucleotide programmable DNA binding domain (e.g., dCas9) and a deaminase domain (e.g, an adenosine deaminase, a cytidine deaminase, or an adenosine deaminase and a cytidine deaminase) or a napDNAbp domain (e.g., Cas12b) and a deaminase domain (e.g., an adenosine deaminase or a cytidine deaminase). In particular embodiments, linkers flank a deaminase domain that is inserted within a Cas protein or fragment thereof. A linker can join different components of, or different portions of components of, a base editor system. For example, in some embodiments, a linker can join a guide polynucleotide binding domain of a polynucleotide programmable nucleotide binding domain and a catalytic domain of a deaminase. In some embodiments, a linker can join a CRISPR polypeptide and a deaminase. In some embodiments, a linker can join a Cas9 and a deaminase. In some embodiments, a linker can join a dCas9 and a deaminase. In some embodiments, a linker can join a nCas9 and a deaminase. For example, in some embodiments, a linker can join a Cas12a / Cpfl, Cas12b / C2¢l, Cas12¢ / C2¢3, Casl12d / CasY, Casl12e / CasX, Casl2g, Cas12h, or Cas12i and a deaminase. In some embodiments, a linker can join a guide polynucleotide and a deaminase. In some embodiments, a linker can join a deaminating component and a polynucleotide programmable nucleotide binding component of a base editor system. In some embodiments, a linker can join an RNA-binding portion of a deaminating component and a napDNAbp component of a base editor system. In some embodiments, a linker can join an RNA-binding portion of a deaminating component and a polynucleotide programmable nucleotide binding component of a base editor system. In some embodiments, a linker can join an RNA-binding portion of a deaminating component and an RNA-binding portion of a polynucleotide programmable nucleotide binding component of a base editor system. A linker can be positioned between, or flanked by, two groups, molecules, or other moieties and connected to each one via a covalent bond or non- covalent interaction, thus connecting the two. In some embodiments, the linker can be an organic molecule, group, polymer, or chemical moiety. In some embodiments, the linker can be a polynucleotide. In some embodiments, the linker can be a DNA linker. In some embodiments, the linker can be an RNA linker. In some embodiments, a linker can comprise an aptamer capable of binding to a ligand. In some embodiments, the ligand may be carbohydrate, a peptide, a protein, or a nucleic acid. In some embodiments, the linker may comprise an aptamer may be derived from a riboswitch. The riboswitch from which the aptamer is derived may be selected from a theophylline riboswitch, a thiamine pyrophosphate (TPP) riboswitch, an adenosine cobalamin (AdoCbl) riboswitch, an S-adenosyl methionine (SAM) riboswitch, an SAH riboswitch, a flavin mononucleotide (FMN) riboswitch, a tetrahydrofolate riboswitch, a lysine riboswitch, a glycine riboswitch, a purine riboswitch, a GImS riboswitch, or a pre-queosinel (PreQ1) riboswitch. In some embodiments, a linker may comprise an aptamer bound to a polypeptide or a protein domain, such as a polypeptide ligand. In some embodiments, the polypeptide ligand may be a K Homology (KH) domain, a MS2 coat protein domain, a PP7 coat protein domain, a SfMu Com coat protein domain, a sterile alpha motif, a telomerase Ku binding motif and Ku protein, a telomerase Sm7 binding motif and Sm7 protein, or an RNA recognition motif. In some embodiments, the polypeptide ligand may be a portion of a base editor system component. For example, a nucleobase editing component may comprise a deaminase domain and an RNA recognition motif. In some embodiments, the linker can be an amino acid or a plurality of amino acids (e.g., a peptide or protein). In some embodiments, the linker can be about 5-100 amino acids in length, for example, about 3, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 20-30, 30- 40, 40-50, 50-60, 60-70, 70-80, 80-90, or 90-100 amino acids in length. In some embodiments, the linker can be about 100-150, 150-200, 200-250, 250-300, 300-350, 350- 400, 400-450, or 450-500 amino acids in length. Longer or shorter linkers can be also contemplated. In some embodiments, a linker joins a gRNA binding domain of an RNA- programmable nuclease, including a Cas9 nuclease domain, and the catalytic domain of a nucleic-acid editing protein (e.g., cytidine or adenosine deaminase). In some embodiments, a linker joins a dCas9 and a nucleic-acid editing protein. For example, the linker is positioned between, or flanked by, two groups, molecules, or other moieties and connected to each one via a covalent bond, thus connecting the two. In some embodiments, the linker is an amino acid or a plurality of amino acids (e.g., a peptide or protein). In some embodiments, the linker is an organic molecule, group, polymer, or chemical moiety. In some embodiments, the linker is 5-200 amino acids in length, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 35, 45, 50, 55, 60, 60, 65, 70, 70, 75, 80, 85, 90, 90, 95, 100, 101, 102, 103, 104, 105, 110, 120, 130, 140, 150, 160, 175, 180, 190, or 200 amino acids in length. Longer or shorter linkers are also contemplated. In some embodiments, the domains of the nuclecbase editor are fused via a linker that comprises the amino acid sequence of SGGSSGSETPGTSESATPESSGGS, SGGSSGGSSGSETPGTSESATPESSGGSSGGS, or GGSGGSPGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTE PSEGSAPGTSTEPSEGSAPGTSESATPESGPGSEPATSGGSGGS. In some embodiments, domains of the nucleobase editor are fused via a linker comprising the amino acid sequence SGSETPGTSESATPES, which may also be referred to as the XTEN linker. In some embodiments, a linker comprises the amino acid sequence SGGS. In some embodiments, a linker comprises (SGGS)s, (GGGS )a, (GGGGS)n, (Gn, (EAAAK), (GGS)n, SGSETPGTSESATPES, or (XP)a motif, or a combination of any of these, wherein n is independently an integer between 1 and 30, and wherein X is any amino acid. In some embodiments, nis 1, 2,3,4,5,6,7,8,9, 10, 11, 12, 13, 14, or 15. In some embodiments, the linker is 24 amino acids in length. In some embodiments, the linker comprises the amino acid sequence SGGSSGGSSGSETPGTSESATPES. In some embodiments, the linker is 40 amino acids in length. In some embodiments, the linker comprises the amino acid sequence SGGSSGGSSGSETPGTSESATPESSGGSSGGSSGGSSGGS. In some embodiments, the linker is 64 amino acids in length. In some embodiments, the linker comprises the amino acid sequence SGGSSGGSSGSETPGTSESATPESSGGSSGGSSGGSSGGSSGSETPGTSESATPESSGGS SGGS. In some embodiments, the linker is 92 amino acids in length. In some embodiments, the linker comprises the amino acid sequence PGSPAGSPTSTEEGTSESATPESGPGTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAPG TSTEPSEGSAPGTSESATPESGPGSEPATS. By “marker” is meant any protein or polynucleotide having an alteration in expression level or activity that is associated with a disease or disorder. The term “mutation,” as used herein, refers to a substitution of a residue within a sequence, e.g., a nucleic acid or amino acid sequence, with another residue, or a deletion or insertion of one or more residues within a sequence. Mutations are typically described herein by identifying the original residue followed by the position of the residue within the sequence and by the identity of the newly substituted residue. Various methods for making the amino acid substitutions (mutations) provided herein are well known in the art, and are provided by, for example, Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)). In some embodiments, the presently disclosed base editors can efficiently generate an “intended mutation,” such as a point mutation, in a nucleic acid (e.g., a nucleic acid within a genome of a subject) without generating a significant number of unintended mutations, such as unintended point mutations. In some embodiments, an intended mutation is a mutation that is generated by a specific base editor (e.g., cytidine base editor or adenosine base editor) bound to a guide polynucleotide (e.g., gRNA), specifically designed to generate the intended mutation. In general, mutations made or identified in a sequence (e.g., an amino acid sequence as described herein) are numbered in relation to a reference (or wild-type) sequence, i.e., a sequence that does not contain the mutations. The skilled practitioner in the art would readily understand how to determine the position of mutations in amino acid and nucleic acid sequences relative to a reference sequence. The term “non-conservative mutations” involve amino acid substitutions between different groups, for example, lysine for tryptophan, or phenylalanine for serine, etc. In this case, it is preferable for the non-conservative amino acid substitution to not interfere with, or inhibit the biological activity of, the functional variant. The non-conservative amino acid substitution can enhance the biological activity of the functional variant, such that the biological activity of the functional variant is increased as compared to the wild-type protein. The term “nuclear localization sequence,” “nuclear localization signal,” or “NLS” refers to an amino acid sequence that promotes import of a protein into the cell nucleus. Nuclear localization sequences are known in the art and described, for example, in Plank ez al., International PCT application, PCT / EP2000 / 011690, filed November 23, 2000, published as W0 / 2001 / 038547 on May 31, 2001, the contents of which are incorporated herein by reference for their disclosure of exemplary nuclear localization sequences. In other embodiments, the NLS is an optimized NLS described, for example, by Koblan ef al., Nature Biotech. 2018 doi:10.1038 / nbt.4172. In some embodiments, an NLS comprises the amino acid sequence KRTADGSEFESPKKKRKV, KRPAATKKAGQAKKKK, KKTELQTTNAENKTKKL, KRGINDRNFWRGENGRKTR, RKSGKIAAIVVKRPRK, PKKKRKV, or MDSLLMNRRKFLYQFKNVRWAKGRRETYLC. The terms “nucleic acid” and “nucleic acid molecule,” as used herein, refer to a compound comprising a nucleobase and an acidic moiety, e.g., a nucleoside, a nucleotide, or a polymer of nucleotides. Typically, polymeric nucleic acids, e.g., nucleic acid molecules comprising three or more nucleotides are linear molecules, in which adjacent nucleotides are linked to each other via a phosphodiester linkage. In some embodiments, “nucleic acid” refers to individual nucleic acid residues (e.g., nucleotides and / or nucleosides). In some embodiments, “nucleic acid” refers to an oligonucleotide chain comprising three or more individual nucleotide residues. As used herein, the terms “oligonucleotide” and “polynucleotide” can be used interchangeably to refer to a polymer of nucleotides (e.g., a string of at least three nucleotides). In some embodiments, “nucleic acid” encompasses RNA as well as single and / or double-stranded DNA. Nucleic acids may be naturally occurring, for example, in the context of a genome, a transcript, an mRNA, tRNA, rRNA, siRNA, snRNA, a plasmid, cosmid, chromosome, chromatid, or other naturally occurring nucleic acid molecule. On the other hand, a nucleic acid molecule may be a non-naturally occurring molecule, e.g., a recombinant DNA or RNA, an artificial chromosome, an engineered genome, or fragment thereof, or a synthetic DNA, RNA, DNA / RNA hybrid, or including non-naturally occurring nucleotides or nucleosides. Furthermore, the terms “nucleic acid,” “DNA,” “RNA,” and / or similar terms include nucleic acid analogs, e.g., analogs having other than a phosphodiester backbone. Nucleic acids can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, etc. Where appropriate, e.g., in the case of chemically synthesized molecules, nucleic acids can comprise nucleoside analogs such as analogs having chemically modified bases or sugars, and backbone modifications. A nucleic acid sequence is presented in the 5' to 3' direction unless otherwise indicated. In some embodiments, a nucleic acid is or comprises natural nucleosides (e.g, adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine); nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, S-methylcytidine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7- deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine); chemically modified bases; biologically modified bases (e.g., methylated bases); intercalated bases; modified sugars ( 2-e.g..fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose); and / or modified phosphate groups (e.g., phosphorothioates and 5'-N- phosphoramidite linkages). The term "nucleic acid programmable DNA binding protein" or "napDNAbp" may be used interchangeably with “polynucleotide programmable nucleotide binding domain” to refer to a protein that associates with a nucleic acid (e.g., DNA or RNA), such as a guide nucleic acid or guide polynucleotide (e.g., gRNA), that guides the napDNADbp to a specific nucleic acid sequence. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable RNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a Cas9 protein. A Cas9 protein can associate with a guide RNA that guides the Cas9 protein to a specific DNA sequence that is complementary to the guide RNA. In some embodiments, the napDNAbp is a Cas9 domain, for example a nuclease active Cas9, a Cas9 nickase (nCas9), or a nuclease inactive Cas9 (dCas9). Non-limiting examples of nucleic acid programmable DNA binding proteins include, Cas9 (e.g., dCas9 and nCas9), Cas12a / Cpfl, Cas12b / C2cl, Cas12¢ / C2c3, Cas12d / CasY, Cas12e / CasX, Casl2g, Cas12h, and Cas12i. Non-limiting examples of Cas enzymes include Casl, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, CasSh, Cas5a, Cas6, Cas7, Cas8, Cas8a, Cas8b, Cas8c, Cas9 (also known as Csnl or Csx12), Cas10, Cas10d, Cas12a / Cpfl, Cas12b / C2cl, Cas12c / C2c3, Cas12d / CasY, Casl2e / CasX, Casl2g, Casl2h, Casl2i, Csyl, Csy2, Csy3, Csy4, Csel, Cse2, Cse3, Cse4, Cse5e, Cscl, Csc2, Csa$, Csnl, Csn2, Csm1, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx18, Csx11, Csfl, Csf2, Cs0, Csf4, Csdl, Csd2, Cstl, Cst2, Cshl, Csh2, Csal, Csa2, Csa3, Csad, Csa5, Type II Cas effector proteins, Type V Cas effector proteins, Type VI Cas effector proteins, CARF, DinG, homologues thereof, or modified or engineered versions thereof. Other nucleic acid programmable DNA binding proteins are also within the scope of this disclosure, although they may not be specifically listed in this disclosure. See, e.g., Makarova ef al. “Classification and Nomenclature of CRISPR-Cas Systems: Where from Here?” CRISPR J. 2018 Oct; 1:325-336. doi: 10.108% / crispr.2018.0033; Yan ef al, “Functionally diverse type V CRISPR-Cas systems” Science. 2019 Jan 4,363(6422):88-91. doi: 10.1126 / science.aav7271, the entire contents of each are hereby incorporated by reference. The term “nucleobase,” “nitrogenous base,” or “base,” used interchangeably herein, refers to a nitrogen-containing biological compound that forms a nucleoside, which in turn is a component of a nucleotide. The ability of nucleobases to form base pairs and to stack one upon another leads directly to long-chain helical structures such as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Five nucleobases — adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U) — are called primary or canonical. Adenine and guanine are derived from purine, and cytosine, uracil, and thymine are derived from pyrimidine. DNA and RNA can also contain other (non-primary) bases that are modified. Non-limiting exemplary modified nucleobases can include hypoxanthine, xanthine, 7-methylguanine, 5,6- dihydrouracil, 5-methylcytosine (m5C), and 5-hydromethylcytosine. Hypoxanthine and xanthine can be created through mutagen presence, both of them through deamination (replacement of the amine group with a carbonyl group). Hypoxanthine can be modified from adenine. Xanthine can be modified from guanine. Uracil can result from deamination of cytosine. A “nucleoside” consists of a nucleobase and a five carbon sugar (either ribose or deoxyribose). Examples of a nucleoside include adenosine, guanosine, uridine, cytidine, 5- methyluridine (m5U), deoxyadenosine, deoxyguanosine, thymidine, deoxyuridine, and deoxycytidine. Examples of a nucleoside with a modified nucleobase includes inosine (I), xanthosine (X), 7-methylguanosine (m7G), dihydrouridine (D), 5-methylcytidine (m5C), and pseudouridine (W). A “nucleotide” consists of a nucleobase, a five carbon sugar (either ribose or deoxyribose), and at least one phosphate group. The term “nucleic acid programmable DNA binding protein” or “napDNAbp” refers to a protein that associates with a nucleic acid (e.g., DNA or RNA), such as a guide nucleic acid, that guides the napDNADbp to a specific nucleic acid sequence. For example, a Cas12 protein can associate with a guide RNA that guides the Cas12 protein to a specific DNA sequence that is complementary to the guide RNA. In some embodiments, the napDNAbp is a Cas12 domain, for example a nuclease active Cas12 domain. Examples of napDNAbps include, Cas12a / Cpfl, Cas12b / C2cl, Cas12¢ / C2¢3, Cas12d / CasY, Cas12e / CasX, Casl2g, Casl2h, and Cas12i. Other napDNADbps are also within the scope of this disclosure, although they may not be specifically listed in this disclosure. See, e.g., Makarova et al. “Classification and Nomenclature of CRISPR-Cas Systems: Where from Here?” CRISPR J. 2018 Oct; 1:325-336. doi: 10.1089 / crispr.2018.0033; Yan et al., “Functionally diverse type V CRISPR-Cas systems” Science. 2019 Jan 4;363(6422):88-91. doi: 10.1126 / science.aav7271, the entire contents of each are hereby incorporated by reference. The terms “nucleobase editing domain” or “nucleobase editing protein,” as used herein, refers to a protein or enzyme that can catalyze a nucleobase modification in RNA or DNA, such as cytosine (or cytidine) to uracil (or uridine) or thymine (or thymidine), and adenine (or adenosine) to hypoxanthine (or inosine) deaminations, as well as non-templated nucleotide additions and insertions. In some embodiments, the nucleobase editing domain is a deaminase domain (e.g., an adenine deaminase or an adenosine deaminase; or a cytidine deaminase or a cytosine deaminase). In some embodiments, the nucleobase editing domain is more than one deaminase domain (e.g., an adenine deaminase or an adenosine deaminase and a cytidine or a cytosine deaminase). In some embodiments, the nucleobase editing domain can be a naturally occurring nucleobase editing domain. In some embodiments, the nucleobase editing domain can be an engineered or evolved nucleobase editing domain from the naturally occurring nucleobase editing domain. The nucleobase editing domain can be from any organism, such as a bacterium, human, chimpanzee, gorilla, monkey, cow, dog, rat, or mouse. For example, nucleobase editing proteins are described in International PCT Application Nos. PCT / 2017 / 045381 (WO 2018 / 027078) and PCT / US2016 / 058344 (WO 2017 / 070632), each of which is incorporated herein by reference for its entirety. Also see, Komor, A.C, et al, “Programmable editing of a target base in genomic DNA without double- stranded DNA cleavage” Nature 533, 420-424 (2016); Gaudelli, N.M,, et al., “Programmable base editing of A*T to G=C in genomic DNA without DNA cleavage” Nature 551, 464-471 (2017); and Komor, A.C,, et al., “Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity” Science Advances 3:eaa04774 (2017), the entire contents of which are hereby incorporated by reference. As used herein, “obtaining” as in “obtaining an agent” includes synthesizing, purchasing, or otherwise acquiring the agent. A “patient” or “subject” as used herein refers to a mammalian subject or individual diagnosed with, at risk of having or developing, or suspected of having or developing a disease or a disorder. In some embodiments, the term “patient” refers to a mammalian subject with a higher than average likelihood of developing a disease or a disorder. Exemplary patients can be humans, non-human primates, cats, dogs, pigs, cattle, cats, horses, camels, llamas, goats, sheep, rodents (e.g., mice, rabbits, rats, or guinea pigs) and other mammalians that can benefit from the therapies disclosed herein. Exemplary human patients can be male and / or female. “Patient in need thereof” or “subject in need thereof” is referred to herein as a patient diagnosed with, at risk or having, predetermined to have, or suspected of having a disease or disorder. The terms “pathogenic mutation,” “pathogenic variant,” “disease casing mutation,” “disease causing variant,” “deleterious mutation,” or “predisposing mutation” refers to a genetic alteration or mutation that increases an individuals susceptibility or predisposition to a certain disease or disorder. In some embodiments, the pathogenic mutation comprises at least one wild-type amino acid substituted by at least one pathogenic amino acid in a protein encoded by a gene. The term “pharmaceutically-acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the compound from one site (e.g., the delivery site) of the body, to another site (e.g., organ, tissue or portion of the body). A pharmaceutically acceptable carrier is “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the tissue of the subject (e.g., physiologically compatible, sterile, physiologic pH, etc.). The terms such as “excipient,” “carrier,” “pharmaceutically acceptable carrier,” “vehicle,” or the like are used interchangeably herein. The term “pharmaceutical composition” can refer to a composition formulated for pharmaceutical use. The terms “protein,” “peptide,” “polypeptide,” and their grammatical equivalents are used interchangeably herein, and refer to a polymer of amino acid residues linked together by peptide (amide) bonds. The terms refer to a protein, peptide, or polypeptide of any size, structure, or function. Typically, a protein, peptide, or polypeptide will be at least three amino acids long. A protein, peptide, or polypeptide can refer to an individual protein or a collection of proteins. One or more of the amino acids in a protein, peptide, or polypeptide can be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modifications, etc. A protein, peptide, or polypeptide can also be a single molecule or can be a multi-molecular complex. A protein, peptide, or polypeptide can be just a fragment of a naturally occurring protein or peptide. A protein, peptide, or polypeptide can be naturally occurring, recombinant, or synthetic, or any combination thereof. The term “fusion protein” as used herein refers to a hybrid polypeptide which comprises protein domains from at least two different proteins. One protein can be located at the amino-terminal (N-terminal) portion of the fusion protein or at the carboxy-terminal (C-terminal) protein thus forming an amino-terminal fusion protein or a carboxy-terminal fusion protein, respectively. A protein can comprise different domains, for example, a nucleic acid binding domain (e.g., the gRNA binding domain of Cas9 that directs the binding of the protein to a target site) and a nucleic acid cleavage domain, or a catalytic domain of a nucleic acid editing protein. In some embodiments, a protein comprises a proteinaceous part, e.g., an amino acid sequence constituting a nucleic acid binding domain, and an organic compound, e.g., a compound that can act as a nucleic acid cleavage agent. In some embodiments, a protein is in a complex with, or is in association with, a nucleic acid, e.g., RNA or DNA. Any of the proteins provided herein can be produced by any method known in the art. For example, the proteins provided herein can be produced via recombinant protein expression and purification, which is especially suited for fusion proteins comprising a peptide linker. Methods for recombinant protein expression and purification are well known, and include those described by Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)), the entire contents of which are incorporated herein by reference. Polypeptides and proteins disclosed herein (including functional portions and functional variants thereof) can comprise synthetic amino acids in place of one or more naturally-occurring amino acids. Such synthetic amino acids are known in the art, and include, for example, aminocyclohexane carboxylic acid, norleucine, a-amino n-decanoic acid, homoserine, S-acetylaminomethyl-cysteine, trans-3- and trans-4-hydroxyproline, 4- aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, B-phenylserine B-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic acid, 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, N’-benzyl-N’-methyl-lysine, N’,N’-dibenzyl-lysine, 6-hydroxylysine, ornithine, a-aminocyclopentane carboxylic acid, a-aminocyclohexane carboxylic acid, o- aminocycloheptane carboxylic acid, a-(2-amino-2-norbornane)-carboxylic acid, o,y- diaminobutyric acid, o,B-diaminopropionic acid, homophenylalanine, and a-tert-butylglycine. The polypeptides and proteins can be associated with post-translational modifications of one or more amino acids of the polypeptide constructs. Non-limiting examples of post- translational modifications include phosphorylation, acylation including acetylation and formylation, glycosylation (including N-linked and O-linked), amidation, hydroxylation, alkylation including methylation and ethylation, ubiquitylation, addition of pyrrolidone carboxylic acid, formation of disulfide bridges, sulfation, myristoylation, palmitoylation, isoprenylation, farnesylation, geranylation, glypiation, lipoylation and iodination. The term “polynucleotide programmable nucleotide binding domain” or “nucleic acid programmable DNA binding protein (napDNAbp)” refers to a protein that associates with a nucleic acid (e.g., DNA or RNA), such as a guide polynucleotide (e.g., guide RNA), that guides the polynucleotide programmable nucleotide binding domain to a specific nucleic acid sequence. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable DNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a polynucleotide programmable RNA binding domain. In some embodiments, the polynucleotide programmable nucleotide binding domain is a Cas12 protein. The term "recombinant" as used herein in the context of proteins or nucleic acids refers to proteins or nucleic acids that do not occur in nature, but are the product of human engineering. For example, in some embodiments, a recombinant protein or nucleic acid molecule comprises an amino acid or nucleotide sequence that comprises at least one, at least two, at least three, at least four, at least five, at least six, or at least seven mutations as compared to any naturally occurring sequence. By “reduces” is meant a negative alteration of at least 10%, 25%, 50%, 75%, or 100%. By “reference” is meant a standard or control condition. In one embodiment, the reference is a wild-type or healthy cell. In other embodiments and without limitation, a reference is an untreated cell that is not subjected to a test condition, or is subjected to placebo or normal saline, medium, buffer, and / or a control vector that does not harbor a polynucleotide of interest. A “reference sequence” is a defined sequence used as a basis for sequence comparison. A reference sequence may be a subset of or the entirety of a specified sequence; for example, a segment of a full-length cDNA or gene sequence, or the complete cDNA or gene sequence. For polypeptides, the length of the reference polypeptide sequence will generally be at least about 16 amino acids, at least about 20 amino acids, at least about 25 amino acids, about 35 amino acids, about 50 amino acids, or about 100 amino acids. For nucleic acids, the length of the reference nucleic acid sequence will generally be at least about 50 nucleotides, at least about 60 nucleotides, at least about 75 nucleotides, about 100 nucleotides or about 300 nucleotides or any integer thereabout or therebetween. In some embodiments, a reference sequence is a wild-type sequence of a protein of interest. In other embodiments, a reference sequence is a polynucleotide sequence encoding a wild-type protein. The term "RNA-programmable nuclease," and "RNA-guided nuclease" are used with (e.g., binds or associates with) one or more RNA(s) that is not a target for cleavage. In some embodiments, an RNA-programmable nuclease, when in a complex with an RNA, may be referred to as a nuclease:RNA complex. Typically, the bound RNA(s) is referred to as a guide RNA (gRNA). gRNAs can exist as a complex of two or more RNAs, or as a single RNA molecule. gRNASs that exist as a single RNA molecule may be referred to as single- guide RNAs (sgRNAs), though "gRNA" is used interchangeably to refer to guide RNAs that exist as either single molecules or as a complex of two or more molecules. Typically, gRNAs that exist as single RNA species comprise two domains: (1) a domain that shares homology to a target nucleic acid (e.g., and directs binding of a Cas9 complex to the target); and (2) a domain that binds a Cas9 protein. In some embodiments, domain (2) corresponds to a sequence known as a tractrRNA, and comprises a stem-loop structure. For example, in some embodiments, domain (2) is identical or homologous to a tractRNA as provided in Jinek et ah, Science 337:816-821(2012), the entire contents of which is incorporated herein by reference. Other examples of gRNAs (e.g., those including domain 2) can be found in U.S. Provisional Patent Application, U.S.S.N. 61 / 874,682, filed September 6, 2013, entitled "Switchable Cas9 Nucleases and Uses Thereof," and U.S. Provisional Patent Application, U.S.S.N. 61 / 874,746, filed September 6, 2013, entitled "Delivery System For Functional Nucleases," the entire contents of each are hereby incorporated by reference in their entirety. In some embodiments, a gRNA comprises two or more of domains (1) and (2), and may be referred to as an "extended gRNA." For example, an extended gRNA will, e.g, bind two or more Cas9 proteins and bind a target nucleic acid at two or more distinct regions, as described herein. The gRNA comprises a nucleotide sequence that complements a target site, which mediates binding of the nuclease / RNA complex to said target site, providing the sequence specificity of the nuclease: RNA complex. In some embodiments, the RNA-programmable nuclease is the (CRISPR-associated system) Cas9 endonuclease, for example, Cas9 (Casnl) from Streptococcus pyogenes (see, e.g., "Complete genome sequence of an Ml strain of Streptococcus pyogenes." Ferretti I.J., et al., Proc. Natl. Acad. Sci. U.S.A. 98:4658-4663(2001), "CRISPR RNA maturation by trans- encoded small RNA and host factor RNase IIL." Deltcheva E., ef al., Nature 471:602- 607(2011). Because RNA-programmable nucleases (e.g., Cas9) use RNA:DNA hybridization to target DNA cleavage sites, these proteins are able to be targeted, in principle, to any sequence specified by the guide RNA. Methods of using RNA-programmable nucleases, such as Cas9, for site-specific cleavage (e.g., to modify a genome) are known in the art (see e.g., Cong, L. et al, Multiplex genome engineering using CRISPR / Cas systems. Science 339, 819-823 (2013); Mali, P. ef al, RNA-guided human genome engineering via Cas9. Science 339, 823- 826 (2013); Hwang, W.Y. et al., Efficient genome editing in zebrafish using a CRISPR-Cas system. Nature biotechnology 31, 227-229 (2013); Jinek, M. ef al., RNA-programmed genome editing in human cells. eLife 2, 00471 (2013); Dicarlo, J.E. ef al., Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems. Nucleic acids research (2013); Jiang, W. et al., RNA-guided editing of bacterial genomes using CRISPR-Cas systems. Nature biotechnology 31, 233-239 (2013); the entire contents of each of which are incorporated herein by reference). The term “single nucleotide polymorphism (SNP)” is a variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population (e.g., > 1%). For example, at a specific base position in the human genome, the C nucleotide can appear in most individuals, but in a minority of individuals, the position is occupied by an A. This means that there is a SNP at this specific position, and the two possible nucleotide variations, C or A, are said to be alleles for this position. SNPs underlie differences in susceptibility to disease. The severity of illness and the way our body responds to treatments are also manifestations of genetic variations. SNPs can fall within coding regions of genes, non-coding regions of genes, or in the intergenic regions (regions between genes). In some embodiments, SNPs within a coding sequence do not necessarily change the amino acid sequence of the protein that is produced, due to degeneracy of the genetic code. SNPs in the coding region are of two types: synonymous and nonsynonymous SNPs. Synonymous SNPs do not affect the protein sequence, while nonsynonymous SNPs change the amino acid sequence of protein. The nonsynonymous SNPs are of two types: missense and nonsense, SNPs that are not in protein-coding regions can still affect gene splicing, transcription factor binding, messenger RNA degradation, or the sequence of noncoding RNA. Gene expression affected by this type of SNP is referred to as an eSNP (expression SNP) and can be upstream or downstream from the gene. A single nucleotide variant (SNV) is a variation in a single nucleotide without any limitations of frequency and can arise in somatic cells. A somatic single nucleotide variation can also be called a single-nucleotide alteration. By "specifically binds" is meant a nucleic acid molecule, polypeptide, or complex thereof (e.g., a nucleic acid programmable DNA binding domain and guide nucleic acid), compound, or molecule that recognizes and binds a polypeptide and / or nucleic acid molecule of the invention, but which does not substantially recognize and bind other molecules in a sample, for example, a biological sample. Nucleic acid molecules useful in the methods of the invention include any nucleic acid molecule that encodes a polypeptide of the invention or a fragment thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence, but will typically exhibit substantial identity. Polynucleotides having “substantial identity” to an endogenous sequence are typically capable of hybridizing with at least one strand of a double-stranded nucleic acid molecule. Nucleic acid molecules useful in the methods of the invention include any nucleic acid molecule that encodes a polypeptide of the invention or a fragment thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence, but will typically exhibit substantial identity. Polynucleotides having “substantial identity” to an endogenous sequence are typically capable of hybridizing with at least one strand of a double-stranded nucleic acid molecule. By "hybridize" is meant pair to form a double-stranded molecule between complementary polynucleotide sequences (e.g., a gene described herein), or portions thereof, under various conditions of stringency. (See, e.g., Wahl, G. M. and S. L. Berger (1987) Methods Enzymol. 152:399; Kimmel, A. R. (1987) Methods Enzymol. 152:507). For example, stringent salt concentration will ordinarily be less than about 750 mM NaCl and 75 mM trisodium citrate, preferably less than about 500 mM NaCl and 50 mM trisodium citrate, and more preferably less than about 250 mM NaCl and 25 mM trisodium citrate. Low stringency hybridization can be obtained in the absence of organic solvent, e.g., formamide, while high stringency hybridization can be obtained in the presence of at least about 35% formamide, and more preferably at least about 50% formamide. Stringent temperature conditions will ordinarily include temperatures of at least about 30° C, more preferably of at least about 37° C, and most preferably of at least about 42° C. Varying additional parameters, such as hybridization time, the concentration of detergent, e.g., sodium dodecyl sulfate (SDS), and the inclusion or exclusion of carrier DNA, are well known to those skilled in the art. Various levels of stringency are accomplished by combining these various conditions as needed. In a one: embodiment, hybridization will occur at 30° C in 750 mM NaCl, 75 mM trisodium citrate, and 1% SDS. In another embodiment, hybridization will occur at 37° C in 500 mM NaCl, 50 mM trisodium citrate, 1% SDS, 35% formamide, and 100 pg / ml denatured salmon sperm DNA (ssDNA). In another embodiment, hybridization will occur at 42° C in 250 mM NaCl, 25 mM trisodium citrate, 1% SDS, 50% formamide, and 200 pg / ml ssDNA. Useful variations on these conditions will be readily apparent to those skilled in the art. For most applications, washing steps that follow hybridization will also vary in stringency. Wash stringency conditions can be defined by salt concentration and by temperature. As above, wash stringency can be increased by decreasing salt concentration or by increasing temperature. For example, stringent salt concentration for the wash steps will preferably be less than about 30 mM NaCl and 3 mM trisodium citrate, and most preferably less than about 15 mM NaCl and 1.5 mM trisodium citrate. Stringent temperature conditions for the wash steps will ordinarily include a temperature of at least about 25° C, more preferably of at least about 42° C, and even more preferably of at least about 68° C. In an embodiment, wash steps will occur at 25° C in 30 mM NaCl, 3 mM trisodium citrate, and 0.1% SDS. In a more preferred embodiment, wash steps will occur at 42 C in 15 mM NaCl, 1.5 mM trisodium citrate, and 0.1% SDS. In a more preferred embodiment, wash steps will occur at 68° C in 15 mM NaCl, 1.5 mM trisodium citrate, and 0.1% SDS. Additional variations on these conditions will be readily apparent to those skilled in the art. Hybridization techniques are well known to those skilled in the art and are described, for example, in Benton and Davis (Science 196:180, 1977); Grunstein and Hogness (Proc. Natl. Acad. Sci., USA 72:3961, 1975); Ausubel ez al. (Current Protocols in Molecular Biology, Wiley Interscience, New York, 2001); Berger and Kimmel (Guide to Molecular Cloning Techniques, 1987, Academic Press, New York); and Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York. By “split” is meant divided into two or more fragments. A "split Cas9 protein” or “split Cas9" refers to a Cas9 protein that is provided as an N- terminal fragment and a C-terminal fragment encoded by two separate nucleotide sequences. The polypeptides corresponding to the N-terminal portion and the C-terminal portion of the Cas9 protein may be spliced to form a “reconstituted” Cas9 protein. In particular embodiments, the Cas9 protein is divided into two fragments within a disordered region of the protein, e.g., as described in Nishimasu et al., Cell, Volume 156, Issue 5, pp. 935-949, 2014, or as described in Jiang et al. (2016) Science 351: 867-871. PDB file: 5F9R, each of which is incorporated herein by reference. In some embodiments, the protein is divided into two fragments at any C, T, A, or S within a region of SpCas9 between about amino acids A292-G364, F445-K483, or E565-T637, or at corresponding positions in any other Cas9, Cas9 variant (e.g., nCas9, dCas9), or other napDNAbp. In some embodiments, protein is divided into two fragments at SpCas9 T310, T313, A456, $469, or C574. In some embodiments, the process of dividing the protein into two fragments is referred to as “splitting” the protein, In other embodiments, the N-terminal portion of the Cas9 protein comprises amino acids 1-573 or 1-637 S. pyogenes Cas9 wild-type (SpCas9) (NCBI Reference Sequence: NC_002737.2, Uniprot Reference Sequence: Q99ZW2) and the C-terminal portion of the Cas9 protein comprises a portion of amino acids 574-1368 or 638-1368 of SpCas9 wild-type. The C-terminal portion of the split Cas9 can be joined with the N-terminal portion of the split Cas9 to form a complete Cas9 protein. In some embodiments, the C-terminal portion of the Cas9 protein starts from where the N-terminal portion of the Cas9 protein ends. As such, in some embodiments, the C-terminal portion of the split Cas9 comprises a portion of amino acids (551-651)-1368 of spCas9. "(551-651)-1368" means starting at an amino acid between amino acids 551-651 (inclusive) and ending at amino acid 1368. For example, the C- terminal portion of the split Cas9 may comprise a portion of any one of amino acid 551-1368, 552-1368, 553-1368, 554-1368, 555-1368, 556-1368, 557-1368, 558-1368, 559-1368, 560- 1368, 561-1368, 562-1368, 563-1368, 564-1368, 565-1368, 566-1368, 567-1368, 568-1368, 569-1368, 570-1368, 571-1368, 572-1368, 573-1368, 574-1368, 575-1368, 576-1368, 577- 1368, 578-1368, 579-1368, 580-1368, 581-1368, 582-1368, 583-1368, 584-1368, 585-1368, 586-1368, 587-1368, 588-1368, 589-1368, 590-1368, 591-1368, 592-1368, 593-1368, 594- 1368, 595-1368, 596-1368, 597-1368, 598-1368, 599-1368, 600-1368, 601-1368, 602-1368, 603-1368, 604-1368, 605-1368, 606-1368, 607-1368, 608-1368, 609-1368, 610-1368, 611- 1368, 612-1368, 613-1368, 614-1368, 615-1368, 616-1368, 617-1368, 618-1368, 619-1368, 620-1368, 621-1368, 622-1368, 623-1368, 624-1368, 625-1368, 626-1368, 627-1368, 628- 1368, 629-1368, 630-1368, 631-1368, 632-1368, 633-1368, 634-1368, 635-1368, 636-1368, 637-1368, 638-1368, 639-1368, 640-1368, 641-1368, 642-1368, 643-1368, 644-1368, 645- 1368, 646-1368, 647-1368, 648-1368, 649-1368, 650-1368, or 651-1368 of spCas9. In some embodiments, the C-terminal portion of the split Cas9 protein comprises a portion of amino acids 574-1368 or 638-1368 of SpCas9. By "subject" is meant a mammal, including, but not limited to, a human or non- human mammal, such as a bovine, equine, canine, ovine, or feline. Subjects include livestock, domesticated animals raised to produce labor and to provide commodities, such as food, including without limitation, cattle, goats, chickens, horses, pigs, rabbits, and sheep. By "substantially identical" is meant a polypeptide or nucleic acid molecule exhibiting at least 50% identity to a reference amino acid sequence (for example, any one of the amino acid sequences described herein) or nucleic acid sequence (for example, any one of the nucleic acid sequences described herein). In one embodiment, such a sequence is at least 60%, 80% or 85%, 90%, 95% or even 99% identical at the amino acid level or nucleic acid to the sequence used for comparison. Sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST, BESTFIT, GAP, or PILEUP / PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and / or other modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. In an exemplary approach to determining the degree of identity, a BLAST program may be used, with a probability score between e”* and e'* indicating a closely related sequence. COBALT is used, for example, with the following parameters: a) alignment parameters: Gap penalties-11,-1 and End-Gap penalties-5,-1, b) CDD Parameters: Use RPS BLAST on; Blast E-value 0.003; Find Conserved columns and Recompute on, and ¢) Query Clustering Parameters: Use query clusters on; Word Size 4; Max cluster distance 0.8; Alphabet Regular. EMBOSS Needle is used, for example, with the following parameters: a) Matrix: BLOSUMS62; b) GAP OPEN: 10; c) GAP EXTEND: 0.5; d) OUTPUT FORMAT: pair; e) END GAP PENALTY: false; f) END GAP OPEN: 10; and 2) END GAP EXTEND: 0.5. The term "target site" refers to a sequence within a nucleic acid molecule that is modified by a nucleobase editor. In one embodiment, the target site is deaminated by a deaminase or a fusion protein comprising a deaminase (e.g., cytidine or adenine deaminase). As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and / or symptoms associated therewith or obtaining a desired pharmacologic and / or physiologic effect. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated. In some embodiments, the effect is therapeutic, i.e., without limitation, the effect partially or completely reduces, diminishes, abrogates, abates, alleviates, decreases the intensity of, or cures a disease and / or adverse symptom attributable to the disease. In some embodiments, the effect is preventative, i.e., the effect protects or prevents an occurrence or reoccurrence of a disease or condition. To this end, the presently disclosed methods comprise administering a therapeutically effective amount of a compositions as described herein. By “uracil glycosylase inhibitor” or “UGI” is meant an agent that inhibits the uracil- excision repair system. In one embodiment, the agent is a protein or fragment thereof that binds a host uracil-DNA glycosylase and prevents removal of uracil residues from DNA. In an embodiment, a UGI is a protein, a fragment thereof, or a domain that is capable of inhibiting a uracil-DNA glycosylase base-excision repair enzyme. In some embodiments, a UGI domain comprises a wild-type UGI or a modified version thereof. In some embodiments, a UGI domain comprises a fragment of the exemplary amino acid sequence set forth below. In some embodiments, a UGI fragment comprises an amino acid sequence that comprises at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of the exemplary UGI sequence provided below. In some embodiments, a UGI comprises an amino acid sequence that is homologous to the exemplary UGI amino acid sequence or fragment thereof, as set forth below. In some embodiments, the UGI, or a portion thereof, is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or 100% identical to a wild- type UGI or a UGI sequence, or portion thereof, as set forth below. An exemplary UGI comprises an amino acid sequence as follows: >splP14739IUNGI_BPPB2 Uracil-DNA glycosylase inhibitor MINLSDIIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVMLLTSD APEYKPWALVIQDSNGENKIKML. The term “vector” refers to a means of introducing a nucleic acid sequence into a cell, resulting in a transformed cell. Vectors include plasmids, transposons, phages, viruses, liposomes, and episome. “Expression vectors” are nucleic acid sequences comprising the nucleotide sequence to be expressed in the recipient cell. Expression vectors may include additional nucleic acid sequences to promote and / or facilitate the expression of the of the introduced sequence such as start, stop, enhancer, promoter, and secretion sequences. Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein. DNA editing has emerged as a viable means to modify disease states by correcting pathogenic mutations at the genetic level. Until recently, all DNA editing platforms have functioned by inducing a DNA double strand break (DSB) at a specified genomic site and relying on endogenous DNA repair pathways to determine the product outcome in a semi- stochastic manner, resulting in complex populations of genetic products. Though precise, user-defined repair outcomes can be achieved through the homology directed repair (HDR) pathway, a number of challenges have prevented high efficiency repair using HDR in therapeutically-relevant cell types. In practice, this pathway is inefficient relative to the competing, error-prone non-homologous end joining pathway. Further, HDR is tightly restricted to the G1 and S phases of the cell cycle, preventing precise repair of DSBs in post- mitotic cells. As a result, it has proven difficult or impossible to alter genomic sequences in a user-defined, programmable manner with high efficiencies in these populations. Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein. DNA editing has emerged as a viable means to modify disease states by correcting pathogenic mutations at the genetic level. Until recently, all DNA editing platforms have functioned by inducing a DNA double strand break (DSB) at a specified genomic site and relying on endogenous DNA repair pathways to determine the product outcome in a semi- stochastic manner, resulting in complex populations of genetic products. Though precise, user-defined repair outcomes can be achieved through the homology directed repair (HDR) pathway, a number of challenges have prevented high efficiency repair using HDR in therapeutically-relevant cell types. In practice, this pathway is inefficient relative to the competing, error-prone non-homologous end joining pathway. Further, HDR is tightly restricted to the G1 and S phases of the cell cycle, preventing precise repair of DSBs in post- mitotic cells. As a result, it has proven difficult or impossible to alter genomic sequences in a user-defined, programmable manner with high efficiencies in these populations. BRIEF DESCRIPTION OF THE DRAWINGS FIGs. 1A - 1C depict plasmids. FIG. 1A is an expression vector encoding a TadA7.10-dCas9 base editor. FIG. 1B is a plasmid comprising nucleic acid molecules encoding proteins that confer chloramphenicol resistance (CamR) and spectinomycin resistance (SpectR). The plasmid also comprises a kanamycin resistance gene disabled by two point mutations. FIG. 1C is a plasmid comprising nucleic acid molecules encoding proteins that confer chloramphenicol resistance (CamR) and spectinomycin resistance (SpectR). The plasmid also comprises a kanamycin resistance gene disabled by three point mutations. FIG. 2 is an image of bacterial colonies transduced with the expression vectors depicted in FIG. 1, which included a defective kanamycin resistance gene. The vectors contained ABE7.10 variants that were generated using error prone PCR. Bacterial cells expressing these “evolved” ABE7.10 variants were selected for kanamycin resistance using increasing concentrations of kanamycin. Bacteria expressing ABE7.10 variants having adenosine deaminase activity were capable of correcting the mutations introduced into the kanamycin resistance gene, thereby restoring kanamycin resistance. The kanamycin resistant cells were selected for further analysis. FIGs. 3A and 3B illustrate editing of a regulatory region of the hemoglobin subunit gamma (HGB1) locus, which is a therapeutically relevant site for upregulation of fetal hemoglobin. FIG. 3A is a drawing of a portion of the regulatory region for the HGB1 gene. FIG. 3B quantifies the efficiency and specificity of adenosine deaminase variants. Editing is assayed at the hemoglobin subunit gamma 1 (HGB1) locus in HEK293T cells, which is therapeutically relevant site for upregulation of fetal hemoglobin. The top panel depicts nucleotide residues in the target region of the regulatory sequence of the HGB1 gene. AS, A8, A9, and A11 denote the edited adenosine residues in HGB1. FIG. 4 illustrates the relative effectiveness of adenosine base editors comprising a dCas9 that recognizes a noncanonical PAM sequence. The top panel depicts the coding sequence of the hemoglobin subunit. The bottom panel is a graph demonstrating the efficiency of adenosine deaminase variant base editors with guide RNAs of varying lengths. FIG. 5 is a graph illustrating the efficiency and specificity of ABES base editors. The percent editing at intended target nucleotides and unintended target nucleotides (bystanders) is quantified. FIG. 6 is a graph illustrating the efficiency and specificity of ABES base editors. The percent editing at intended target nucleotides and unintended target nucleotides (bystanders) is quantified. FIGs. 7A - 7D depict eighth generation adenine base editors mediate superior A*T to GC conversion in human cells. FIG. 7A illustrates an overview of adenine base editing: i) ABES creates an R-loop at a sgRNA-targeted site in the genome; ii) TadA* deaminase chemically converts adenine to inosine via hydrolytic deamination on the ss-DNA portion of the R-loop; iii) D10A nickase of Cas9 nicks the strand opposite of the inosine containing strand; iv) the inosine containing strand can be used as a template during DNA replication; v) inosine preferentially base pairs with cytosine in the context of DNA polymerases; and vi) following replication, inosine may be replaced by guanosine. FIG. 7B illustrates the architecture of ABE8.x-m and ABE8.x-d. FIG. 7C illustrates three perspectives of the E. coli TadA deaminase (PDB 1Z3A) aligned with the S. aureus TadA (not shown) complexed with tRNAArg2 (PDB 2B3J). Mutations identified in eighth round of evolution are highlighted. FIG. 7D are graphs depicting A+T to G+C base editing efficiencies of core ABES constructs relative to ABE7.10 constructs in Hek293T cells across eight genomic sites. Values and error bars reflect the mean and s.d. of three independent biological replicates performed on different days. FIGS 8A-8C depict Cas9 PAM-variant ABE8s and catalytically dead Cas9 ABE8 variants mediate higher AT to G=C conversion than corresponding ABE7.10 variants in human cells. Values and error bars reflect the mean and s.d. of three independent biological replicates performed on different days. FIG. 8A is a graph depicting A*T to GC conversion in Hek293T cells with NG-Cas9 ABES8s (-NG PAM). FIG. 8B is a graph depiecting A*T to GC conversion in Hek293T cells with Sa-Cas9 ABE8s (-NNGRRT PAM). FIG. 8C isa graph depiecting A+T to G=C conversion in Hek293T cells with catalytically inactivated, dCas9-ABESs (D10A, H840A in S. pyogenes Cas9). FIGs. 9A-9E depict the comparison between the on- and off-target editing frequencies between ABE7.10, ABEmax and ABEmax with one BPNLS in Hek293T cells. Individual data points are shown and error bars represent s.d. for n=3 independent biological replicates, performed on different days. FIGs 9A and 9B are graphs that depict on-target DNA editing frequencies. FIGs 9B and 9C are graphs that depict sgRNA-guided DNA-off- target editing frequencies. FIG 9E is a graph depicting RNA off-target editing frequencies. FIGs. 10A-10B depict the median A+T to G+C conversion and corresponding INDEL formation of TadA, C-terminal alpha-helix truncation ABE constructs in HEK293T cells. FIG 10A is a heat map depicting A+T to GC median editing conversion across 8 genomic sites. FIG 10B is a heat map depicting INDEL formation. Delta residue value corresponds to deletion position in TadA. Median value generated from n=3 biological replicate. FIG 11 are heat maps depicting the median A«T to G+C conversion of 40 ABE8 constructs in HEK293T cells across 8 genomic sites. Median values were determined from two or greater biological replicates. FIG. 12 is a heat map depicting median INDEL % of 40 ABES constructs in HEK293T cells across 8 genomic sites. Median values were determined from two or greater biological replicates. FIG. 13 is a graph depicting fold change in editing, ABE8:ABE7. Representation of average ABE8:ABE7 AT to G+C editing in Hek293T cells across all A positions within the target of eight different genomic sites. Positions 2-12 denote location of a target adenine within the 20-nt protospacer with position 20 directly 5° of the -NGG PAM. FIG. 14 depicts a dendrogram of ABE8s. Core ABE8 constructs selected for further studies highlighted in in black. FIG. 15 are heat maps depicting median AT to G+C conversion of core eight ABE8 constructs in HEK293T cells across 8 genomic sites. Median values were determined from three or greater biological replicates. FIG. 16 is a heat map depicting median INDEL frequency of core 8 ABES8s tested at 8 genomic sites in HEK293T cells. FIG. 17 are heat maps depicting median A*T to G+C conversion of core NG-ABE8 constructs 9 (-NG PAM) at six genomic sites in HEK293T cells. Median value generated from n=3 biological replicate. FIG. 18 is a heat map depicting median INDEL frequency of core NG-ABESs tested at six genomic sites in HEK293T cells. Median value generated from n=3 biological replicate. FIG. 19 are heat maps depicting median A«T to G+C conversion of core Sa-ABE8 constructs (-NNGRRT PAM) at six genomic sites in HEK293T cells. Site positions are numbered -2 to 20 (5° to 3’) within the 22-nt protospacer. Position 20 is 5’ to the NNGRRT PAM. Median value generated from n=3 biological replicate. FIG. 20 is a heat map depicting median INDEL frequency of core Sa-ABE8s tested at 8 genomic sites in HEK293T cells. Median value generated from n=3 biological replicate. FIG. 21 are heat maps depicting median AT to G+C conversion of core dC9-ABES- m constructs at eight genomic sites in HEK293T cells. Dead Cas9 (dC9) is defined as D10A and H840A mutations within S. pyogenes Cas9. Median value generated from n>3 biological replicate. FIG. 22 are heat maps depicting median A*T to G*C conversion of core dC9-ABE8-d constructs at eight genomic sites in HEK293T cells. Dead Cas9 (dC9) is defined as D10A and H840A mutations within S. pyogenes Cas9. Median value generated from n>3 biological replicate. FIGs. 23A and 23B depict Median INDEL frequency of core dC9-ABESs tested at 8 genomic sites in HEK293T cells. Median value generated from n>3 biological replicate. FIG. 23A is a heat map depicting indel frequency shown for dC9-ABES-m variants relative to ABE7.10. FIG. 23B is a heat map depicting indel frequency shown for dC9-ABE8-d variants relative to ABE7.10. FIG. 24 is a graph depicting C+G to T+A editing with Hek293T cells treated with ABE8s and ABE7.10. Editing frequencies for each site averaged across all C positions within the target. Cytosines within the protospacer are indicted with shading. FIGs. 25A-25H depict DNA on-target and sgRNA-dependent DNA off-target editing by ABES constructs and ABES constructs with TadA mutations to improve specificity for DNA. Individual data points are shown and error bars represent s.d. for n=3 independent biological replicates, performed on different days. FIGs. 25A and 25B are graph depicting on-target DNA editing frequencies for core ABE8 constructs as compared to ABE7. FIGs. 25C and 25D are graphs depicting on-target DNA editing frequencies for ABE8 with mutations that improve RNA off-target editing. FIGs. 25E and 25F are graphs depicting sgRNA-guided DNA-off-target editing frequencies for core ABE 8 constructs as compared to ABET. FIGs. 25G and 25H are graphs depicting sgRNA-guided DNA-off-target editing frequencies for ABE 8 constructs with mutations that improve RNA off-target editing. FIG. 26 is a graph depicting indel frequencies at 12 previously identified sgRNA- dependent Cas9 off-target loci in human cells Individual data points are shown and error bars represent s.d. for n=3 independent biological replicates, performed on different days. FIGs. 27A and 27B depict A*T to G+C conversion and phenotypic outcomes in primary cells. FIG. 27A is a graph depicting A*T to G*C conversion at -198 HBG1 / 2 site in CD34+ cells treated with ABE from two separate donors. NGS analysis conducted at 48 and 144h post treatment. -198 HBG1 / 2 target sequence shown with A7 highlighted. Percent AsT to G+C plotted for A7. FIG. 27B is a graph depicting percentage of y-globin formed as a fraction of alpha-globin. Values shown from two different donors, post ABE treatment and erythroid differentiation. FIGs. 28A and 28B depict AT to GC conversion of CD34+ cells treated with ABE8 at the -198 promoter site upstream of HBG1 / 2. FIG. 28A is a heat map depicting Ato G editing frequency of ABE8s in CD34+ cells from two donors, where Donor 2 is heterozygous for sickle cell disease, at 48 and 144h post editor treatment. FIG. 28B is a graphical representation of distribution of total sequencing reads which contain either A7 only edits or combined (A7 + AB) edits. FIG. 29 is a heat map depicting INDEL frequency of CD34+ cells treated with ABE8 at the -198 site of the gamma-globin promoter. Frequencies shown from two donors at 48h and 144h time points. FIG. 30 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of untreated differentiated CD34+ cells (donor 1). FIG. 31 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE7.10-m (donorl) FIG. 32 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE7.10-d (donorl). FIG. 33 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.8-m (donor1) FIG. 34 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.8-d (donorl). FIG. 35 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES8.13-m (donorl). FIG. 36 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.13-d (donorl). FIG. 37 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES8.17-m (donorl). FIG. 38 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.17-d (donorl). FIG. 39 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE8.20-m (donorl). FIG. 40 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES,20-d (donor 1). FIG. 41 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells untreated (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 42 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE7.10-m (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 43 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE7.10-d (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 44 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.8-m (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 45 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.8-d (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 46 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES8.13-m (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 47 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE8.13-d (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 48 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE8.17-m (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 49 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABES.17-d (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 50 depicts an UHPLC UV-Vis trace (220 nm) and integration of globin chain levels of differentiated CD34+ cells treated with ABE8.20-m (donor 2). Note: donor 2 is heterozygous for sickle cell disease. FIG. 51A-51E depict editing with ABE8.8 at two independent sites reached over 90% editing on day 11 post erythroid differentiation before enucleation and about 60% of gamma globin over alpha globin or total beta family globin on day 18 post erythroid differentiation. FIG. 51A is a graph depicting an average of ABES.8 editing in 2 healthy donors in 2 independent experiments. Editing efficiency was measured with primers that distinguish HBGI and HBG2. FIG. 51B is a graph depicting an average of 1 healthy donor in 2 independent experiments. Editing efficiency was measured with primers that recognize both HBGI1 and HBG2. FIG. 51C is a graph depicting editing of ABE8.8 in a donor with heterozygous E6V mutation. FIGs. 51D and S1E are graphs depicting gamma globin increase in the ABER .8 edited cells. FIGs. 52A and 52B depict percent editing using ABE variants to correct sickle cell mutations. FIG. 52A is a graph depicting a screen of different editor variants with about 70% editing in SCD patient fibroblasts. FIG. 52B is a graph depicting CD34 cells from healthy donors edited with a lead ABE variant, targeting a synonymous mutation A13 in an adjacent proline that resides within the editing window and serves as a proxy for editing the SCD mutation. ABES variants showed an average editing frequency around 40% at the proxy Al3. FIGs. 53A and 53B depict RNA amplicon sequencing to detect cellular A-to-I editing in RNA associated with ABE treatment. Individual data points are shown and error bars represent s.d. for n=3 independent biological replicates, performed on different days. FIG. 53A is a graph depicting A-to-I editing frequencies in targeted RNA amplicons for core ABE 8 constructs as compared to ABE7 and Cas9(D10A) nickase control. FIG. 53B is a graph depicting A-to-I editing frequencies in targeted RNA amplicons for ABE8 with mutations that have been reported to improve RNA off-target editing. FIG. 54 is a schematic diagram illustrating the loss of dopamine that results from the loss of dopaminergic neurons in Parkinson Disease. FIG. 55 is a schematic diagram showing a guide RNA and target sequences for the correction of R1441C and R1441H mutations in LRRK2 associated with Parkinson’s Disease. FIG. 56 is a schematic diagram showing target sequences for correction of the Y1699C, G20198S, and 12020 mutations in LRRK?2 associated with Parkinson’s Disease. FIG. 57A-57C provides a graph, a schematic diagram, and a table. FIG. 57A quantifies the percent conversion of A to G at nucleic acid position 7 of the LRRK?2 target sequence. The editors used are designated PV1-PV 14, a description of this which is provided below. pCMV designates the CMV promoter; bpNLS designates a bipartite Nuclear Localization Signal; monoABES.1 designates a monomeric form of the ABE8.1 base editor. FIG. 57B depicts target sequences and guide RNA for correction of the R1441C mutation in LRRK?2 associated with Parkinson’s Disease. FIG. 57C shows the percent conversion of A to G at nucleic acid position 7 of the LRRK2 target sequence. Editors PV1-14 were used to edit LRRK2 R1441C. Editors (15-28) were used to edit G2109. The editors (PV1-28) used for correction of the LRRK2 mutations follows: PVI1 (also termed PV15). pCMV _monoABES8.1 bpNLS + Y147T MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLY VTFEPCYMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHYPGMNHRVEITEGILADECAALLCTFFRMPRQVFNAQKKAQSSTD PV2 (also termed PV16). pCMV_monoABES.1 bpNLS + Y147R MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLY VTFEPCYMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHYPGMNHRVEITEGILADECAALLCRFFRMPRQVFNAQKKAQSSTD PV3 (also termed PV17). pPCMV_monoABES8.1 bpNLS + Q154S MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLYVTFEPCYMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRSVFNAQKKAQSSTD PV4 (also termed PV18). pPCMV_monoABES8.1 bpNLS + Y123H MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLYVTFEPCYMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHHPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD PVS5 (also termed PV19). pCMV _monoABES.1 bpNLS + V82S MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLYSTFEPCYMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSTD PV6 (also termed PV20). pCMV _monoABES8.1 bpNLS + T166R MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLYVTFEPCYMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRQVFNAQKKAQSSRD PV7 (also termed PV21). pCMV_monocABES.1 bpNLS + Q154R MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLYVTFEPCYMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRRVFNAQKKAQSSTD PV8 (also termed PV22). p>CMV_monoABES8.1_bpNLS + Y147R_Q154R_Y123H MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLYVTFEPCYMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHHPGMNHRVEITEGILADECAALLCRFFRMPRRVFNAQKKAQSSTD PV9 (also termed PV23). pCMV_monoABES.1_bpNLS + Y147R_Q154R_I76Y MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLYDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAK TGAAGSLMDVLHYPGMNHR VEITEGILADECAALLCRFFRMPRRVFNAQKKAQSST D PV10 (also termed PV24). pCMV_monoABES8.1_bpNLS + Y147R_Q154R_T166R MSEVEFSHEYWMRHALTL AKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHYPGMNHR VEITEGIL ADECAALLCRFFRMPRRVENAQKKAQSSRD PV11 (also termed PV25). pPCMV_monoABES8.1_bpNLS + Y147T_Q154R MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHYPGMNHRVEITEGILADECAALLCTFFRMPRRVFNAQKKAQSSTD PV12 (also termed PV26). pCMV_monoABES.1_bpNLS + Y147T_Q154S MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLYVTFEPCYMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHYPGMNHR VEITEGIL ADECAALLCTFFRMPRS VFNAQKKAQSSTD PV13 (also termed PV27). pPCMV_monoABES.1 bpNLS + HI123Y123H _Y147R_QI154R _176Y MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLYDATLYVTFEPCVYMCAGAMIHSRIGRVVFGVRNAK TGAAGSLMDVLHHPGMNHR VEITEGILADECAALLCRFFRMPRRVFNAQKKAQSST D PV14 (also termed PV28). pPCMV_monoABES8.1_bpNLS + V82§ + Q154R MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPT AHAEIMALRQGGLVMQNYRLIDATLYSTFEPCVMCAGAMIHSRIGRVVFGVRNAKT GAAGSLMDVLHYPGMNHRVEITEGILADECAALLCYFFRMPRRVFNAQKKAQSSTD FIG. 58A-58C provides a graph, a schematic diagram, and a table. FIG. 58A quantifies the percent conversion of A to G at nucleic acid position 6 of the LRRK2 target sequence. The editors used are designated PV15-PV28, a description of this which is provided above. pCMV designates the CMV promoter; bpNLS designates a bipartite Nuclear Localization Signal, monoABES.1 designates a monomeric form of the ABE8.1 base editor. FIG. 58B depicts target sequences and guide RNAs for correction of the G2019S mutation in LRRK2 associated with Parkinson’s Disease. FIG. 58C shows the percent conversion of A to G at nucleic acid positions 4 and 6 of the LRRK?2 target sequence. The A to G transition at position 4 is a bystander effect. FIGS. 59A-59L depicts the sequence reads for the A to G transition at position 7 of the LRRK2 target sequence, which encodes R1441C (See FIG. 57A-57C). The editor is indicated (PV1-14). A description of PV 1-28 is provided at FIG. 56. FIGS. 60A-60W depicts the sequence reads for the A to G transition at positions 4 and 6 of the LRRK2 target sequence, which encodes G2019S (See FIG. 58A-58C). FIG. 61A provides a schematic diagram depicting the target sequence for correction of a pathogenic mutation A419V in LRRK?2, which is encoded by an antisense strand G>A mutation. The mutation is corrected using an ABE targeting the A at position 12 using an SpCas9 variant that has specificity for a TGG PAM. FIG. 61B provides a schematic diagram depicting the target sequence for correction of a pathogenic mutation L1114L in LRRK2, which is associated with Parkinson Disease. The mutation is an antisense strand T>C, which is corrected using a base editor having cytidine deaminase activity (CBE). FIG. 61C provides a schematic diagram depicting the target sequence for correction of a pathogenic mutation I1122V in LRRK?2, which is associated with Parkinson Disease. The mutation is an antisense strand T>C, which is corrected using a base editor having cytidine deaminase activity (CBE). FIG.61D provides a schematic diagram depicting the target sequence for correction of a pathogenic mutation M1869V in LRRK?2, which is associated with Parkinson Disease. The mutation is an antisense strand T>C, which is corrected using a base editor having cytidine deaminase activity (CBE). FIGS. 62A and 62B depict the precise base editing correction of the Mus musculus IDUA W401X mutation in HEK293T cells. FIG. 62A is a graph depicting the percentage of base editing of the Mus musculus IDUA W401X mutation using ABE8 base editor variants using a 21-nucleotide guide RNA. FIG. 62B is a graph depicting the percent indels for the ABES base editor variants using a 21-nucleotide guide RNA. FIG. 63 is a graph depicting the percentage of base editing of the Mus musculus IDUA W401X mutation using ABES base editor variants using either a 20-nucleotide guide RNA or a 21-nucleotide guide RNA. FIG. 64 depicts a diagramic illustration of the Homo sapiens IDUA genomic nucleic acid and amino acid sequence as a target for A-to-G nucleotide base editing to correct the W402X mutation. Also shown in the figure is the nucleic acid sequence of a corresponding guide RNA (gRNA). Noted in the figure is the target adenosine (A) nucleobase (boxed) in the IDUA nucleic acid sequence. FIGS. 65A and 65B depict the precise base editing correction of the Homo sapiens IDUA W402X mutation in HEK293T cells. FIG. 65A is a graph depicting the percentage of base editing of the Homo sapiens IDUA W402X mutation using ABES base editor variants using a 20-nucleotide guide RNA. FIG. 65B is a graph depicting the percent indels for the ABES base editor variants using a 20-nucleotide guide RNA. FIGS. 66A through 660 are tables depicting the efficiency of percentage of A-to-G nucleotide change in the IDUA nucleic acid sequence using ABE8 base editor variants, as detected by deep sequencing (My Seq) following PCR of the genomic DNA in cells in which base editing had occurred. FIGS. 66A through 66M depict the percent of A to G base editing at position 6 in the IDUA nucleic acid target site using three samples of each ABE8 base editor variants ABE8.1 through ABES.13, respectively. FIG. 66N depicts the percent of A to G base editing at position 6 in the [DUA nucleic acid target site using three samples of positive control base editor ABE7.10. FIG. 660 depicts the percent of A to G base editing at position 6 in the IDUA nucleic acid target site using two samples of negative control. FIG. 67 illustrates Rett / MECP2: Mutation correction. MECP2 loss of function — can result from many different de novo mutations. X-linked: XX patients are mosaic for MECP2 loss; XY usually results in infant mortality. FIG. 68 illustrates Rett Syndrome R106W mutation correction for top 3 guide sequences. FIG. 69 illustrates Rett Syndrome R255X mutation correction with editors having NGTT PAM optimization. FIGS. 70A-C: Hurler / IDUA mutation correction. FIG. 70A illustrates experiment design of IDUA W402X mutation correction. FIG. 70B illustrates the percent editing for each editor construct. FIG. 70C illustrates specific activity (nmol / mg / h) for edited and unedited constructs. FIG. 71 depicts / n vivo base editing with ABE 8.8. From left to right for each of each sample: Guide 11 (AAV9), Guide 12 (AAV9), Guide 11 (PHP.eB), Guide 12 (PHP eB), and Control. FIGS. 72A-72B. A°T to G*C conversion by ABE7.10 and ABES variants at the ABCA4 G1961E allele in a model cell line. FIG. 72A: AT to G*C conversion in HEK293T cells at an integrated disease allele and wobble base of the ABCA4 G1961E codon after plasmid lipofection of the 21-nt spacer sgRNA and base editor variant. Cells incubated for 5 days after lipofection and were then assessed for editing. FIG. 72B: The DNA sequence at the site of interest including the ABCA4 G1961E disease allele, the wobble base of the codon, and the -NGG PAM used by the 21-nt spacer sgRNA. Error bars represent the s.d. of three replicates. In each data set, the disease allele is on the left and the wobble base is on the right. FIG. 73. AT to G*C conversion by sgRNA spacer-length variants at the ABCA4 G1961E allele in a model cell line. A+T to G+C conversion in HEK293T cells at an integrated disease allele and wobble base of the ABCA+ G1961E codon after plasmid lipofection of the sgRNA of varied spacer lengths and ABE7.10. Cells incubated for 5 days after lipofection and were then assessed for editing. hRz = inclusion of a self-cleaving hammer head ribozyme at the 5’-end of the sgRNA. Error bars represent the s.d. of three replicates. In each data set, the disease allele is on the left and the wobble base is on the right. FIG. 74. Schematic of the dual AAV delivery of a split base editor using split intein reconstitution. Two AAV particles are packaged separately with the components required for base editing. One virus encodes the C-terminal region of the base editor with an N-terminal split intein fusion, and a complementary virus encodes the N- terminal region of the base editor with a C-terminal split intein fusion as well as the sgRNA. Upon co-transduction of the complementary viruses, the sgRNA is transcribed and each half of the base editor is expressed and recombined through protein trans-splicing via the split intein. FIGS. 75A-75B. A°T to G*C conversion by dual AAV delivery of split ABE variants at the ABCA4 G1961 in wild type cells. FIG. 75A: A+T to G+C and C*G to TA conversion in wild type ARPE-19 cells at the wild type ABCA+4 G1961 target site, in which editing at position 8A serves as a surrogate target for editing in these cells. Cells infected at a MOI of 5E+4 viral genomes per virus per cell. Cells were incubated for 2 weeks post infection and were then assessed for editing. Error bars represent the s.d. of six replicates. For each data point, samples treated with Pos. 8 (A>G)- surrogate site are shown on the left and Pos. 5 (C>T) are shown on the right. FIG. 75B: The DNA sequence at the wild type target site including the ABCA+ G1961 allele and the -NGG PAM used by the 21-nt spacer sgRNA targeting the wild type sequence. FIGS. 76A-76B. Off target base editing in wild type ARPE-19 cells dual infected with AAV2 expressing split ABE7.10 and sgRNA targeting the disease allele of ABCA+4 G1961E. FIG. 76A: Maximum AT to G+C conversion across the target or off- target protospacers 2 weeks after co-infection with the dual AAV (teal) compared to untreated controls (gray). FIG. 76B; Maximum non-A+T to G+C conversion across the target or off-target protospacers 2 weeks after co-infection with the dual AAV (teal) compared to untreated controls (gray). For each data point, samples treated with wild type (wt) ARPE-19 cells are shown on the left and untreated wt ARPE-19 cells are shown on the right. FIG. 77. Indel formation due to base editing in wild type ARPE-19 cells dual infected with AAV2 expressing split ABE7.10 and sgRNA targeting the disease allele of ABCA4 G1961E. Percentage of indels formed within or proximal to the target or off-target protospacers 2 weeks after co-infection with the dual AAV (teal) compared to untreated controls (gray). For each data point, samples treated with wild type (wt) ARPE-19 cells are shown on the left and untreated wt ARPE-19 cells are shown on the right. FIG. 78: Primate Retina Integrity and GFP expression at Day 22 post-culture. Sections were immunolabeled with anti-Rhodopsin, anti-GFP, and biotinylated peanut agglutinin antibodies overnight at 4°C. Anc80L65.hGRK.eGFP showed GFP to be observed exclusively in the photoreceptor-containing outer nuclear layer (ONL) confirming photoreceptor-specific activity of the GRK promoter. Top row is Day 0, untransduced. The second row is Day 22, untransduced. Third row is Day 22, GRK. Fourth row is Day 22, CMB. Columns are unstained (1% column), DAPI (2 column), GFP (3rd column), PNA (4th column), and rhodopsin (5th column). FIG. 79: Cas9 Expression in NHP. Cas9 expression is detected in primate retina as early as day 6 post-culture. Results are shown for ABE7.10 (columns 1 and 2), ABE8.5 (columns 2 and 3), and ABE8.9 (columns 3 and 4). Top row: day 6 post-culture. Bottom row: day 17 post-culture. The results demonstrate that the AAV system delivers split-inteins that express Cas9. Scale Bar: 100 um DETAILED DESCRIPTION OF THE INVENTION The invention provides compositions comprising novel adenine base editors (e.g., ABES) that have increased efficiency and methods of using them to generate modifications in target nucleobase sequences. NUCLEOBASE EDITOR Disclosed herein is a base editor or a nucleobase editor for editing, modifying or altering a target nucleotide sequence of a polynucleotide. Described herein is a nucleobase editor or a base editor comprising a polynucleotide programmable nucleotide binding domain (e.g., Cas9) and a nucleobase editing domain (e.g., adenosine deaminase). A polynucleotide programmable nucleotide binding domain (e.g., Cas), when in conjunction with a bound guide polynucleotide (e.g., gRNA), can specifically bind to a target polynucleotide sequence (i.e., via complementary base pairing between bases of the bound guide nucleic acid and bases of the target polynucleotide sequence) and thereby localize the base editor to the target nucleic acid sequence desired to be edited. In some embodiments, the target polynucleotide sequence comprises single-stranded DNA or double-stranded DNA. In some embodiments, the target polynucleotide sequence comprises RNA. In some embodiments, the target polynucleotide sequence comprises a DNA-RNA hybrid. Polynucleotide Programmable Nucleotide Binding Domain It should be appreciated that polynucleotide programmable nucleotide binding domains can also include nucleic acid programmable proteins that bind RNA. For example, the polynucleotide programmable nucleotide binding domain can be associated with a nucleic acid that guides the polynucleotide programmable nucleotide binding domain to an RNA. Other nucleic acid programmable DNA binding proteins are also within the scope of this disclosure, though they are not specifically listed in this disclosure. A polynucleotide programmable nucleotide binding domain of a base editor can itself comprise one or more domains. For example, a polynucleotide programmable nucleotide binding domain can comprise one or more nuclease domains, In some embodiments, the nuclease domain of a polynucleotide programmable nucleotide binding domain can comprise an endonuclease or an exonuclease. Herein the term “exonuclease” refers to a protein or polypeptide capable of digesting a nucleic acid (e.g., RNA or DNA) from free ends, and the term “endonuclease” refers to a protein or polypeptide capable of catalyzing (e.g, cleaving) internal regions in a nucleic acid (e.g., DNA or RNA). In some embodiments, an endonuclease can cleave a single strand of a double-stranded nucleic acid. In some embodiments, an endonuclease can cleave both strands of a double-stranded nucleic acid molecule. In some embodiments a polynucleotide programmable nucleotide binding domain can be a deoxyribonuclease. In some embodiments a polynucleotide programmable nucleotide binding domain can be a ribonuclease. In some embodiments, a nuclease domain of a polynucleotide programmable nucleotide binding domain can cut zero, one, or two strands of a target polynucleotide. In some embodiments, the polynucleotide programmable nucleotide binding domain can comprise a nickase domain. Herein the term “nickase” refers to a polynucleotide programmable nucleotide binding domain comprising a nuclease domain that is capable of cleaving only one strand of the two strands in a duplexed nucleic acid molecule (e.g, DNA). In some embodiments, a nickase can be derived from a fully catalytically active (e.g., natural) form of a polynucleotide programmable nucleotide binding domain by introducing one or more mutations into the active polynucleotide programmable nucleotide binding domain. For example, where a polynucleotide programmable nucleotide binding domain comprises a nickase domain derived from Cas9, the Cas9-derived nickase domain can include a D10A mutation and a histidine at position 840. In such embodiments, the residue H840 retains catalytic activity and can thereby cleave a single strand of the nucleic acid duplex. In another example, a Cas9-derived nickase domain can comprise an H840A mutation, while the amino acid residue at position 10 remains a D. In some embodiments, a nickase can be derived from a fully catalytically active (e.g, natural) form of a polynucleotide programmable nucleotide binding domain by removing all or a portion of a nuclease domain that is not required for the nickase activity. For example, where a polynucleotide programmable nucleotide binding domain comprises a nickase domain derived from Cas9, the Cas9-derived nickase domain can comprise a deletion of all or a portion of the RuvC domain or the HNH domain. The amino acid sequence of an exemplary catalytically active Cas9 is as follows: MDKKYSIGLDIGINSVGWAVITDEYKVPSKKFKVLGNTDRHS IKKNLIGALLFDSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFI QLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLARKNLSDAILLSDILRVNT EITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VIVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRY TGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVV DELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQL QONEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDS IDNKVLTRSDKNRGKSD NVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKH VAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVRE INNYHHAHDAYLNAV VGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLAN GEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNS DKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNP IDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLAS HYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPI REQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQ 1.GCD. A base editor comprising a polynucleotide programmable nucleotide binding domain comprising a nickase domain is thus able to generate a single-strand DNA break (nick) at a specific polynucleotide target sequence (e.g., determined by the complementary sequence of a bound guide nucleic acid). In some embodiments, the strand of a nucleic acid duplex target polynucleotide sequence that is cleaved by a base editor comprising a nickase domain (e.g., Cas9-derived nickase domain) is the strand that is not edited by the base editor (i.e., the strand that is cleaved by the base editor is opposite to a strand comprising a base to be edited). In other embodiments, a base editor comprising a nickase domain (e.g., Cas9- derived nickase domain) can cleave the strand of a DNA molecule which is being targeted for editing. In such embodiments, the non-targeted strand is not cleaved. Also provided herein are base editors comprising a polynucleotide programmable nucleotide binding domain which is catalytically dead (i.e., incapable of cleaving a target polynucleotide sequence). Herein the terms “catalytically dead” and “nuclease dead” are used interchangeably to refer to a polynucleotide programmable nucleotide binding domain which has one or more mutations and / or deletions resulting in its inability to cleave a strand of a nucleic acid. In some embodiments, a catalytically dead polynucleotide programmable nucleotide binding domain base editor can lack nuclease activity as a result of specific point mutations in one or more nuclease domains. For example, in the case of a base editor comprising a Cas9 domain, the Cas9 can comprise both a D10A mutation and an H840A mutation. Such mutations inactivate both nuclease domains, thereby resulting in the loss of nuclease activity. In other embodiments, a catalytically dead polynucleotide programmable nucleotide binding domain can comprise one or more deletions of all or a portion of a catalytic domain (e.g., RuvC1 and / or HNH domains). In further embodiments, a catalytically dead polynucleotide programmable nucleotide binding domain comprises a point mutation (e.g., D10A or H840A) as well as a deletion of all or a portion of a nuclease domain. Also contemplated herein are mutations capable of generating a catalytically dead polynucleotide programmable nucleotide binding domain from a previously functional version of the polynucleotide programmable nucleotide binding domain. For example, in the case of catalytically dead Cas9 (“dCas9”), variants having mutations other than D10A and HB840A are provided, which result in nuclease inactivated Cas9. Such mutations, by way of example, include other amino acid substitutions at D10 and H840, or other substitutions within the nuclease domains of Cas9 (e.g., substitutions in the HNH nuclease subdomain and / or the RuvC1 subdomain). Additional suitable nuclease-inactive dCas9 domains can be apparent to those of skill in the art based on this disclosure and knowledge in the field, and are within the scope of this disclosure. Such additional exemplary suitable nuclease-inactive Cas9 domains include, but are not limited to, D10A / H840A, D10A / D839A / H840A, and D10A / D839A / H840A / N863 A mutant domains (See, e.g, Prashant ef al., CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nature Biotechnology. 2013; 31(9): 833-838, the entire contents of which are incorporated herein by reference). Non-limiting examples of a polynucleotide programmable nucleotide binding domain which can be incorporated into a base editor include a CRISPR protein-derived domain, a restriction nuclease, a meganuclease, TAL nuclease (TALEN), and a zinc finger nuclease (ZFN). In some embodiments, a base editor comprises a polynucleotide programmable nucleotide binding domain comprising a natural or modified protein or portion thereof which via a bound guide nucleic acid is capable of binding to a nucleic acid sequence during CRISPR (i.e., Clustered Regularly Interspaced Short Palindromic Repeats)-mediated modification of a nucleic acid. Such a protein is referred to herein as a “CRISPR protein.” Accordingly, disclosed herein is a base editor comprising a polynucleotide programmable nucleotide binding domain comprising all or a portion of a CRISPR protein (i.e. a base editor comprising as a domain all or a portion of a CRISPR protein, also referred to as a “CRISPR protein-derived domain” of the base editor). A CRISPR protein-derived domain incorporated into a base editor can be modified compared to a wild-type or natural version of the CRISPR protein. For example, as described below a CRISPR protein-derived domain can comprise one or more mutations, insertions, deletions, rearrangements and / or recombinations relative to a wild-type or natural version of the CRISPR protein. CRISPR is an adaptive immune system that provides protection against mobile genetic elements (viruses, transposable elements and conjugative plasmids). CRISPR clusters contain spacers, sequences complementary to antecedent mobile elements, and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA). In type II CRISPR systems, correct processing of pre-crRNA requires a trans- encoded small RNA (tracrRNA), endogenous ribonuclease 3 (rnc) and a Cas9 protein. The tracrRNA serves as a guide for ribonuclease 3-aided processing of pre-crRNA. Subsequently, Cas9 / crRNA / tractRNA endonucleolytically cleaves linear or circular dsDNA target complementary to the spacer. The target strand not complementary to crRNA is first cut endonucleolytically, and then trimmed 3'-5' exonucleolytically. In nature, DNA-binding and cleavage typically requires protein and both RNAs. However, single guide RNAs (“sgRNA,” or simply “gNRA”) can be engineered so as to incorporate aspects of both the crRNA and tracrRNA into a single RNA species. See, e.g., Jinek M., et al., Science 337:816- 821(2012), the entire contents of which is hereby incorporated by reference. Cas9 recognizes a short motif in the CRISPR repeat sequences (the PAM or protospacer adjacent motif) to help distinguish self versus non-self. In some embodiments, the methods described herein can utilize an engineered Cas protein. A guide RNA (gRNA) is a short synthetic RNA composed of a scaffold sequence necessary for Cas-binding and a user-defined ~20 nucleotide spacer that defines the genomic target to be modified. Thus, a skilled artisan can change the genomic target of the Cas protein specificity is partially determined by how specific the gRNA targeting sequence is for the genomic target compared to the rest of the genome. In some embodiments, the gRNA scaffold sequence is as follows: GUUUUAGAGC UAGAAAUAGC AAGUUAAAAU AAGGCUAGUC CGUUAUCAAC UUGAAAAAGU GGCACCGAGU CGGUGCUUUU. In some embodiments, a CRISPR protein-derived domain incorporated into a base editor is an endonuclease (e.g., deoxyribonuclease or ribonuclease) capable of binding a target polynucleotide when in conjunction with a bound guide nucleic acid. In some embodiments, a CRISPR protein-derived domain incorporated into a base editor is a nickase capable of binding a target polynucleotide when in conjunction with a bound guide nucleic acid. In some embodiments, a CRISPR protein-derived domain incorporated into a base editor is a catalytically dead domain capable of binding a target polynucleotide when in conjunction with a bound guide nucleic acid. In some embodiments, a target polynucleotide bound by a CRISPR protein derived domain of a base editor is DNA. In some embodiments, a target polynucleotide bound by a CRISPR protein-derived domain of a base editor is RNA. Cas proteins that can be used herein include class 1 and class 2. Non-limiting examples of Cas proteins include Casl, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, Cas5h, Cas5a, Cas6, Cas7, Cas8, Cas9 (also known as Csnl or Csx12), Casl0, Csyl , Csy2, Csy3, Csy4, Csel, Cse2, Cse3, Cse4, CseSe, Cscl, Csc2, Csa5, Csnl, Csn2, Csm1, Csm2, Csm3, Csm4, CsmS5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx18, Csfl, Csf2, CsO, Csf4, Csd1, Csd2, Cstl, Cst2, Cshl, Csh2, Csal, Csa2, Csa3, Csa4, Csa5, Cas12a / Cpfl, Cas12b / C2cl, Cas12¢ / C2c3, Casl2d / CasY, Cas12e / CasX, Casl2g, Cas12h, and Cas12i, CARF, DinG, homologues thereof, or modified versions thereof. An unmodified CRISPR enzyme can have DNA cleavage activity, such as Cas9, which has two functional endonuclease domains: RuvC and HNH. A CRISPR enzyme can direct cleavage of one or both strands at a target sequence, such as within a target sequence and / or within a complement of a target sequence. For example, a CRISPR enzyme can direct cleavage of one or both strands within about 1, 2, 3, 4, 5,6,7,8,9, 10, 15, 20, 25, 50, 100, 200, 500, or more base pairs from the first or last nucleotide of a target sequence. A vector that encodes a CRISPR enzyme that is mutated to with respect, to a corresponding wild-type enzyme such that the mutated CRISPR enzyme lacks the ability to cleave one or both strands of a target polynucleotide containing a target sequence can be used. Cas9 can refer to a polypeptide with at least or at least about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity and / or sequence homology to a wild-type exemplary Cas9 polypeptide (e.g., Cas9 from S. pyogenes). Cas9 can refer to a polypeptide with at most or at most about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity and / or sequence homology to a wild-type exemplary Cas9 polypeptide (e.g., from S. pyogenes). Cas9 can refer to the wild-type or a modified form of the Cas9 protein that can comprise an amino acid change such as a deletion, insertion, substitution, variant, mutation, fusion, chimera, or any combination thereof. In some embodiments, a CRISPR protein-derived domain of a base editor can include all or a portion of Cas9 from Corynebacterium ulcerans (NCBI Refs: NC_015683.1, NC_017317.1); Corynebacterium diphtheria (NCBI Refs: NC_016782.1, NC_016786.1); Spiroplasma syrphidicola (NCBI Ref: NC_021284.1); Prevotella intermedia (NCBI Ref: NC_017861.1); Spiroplasma taiwanense (NCBI Ref: NC_021846.1); Streptococcus iniae (NCBI Ref: NC_021314.1); Belliella baltica NCBI Ref: NC_018010.1); Psychroflexus torquis (NCBI Ref: NC_018721.1); Streptococcus thermophilus NCBI Ref: YP_820832.1); Listeria innocua (NCBI Ref: NP_472073.1); Campylobacter jejuni (NCBI Ref: YP_002344900.1); Neisseria meningitidis (NCBI Ref: YP_002342100.1), Streptococcus pyogenes, or Staphylococcus aureus. Cas9 domains of Nucleobase Editors Cas9 nuclease sequences and structures are well known to those of skill in the art (See, e.g., “Complete genome sequence of an Ml strain of Streptococcus pyogenes.” Ferretti et al., Proc. Natl. Acad. Sci. U.S.A. 98:4658-4663(2001); “CRISPR RNA maturation by trans-encoded small RNA and host factor RNase IIL.” Deltcheva E., et al., Nature 471:602- 607(2011); and “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.” Jinek M., et al., Science 337:816-821(2012), the entire contents of each of which are incorporated herein by reference). Cas9 orthologs have been described in various species, including, but not limited to, S. pyogenes and S. thermophilus. Additional suitable Cas9 nucleases and sequences will be apparent to those of skill in the art based on this disclosure, and such Cas9 nucleases and sequences include Cas9 sequences from the organisms and loci disclosed in Chylinski, Rhun, and Charpentier, “The tractRNA and Cas9 families of type IT CRISPR-Cas immunity systems” (2013) RNA Biology 10:5, 726-737; the entire contents of which are incorporated herein by reference. In some embodiments, a nucleic acid programmable DNA binding protein (napDNAbp) is a Cas9 domain. Non-limiting, exemplary Cas9 domains are provided herein. The Cas9 domain may be a nuclease active Cas9 domain, a nuclease inactive Cas9 domain (dCas9), or a Cas9 nickase (nCas9). In some embodiments, the Cas9 domain is a nuclease active domain. For example, the Cas9 domain may be a Cas9 domain that cuts both strands of a duplexed nucleic acid (e.g., both strands of a duplexed DNA molecule). In some embodiments, the Cas9 domain comprises any one of the amino acid sequences as set forth herein. In some embodiments the Cas9 domain comprises an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identical to any one of the amino acid sequences set forth herein. In some embodiments, the Cas9 domain comprises an amino acid sequence that has 1,2, 3,4, 5,6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more or more mutations compared to any one of the amino acid sequences set forth herein. In some embodiments, the Cas domain comprises an amino acid sequence that has at least 10, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1100, or at least 1200 identical contiguous amino acid residues as compared to any one of the amino acid sequences set forth herein. In some embodiments, proteins comprising fragments of Cas9 are provided. For example, in some embodiments, a protein comprises one of two Cas9 domains: (1) the gRNA binding domain of Cas9; or (2) the DNA cleavage domain of Cas9. In some embodiments, proteins comprising Cas9 or fragments thereof are referred to as “Cas9 variants.” A Cas9 variant shares homology to Cas9, or a fragment thereof. For example, a Cas9 variant is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to wild-type Cas9. In some embodiments, the Cas9 variant may have 1, 2, 3, 4,5,6,7,8,9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 21, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more amino acid changes compared to wild-type Cas9. In some embodiments, the Cas9 variant comprises a fragment of Cas9 (e.g., a gRNA binding domain or a DNA-cleavage domain), such that the fragment is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to the corresponding fragment of wild-type Cas9. In some embodiments, the fragment is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% identical, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of the amino acid length of a corresponding wild-type Cas9. In some embodiments, the fragment is at least 100 amino acids in length. In some embodiments, the fragment is at least 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, or at least 1300 amino acids in length. In some embodiments, Cas9 fusion proteins as provided herein comprise the full-length amino acid sequence of a Cas9 protein, e.g., one of the Cas9 sequences provided herein. In other embodiments, however, fusion proteins as provided herein do not comprise a full-length Cas9 sequence, but only one or more fragments thereof, Exemplary amino acid sequences of suitable Cas9 domains and Cas9 fragments are provided herein, and additional suitable sequences of Cas9 domains and fragments will be apparent to those of skill in the art, A Cas9 protein can associate with a guide RNA that guides the Cas9 protein to a specific DNA sequence that has complementary to the guide RNA. In some embodiments, the polynucleotide programmable nucleotide binding domain is a Cas9 domain, for example a nuclease active Cas9, a Cas9 nickase (nCas9), or a nuclease inactive Cas9 (dCas9). Examples of nucleic acid programmable DNA binding proteins include, without limitation, Cas9 (e.g., dCas9 and nCas9), CasX, CasY, Cpfl, Cas12b / C2C1, and Cas12c / C2C3. In some embodiments, wild-type Cas9 corresponds to Cas9 from Streptococcus pyogenes (NCBI Reference Sequence: NC_017053.1, nucleotide and amino acid sequences as follows). ATGGATAAGAAATACTCAATAGGCTTAGATATCGGCACAARATAGCGTCGGATGGGCGGTGAT CACTGATGATTATAAGGTTCCGTCTAAAARAGT TCAAGGTTCTGGGAAATACAGACCGCCACA GTATCARAAAARATCTTATAGGGGCTCTTTTATTTGGCAGTGGAGAGACAGCGGAAGCGACT CGTCTCAAACGGACAGCTCGTAGAAGGTATACACGTCGGAAGAATCGTATTTGTTATCTACA GGAGATTTTTTCAAATGAGATGGCGAAAGTAGATGATAGTTTCTTTCATCGACTTGAAGAGT CTTTTTTGGTGGAAGAAGACAAGAAGCATGAACGTCATCCTATTTTTGGAAATATAGTAGAT GAAGTTGCTTATCATGAGAAATATCCAACTATCTATCATCTGCGARAAARATTGGCAGATTC TACTGATAAAGCGGATTTGCGCTTAATCTATTTGGCCTTAGCGCATATGATTAAGTTTCGTG GICATTTTTTGATTGAGGGAGATTTAAATCCTGATAATAGTGATGTGGACAAACTATTTATC CAGTTGGTACAAATCTACAATCAATTATTTGAAGAAAACCCTATTAACGCAAGTAGAGTAGA TGCTAAAGCGATTCTTTCTGCACGATTGAGTAAATCAAGACGATTAGARAATCTCATTGCTC AGCTCCCCGGTGAGAAGAGAAATGGCTTGTTTGGGAATCTCATTGCTTTGTCATTGGGATTG ACCCCTAATTTTAAATCAAATTTTGATTTGGCAGAAGATGCTAAATTACAGCTTTCAAAAGA TACTTACGATGATGATTTAGATAATTTATTGGCGCAAATTGGAGATCAATATGCTGATTTGT TTTTGGCAGCTAAGAATTTATCAGATGCTATTTTACTTTCAGATATCCTAAGAGTAAATAGT GAAATAACTAAGGCTCCCCTATCAGCTTCAATGATTAAGCGCTACGATGARCATCATCAAGA CTTGACTCTTTTAAAAGCTTTAGTTCGACAACAACTTCCAGAAAAGTATARAGARAATCTTTT TTGATCAATCAAAAAACGGATATGCAGGTTATATTGATGGGGGAGCTAGCCAAGAAGAATTT TATAAATTTATCARACCAATTTTAGAAARAATGGATGGTACTGAGGAATTATTGGTGAAACT AAATCGTGAAGATTTGCTGCGCAAGCAACGGACCTTTGACARCGGCTCTATTCCCCATCARA TTCACTTGGGTGAGCTGCATGCTATTTTGAGAAGACAAGAAGACTTTTATCCATTTTTAAAA GACAATCGTGAGAAGATTGAARARATCTTGACTTTTCGAATTCCTTATTATGTTGGTCCATT GGCGCGTGGCAATAGTCGTTTTGCATGGATGACTCGGAAGTCTGAAGAAACAATTACCCCAT GGAATTTTGAAGAAGTTGTCGATAAAGGTGCTTCAGCTCAATCATTTATTGAACGCATGACA AACTTTGATAAARATCTTCCARATGARARAGTACTACCAAARCATAGTTTGCTTTATGAGTA TTTTACGGTTTATAACGAATTGACAAAGGTCARATATGT TACTGAGGGAATGCGAARACCAG CATTTCTTTCAGGTGARCAGARGAAAGCCATTGTTGATTTACTCTTCARAARCARATCGAARA GTAACCGTTAAGCAATTAAAAGAAGATTATTTCAAAAARAATAGAATGTTTTGATAGTGTTGA AATTTCAGGAGTTGAAGATAGATTTAATGCTTCATTAGGCGCCTACCATGATTTGCTAAARA TTATTAAAGATAAAGATTTTTTGGATAATGAAGAAAATGAAGATATCTTAGAGGATATTGTT TTAACATTGACCTTATTTGAAGATAGGGGGATGAT TGAGGAARGACTTARAACATATGCTCA CCTCTTTGATGATAAGGTGATGAAACAGCTTAAACGTCGCCGTTATACTGGTTGGGGACGTT TGTCTCGAAAATTGATTAATGGTATTAGGGATARGCAATCTGGCAAAACAATATTAGATTTT TTGAAATCAGATGGTTTTGCCAATCGCAATTTTATGCAGC TGATCCATGATGATAGTTTGAC ATTTAAAGAAGATATTCAAAAAGCACAGGTGTCTGGACAAGGCCATAGTTTACATGAACAGA TTGCTAACTTAGCTGGCAGTCCTGCTATTARAAAAGGTATTTTACAGACTGTAAARATTGTT GATGAACTGGTCAAAGTAATGGGGCATAAGCCAGARAAATATCGTTATTGARATGGCACGTGA AAATCAGACAACTCAAAAGGGCCAGAAAAATTCGCGAGAGCGTATGAAACGAATCGAAGAAG GTATCARAAGAATTAGGAAGTCAGATTCTTAAAGAGCATCCTGTTGAAAATACTCAATTGCAA AATGAAAAGCTCTATCTCTATTATCTACAAAATGGAAGAGACATGTATGTGGACCAAGAATT AGATATTAATCGTTTAAGTGATTATGATGTCGATCACATTGTTCCACAAAGTTTCATTAAAG ACGATTCAATAGACAATAAGGTACTAACGCGTTCTGATAAAAATCGTGGTARATCGGATAAC GTTCCAAGTGAAGAAGTAGTCAAAAAGATGAAARACTATTGGAGACAACTTCTAARCGCCAA GTTAATCACTCAACGTAAGTTTGATAATTTAACGARAGCTGAACGTGGAGGTTTGAGTGAAC TTGATAAAGCTGGTTTTATCAAACGCCAATTGGT TGARACTCGCCARATCACTAAGCATGTG GCACAAATTTTGGATAGTCGCATGAATACTARATACGATGAARATGATAAACTTATTCGAGA GGTTAAAGTGATTACCTTAAAATCTAAATTAGTTTCTGACTTCCGAAAAGATTTCCAATTCT ATAAAGTACGTGAGATTAACAATTACCATCATGCCCATGATGCGTATCTAAATGCCGTCGTT GGAACTGCTTTGATTAARGAAATATCCAARACTTGAATCGGAGTTTGTCTATGGTGATTATAA AGTTTATGATGTTCGTARAATGATTGCTAAGTCTGAGCAAGARATAGGCARAGCARCCGCAA AATATTTCTTTTACTCTAATATCATGAACTTCTTCARAACAGAAATTACACTTGCAAATGGA GAGATTCGCAAACGCCCTCTAATCGARACTAATGGGGARACTGGAGARATTGTCTGGGATAA AGGGCGAGATTTTGCCACAGTGCGCARAGTATTGTCCATGCCCCAAGTCAATATTGTCAAGA AAACAGAAGTACAGACAGGCGGATTCTCCAAGGAGTCAATTTTACCAARAAGARATTCGGAC AAGCTTATTGCTCGTAARAAAGACTGGGATCCAAAARAATATGGTGGTTTTGATAGTCCAAC GGTAGCTTATTCAGTCCTAGTGGTTGCTAAGGTGGAARAAGGGARATCGAAGAAGTTAARAT CCGTTARAGAGTTACTAGGGATCACAATTATGGAARGAAGTTCCTTTGAAAAAAATCCGATT GACTTTTTAGAAGCTARAGGATATAAGGAAGTTAAAAAAGACTTAATCATTAAACTACCTAA ATATAGTCTTTTTGAGT TAGAARACGGTCGTARACGGATGCTGGCTAGTGCCGGAGAATTAC AARAAGGAAATGAGCTGGCTCTGCCAAGCAAATATGTGAATTTTTTATATTTAGCTAGTCAT TATGAAAAGT TGARGGGTAGTCCAGAAGATAACGAACAARAACAATTGTTTGTGGAGCAGCA TAAGCATTATTTAGATGAGATTATTGAGCAAATCAGTGAATTTTCTAAGCGTGTTATTTTAG CAGATGCCAATTTAGATARAGTTCTTAGTGCATATAACAARCATAGAGACARACCAATACGT GAACAAGCAGAAAATATTATTCATTTATTTACGTTGACGAATCTTGGAGCTCCCGCTGCTTT TAAATATTTTGATACAACAATTGATCGTARACGATATACGTCTACARRAGAAGTTTTAGATG CCACTCTTATCCATCAATCCATCACTGGTCTTTATGAAACACGCATTGATTTGAGTCAGCTA CCAGCTCGACTCA. MDKKYSIGLDIGTNSVGWAVITDDYKVPSKKFKVLGNTDRHSIKKNL IGALLFGSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLADSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEI QLVQIYNQLFEENPINASRVDAKAILSARLSKSRRLENLIAQLPGEKRNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNS EITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGAYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDRGMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGHSLHEQIANTAGSPATKKGILOTVKIV DELVKVMGHKPENIVIEMARENQTTQKGOKNSRERMKRIEEGIKELGSQILKEHPVENTQLQ NEKLYLYYLONGRDMYVDQELDINRLSDYDVDHIVPQSFIKDDS IDNKVLTRSDKNRGKSDN VPSEEVVKKMKNYWRQLLNAKL ITQRKFDNLTKAERGGLSELDKAGE IKROLVETRQITKHV AQTTL.DSRMNTKYDENDKL IREVKVITLKSKIVSDFRKDFQFYKVRE INNYHHAHDAYTL.NAVYV GTALIKKYPKIESEFVYGDYKVYDVRKMIAKSEQF IGKATAKYFFYSNIMNEFFKTE ITLANG EIRKRPLIETNGETGEIVWDKGRDFATVRRVI.SMPOVNIVKKTEVOTGGFSKESILPKRNSD KLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPI DFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASH YEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIR EQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQL GGD (single underline: HNH domain; double underline: RuvC domain) In some embodiments, wild-type Cas9 corresponds to, or comprises the following nucleotide and / or amino acid sequences: ATGGATAAAAAGTATTCTATTGGTTTAGACATCGGCACTAATTCCGTTGGATGGGCTGTCAT AACCGATGAATACAAAGTACCTTCAAAGAAATTTAAGGTGT TGGGGAACACAGACCGTCATT CGATTAAARAGAATCTTATCGGTGCCCTCCTATTCGATAGTGGCGARACGGCAGAGGCGACT CGCCTGAAACGAACCGCTCGGAGAAGGTATACACGTCGCAAGAACCGAATATGTTACTTACA AGAAATTTTTAGCAATGAGATGGCCAAAGTTGACGATTCTTTCTTTCACCGTTTGGAAGAGT CCTTCCTTGTCGAAGAGGACAAGAAACATGAACGGCACCCCATCTTTGGARACATAGTAGAT GAGGTGGCATATCATGAAARAGTACCCAACGATTTATCACCTCAGARARAAGCTAGTTGACTC AACTGATAAAGCGGACCTGAGGTTAATCTACTTGGC TC TTGCCCATATGATAAAGTTCCGTG GGCACTTTCTCATTGAGGGTGATCTAAATCCGGACAACTCGGATGTCGACAAACTGTTCATC CAGTTAGTACAAACCTATAATCAGTTGTTTGAAGAGAACCCTATAAATGCAAGTGGCGTGGA TGCGAAGGCTATTCTTAGCGCCCGCCTCTCTAAATCCCGACGGCTAGARAACCTGATCGCAC AATTACCCGGAGAGAAGAARAATGGGTTGTTCGGTAACCTTATAGCGCTCTCACTAGGCCTG ACACCAAATTTTAAGTCGAACTTCGACTTAGCTGAAGATGCCARATTGCAGCTTAGTAAGGA CACGTACGATGACGATCTCGACAATCTACTGGCACAAATTGGAGATCAGTATGCGGACTTAT TTTTGGCTGCCAARAACCTTAGCGATGCAATCCTCCTATCTGACATACTGAGAGTTAATACT GAGATTACCAAGGCGCCGTTATCCGCTTCAATGATCAAAAGGTACGATGAACATCACCAAGA CTTGACACTTCTCAAGGCCCTAGTCCGTCAGCAACTGCCTGAGARAATATAAGGARATATTCT TTGATCAGTCGAAAAACGGGTACGCAGGTTATATTGACGGCGGAGCGAGTCAAGAGGAATTC TACAAGTTTATCAAACCCATATTAGAGARAGATGGATGGGACGGAAGAGTTGCTTGTAAAACT CAATCGCGAAGATCTACTGCGAAAGCAGCGGACTTTCGACAACGGTAGCATTCCACATCARA TCCACTTAGGCGAATTGCATGCTATACT TAGAAGGCAGGAGGATTTTTATCCGTTCCTCAAA GACAATCGTGAAAAGATTGAGARRATCCTAACCTTTCGCATACCTTACTATGTGGGACCCCT GGCCCGAGGGARACTCTCGGTTCGCATGGATGACAAGAAAGTCCGAAGAAACGATTACTCCAT GGAATTTTGAGGAAGTTGTCGATAAAGGTGCGTCAGCTCAATCGTTCATCGAGAGGATGACC AACTTTGACAAGAATTTACCGAACGARAAAGTATTGCCTAAGCACAGTTTACTTTACGAGTA TTTCACAGTGTACAATGAACTCACGAAAGT TARGTATGTCACTGAGGGCATGCGTARACCCG CCTTTCTAAGCGGAGAACAGARGAAAGCAATAGTAGATCTGTTATTCAAGACCAACCGCARA GTGACAGTTAAGCAATTGAAAGAGGACTACTTTAAGARRATTGAATGCTTCGATTCTGTCGA GATCTCCGGGGTAGAAGATCGATTTAATGCGTCACTTGGTACGTATCATGACCTCCTAAAGA TAATTAAAGATAAGGACTTCCTGGATAACGAAGAGAATGAAGATATCTTAGAAGATATAGTG TTGACTCTTACCCTCTTTGAAGATCGGGAAATGAT TGAGGAARGACTAAAAACATACGCTCA CCTGTTCGACGATAAGGTTATGAAACAGTTAAAGAGGCGTCGCTATACGGGCTGGGGACGAT TGTCGCGGAAACTTATCARCGGGATAAGAGACARGCAARGTGGTARAACTATTCTCGATTTT CTAAAGAGCGACGGCTTCGCCAATAGGAACTTTATGCAGCTGATCCATGATGACTCTTTAAC CTTCAAAGAGGATATACARAAGGCACAGGTTTCCGGACAAGGGGACTCATTGCACGARCATA TTGCGAATCTTGCTGGTTCGCCAGCCATCAAARAGGGCATACTCCAGACAGTCAAAGTAGTG GATGAGCTAGTTAAGGTCATGGGACGTCACARACCGGAAARCATTGTAATCGAGATGGCACG CGAAAATCAAACGACTCAGAAGGGGCAAAAAAACAGTCGAGAGCGGATGARGAGAATAGAAG AGGGTATTAAAGAACTGGGCAGCCAGATCTTARAGGAGCATCCTGTGGARAATACCCAATTG CAGAACGAGAAACTTTACCTCTATTACCTACAAAATGGAAGGGACATGTATGTTGATCAGGA ACTGGACATAAACCGTTTATCTGATTACGACGTCGATCACATTGTACCCCAATCCTTTTTGA AGGACGATTCAATCGACAATAALGTGCTTACACGCTCGGATAAGANMCCGAGGGAAMAAAGTGAC AATGTTCCAAGCGAGGAAGTCGTAAAGAAARATGAAGAACTATTGGCGGCAGCTCCTAAATGC GAAACTGATAACGCAAAGAAAGTTCGATAACTTAACTAAAGCTGAGAGGGGTGGCTTGTCTG AACTTGACAAGGCCGGATTTATTAAACGTCAGCTCGTGGAARCCCGCCAAATCACARAGCAT GTTGCACAGATACTAGATTCCCGAATGAATACGAAATACGACGAGAACGATAAGCTGATTCG GGAAGTCAAAGTAATCACTTTAAAGTCAAAATTGGTGTCGGACTTCAGAAAGGATTTTCAAT TCTATAAAGTTAGGGAGATARATAACTACCACCATGCGCACGACGCTTATCTTAATGCCGTC GTAGGGACCGCACTCATTAAGAAATACCCGAAGCTAGARAGTGAGTTTGTGTATGGTGATTA CAAAGTTTATGACGTCCGTAAGATGATCGCGARAAGCGAACAGGAGATAGGCAAGGCTACAG CCAAATACTTCTTTTATTCTAACATTATGAATTTCTTTAAGACGGAAATCACTCTGGCARAC GGAGAGATACGCARACGACCTTTAATTGAAACCAATGGGGAGACAGGTGARATCGTATGGGA TAAGGGCCGGGACTTCGCGACGGTGAGAAAAGTTTTGTCCATGCCCCAAGTCAACATAGTAA AGAARACTGAGGTGCAGACCGGAGGGTTTTCAAAGGAATCGATTCTTCCAARAAGGAATAGT GATAAGCTCATCGCTCGTAAARAGGACTGGGACCCGAAAARGTACGGTGGCTTCGATAGCCC TACAGTTGCCTATTCTGTCCTAGTAGTGGCAARAGTTGAGAAGGGAARATCCAAGAAACTGA AGTCAGTCAAAGAATTATTGGGGATAACGATTATGGAGCGCTCGTCTTTTGAAAAGAACCCC ATCGACTTCCTTGAGGCGARAGGT TACAAGGAAGTARARAAGGATCTCATAATTAARCTACC AARAGTATAGTCTGTTTGAGTTAGAAAATGGCCGAAARCGGATGTTGGCTAGCGCCGGAGAGC TTCAARAGGGGAACGAACTCGCACTACCGTCTARATACGTGAATTTCCTGTATTTAGCGTCC CATTACGAGAAGTTGARAGGTTCACCTGAAGATAACGAACAGAAGCAACTTTTTGTTGAGCA GCACAAACATTATCTCGACGARATCATAGAGCAAATTTCGGAATTCAGTAAGAGAGTCATCC TAGCTGATGCCAATCTGGACAAAGTATTAAGCGCATACAACARGCACAGGGATAAACCCATA CGTGAGCAGGCGGAAAATATTATCCATTTGTTTACTCTTACCAACCTCGGCGCTCCAGCCGC ATTCAAGTATTTTGACACAACGATAGATCGCARACGATACACTTCTACCAAGGAGGTGCTAG ACGCGACACTGATTCACCAATCCATCACGGGATTATATGAAACTCGGATAGATTTGTCACAG CTTGGGGGTGACGGATCCCCCAAGAAGARAGAGGAAAGTCTCGAGCGACTACARAGACCATGA CGGTGATTATAAAGATCATGACATCGATTACAAGGATGACGATGACAAGGCTGCAGGA MDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEAT RLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVD EVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLEI QLVQTYNQLFEENP INASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGL TPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNT EITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEF YKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLK DNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMT NFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRK VIVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIV LTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDF LKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGS PATKKGILQTVKVV DELVKVMGRHKPENIVIEMARENQTTQKGOKNSRER...

Claims

CLAIMS ‘What is claimed is: 1s A method of treating a neurological disorder in a subject, the method comprising: administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a target gene or a regulatory element thereof associated with the neurological disorder in the subject, thereby treating the neurological disorder in the subject.

2. The method of claim 1, wherein the target gene is an alpha-L-iduronidase (IDUA) gene and the neurological disease is Hurler syndrome.

3. A method of treating Hurler syndrome in a subject, the method comprising administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in an alpha-L-iduronidase (IDUA) gene or a regulatory element thereof in the subject, thereby treating Hurler syndrome in the subject. 4, The method of claim 2 or 3, wherein the administration ameliorates at least one symptom related to Hurler syndrome.

5. The method of claim 4, wherein the administration results in faster amelioration of at least one symptom related to Hurler syndrome as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase.

6. The method of any one of claims 2-5, wherein the IDUA gene or regulatory element thereof comprises a SNP associated with Hurler syndrome.

7. The method of any one of claims 2-6, wherein the A-to-G nucleobase alteration is at the SNP associated with Hurler syndrome.

8. The method of claim 6 or 7, wherein the SNP associated with Hurler syndrome results in a W402X or a W401X amino acid mutation in an IDUA polypeptide as numbered in SEQ ID NO: 4, or a variant thereof, encoded by the IDUA gene, wherein X is a stop codon.

9. The method of any one of claims 6-8, wherein the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a wild type nucleobase.

10. The method of any one of claims 6-8, wherein the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a non-wild type nucleobase that results in one or more ameliorated symptoms of Hurler syndrome.

11. The method of any one of claims 6-10, wherein the A-to-G alteration at the SNP associated with Hurler Syndrome changes a stop codon to a tryptophan in an IDUA polypeptide encoded by the IDUA gene.

12. The method of any one of claims 6-10, wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the JDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome.

13. The method of any one of claims 6-12, wherein the adenosine base editor is in complex with a single guide RNA (sgRINA) comprising a nucleic acid sequence complementary to the IDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome.

14. The method of claim 13, wherein the sgRNA comprises a nucleic acid sequence selected from the group consisting of: 5'- GACUCUAGGCAGAGGUCUCAA -3', 5'- ACUCUAGGCAGAGGUCUCAA-3', 5'- CUCUAGGCCGAAGUGUCGC -3', and 5'- GCUCUAGGCCGAAGUGUCGC-3".

15. The method of claim 1, wherein the target gene is a leucine-rich repeat kinase-2 (LRRK2) gene and the neurological disease is Parkinson’s disease.

16. A method of treating Parkinson’s disease in a subject, the method comprising: administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration a leucine-rich repeat kinase-2 (LRRK2) gene or a regulatory element thereof in the subject, thereby treating Parkinson’s disease in the subject.

17. The method of any one of claims 1, 15, or 16 wherein the administration ameliorates at least one symptom related to Parkinson’s disease.

18. The method of claim 17, wherein the administration results in faster amelioration of at least one symptom related to Parkinson’s disease as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase.

19. The method of any one of claims 15-18, wherein the LRRK2 gene or regulatory element thereof comprises a SNP associated with Parkinson’s disease.

20. The method of claim 19, wherein the A-to-G nucleobase alteration is at the SNP associated with Parkinson’s disease.

21. The method of claim 19 or 20, wherein the SNP associated with Parkinson Disease results ina A419V, aR1441C, aR1441H, or a G2019S amino acid mutation in a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof, encoded by the LRRK2 gene.

22. The method of any one of claims 19-21, wherein the A-to-G nucleobase alteration changes the SNP associated with Parkinson’s disease to a wild type nucleobase.

23. The method of any one of claims 19-21, wherein the A-to-G nucleobase alteration changes the SNP associated with Parkinson’s disease to a non-wild type nucleobase that results in one or more ameliorated symptoms of Parkinson’s disease. 24, The method of any one of claims 19-22, wherein the A-to-G nucleobase alteration changes a Cysteine or Histidine to an Arginine in a LRRK2 polypeptide encoded by the LRRK2 gene.

25. The method of any one of claims 19-22, wherein the A-to-G alteration changes a Serine to a Glycine in a LRRK2 polypeptide encoded by the LRRK?2 gene.

26. The method of any one of claims 19-22, wherein the A-to-G alteration replaces the Cysteine (C) or Histidine (H) with an Arginine (R) at position 144 or replaces the Serine with a Glycine (G) at position 2019 of a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof, encoded by the LRRK?2 gene.

27. A method of treating Parkinson’s disease in a subject, the method comprising: administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration at a SNP in a LRRK2 gene associated with Parkinson’s disease, wherein the SNP does not encode a G2019S mutation in a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof.

28. The method of claim 27, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof.

29. The method of any one of claims 15-28, wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the LRRK?2 gene or regulatory element thereof comprising the SNP associated with Parkinson’s Disease.

30. The method of any one of claims 15-28, wherein the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the LRRK?2 gene or regulatory element thereof comprising the SNP associated with Parkinson Disease.

31. The method of claim 30, wherein the sgRNA comprises a nucleic acid sequence: 5'- AAGCGCAAGCCUGGAGGGAA -3'; or 5-ACUACAGCAUUGCUCAGUAC-3".

32. The method of claim 1, wherein the target gene is a methyl CpG binding protein 2 (MECP2) gene and the neurological disease is Rett syndrome.

33. A method of treating Rett syndrome in a subject, the method comprising administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a methyl CpG binding protein 2 (MECP2) gene or a regulatory element thereof in the subject, thereby treating Rett syndrome in the subject. 34, The method of claim 32 or 33, wherein the administration ameliorates at least one symptom related to Rett syndrome.

35. The method of claim 34, wherein the administration results in faster amelioration of at least one symptom related to Rett syndrome as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase.

36. The method of any one of claims 32-35, wherein the MECP2 gene or regulatory element thereof comprises a SNP associated with Rett syndrome.

37. The method of claim 36, wherein the A-to-G nucleobase alteration is at the SNP associated with Rett Syndrome.

38. The method of claim 36 or 37, wherein the SNP associated with Rett syndrome results in a R106W or a T158M amino acid mutation in a MECP2 polypeptide as numbered in SEQ ID NO: 5, or a variant thereof, encoded by the MECP2 gene.

39. The method of claim 36 or 37, wherein the SNP associated with Rett syndrome results in aR255X or a R270X amino acid mutation in a MECP2 polypeptide encoded by the MECP?2 gene, wherein X is a stop codon.

40. The method of any one of claims 36-39, wherein the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a wild type nucleobase.

41. The method of any one of claims 36-39, wherein the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a non-wild type nucleobase that results in ameliorated Rett syndrome symptoms.

42. The method of any one of claims 36-39, wherein the A-to-G nucleobase alteration at the SNP associated with Rett Syndrome changes a stop codon to tryptophan in MECP2 polypeptide.

43. The method of any one of claims 36-42 wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the MECP2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome.

44. The method of any one of claims 36-42, wherein the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the MECP?2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome.

45. The method of claim 44, wherein the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of: 5'- CUUUUCACUUCCUGCCGGGG-3', 5'-AGCUUCCAUGUCCAGCCUUC-3", 5'- ACCAUGAAGUCAAAAUCAUU-3', and 5. GCUUUCAGCCCCGUUUCUUG-3".

46. The method of claim 1, wherein the target gene is an ATP-binding cassette subfamily member 4 (ABCA4) gene and the neurological disease is Stargardt disease.

47. A method of treating Stargardt disease in a subject, the method comprising administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in an ATP-binding cassette subfamily member 4 (ABCA4) gene or a regulatory element thereof in the subject, thereby treating Stargardt disease in the subject. 48, The method of claim 46 or 47, wherein the administration ameliorates at least one symptom related to Stargardt disease. 49, The method of claim 48, wherein the administration results in faster amelioration of at least one symptom related to Stargardt disease as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase.

50. The method of any one of claims 46-49, wherein the ABCA4 gene comprises a SNP associated with Stargardt disease.

51. The method of claim 50, wherein the A-to-G nucleobase alteration is at the SNP associated with Stargardt disease.

52. The method of claim 50 or 51, wherein the SNP associated with Stargardt disease results in a A1038V or a G1961E amino acid mutation in an ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof, encoded by the ABCA4 gene.

53. The method of claim 52, wherein the SNP associated with Stargardt disease results in a G1961E amino acid mutation in the ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof 54. The method of any one of claims 51-53, wherein the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a wild type nucleobase.

55. The method of any one of claims 51-53, wherein the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a non-wild type nucleobase that results in one or more ameliorated symptoms of Stargardt disease.

56. The method of any one of claims 51-55, wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt disease. 37, The method of any one of claims 51-56, wherein the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt Disease.

58. The method of claim 57, wherein the sgRNA comprises the sequence 5'- CUCCAGGGCGAACUUCGACACACAGC-3".

59. The method of any one of the preceding claims wherein the treatment results in ameliorated symptoms of the neurological disorder compared to treatment with a base editor comprising an adenosine deaminase domain without the amino acid substitutions.

60. A method of editing a target gene or regulatory element thereof associated with a neurological disorder, the method comprising contacting the target gene or regulatory element thereof with (i) an adenosine base editor and (ii) a guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a target gene or a regulatory element thereof associated with the neurological disorder.

61. The method of claim 60, wherein the target gene is a leucine-rich repeat kinase-2 (LRRK2) gene and the neurological disease is Parkinson’s disease.

62. A method of editing a leucine-rich repeat kinase-2 (LRRK2) gene or a regulatory element thereof, the method comprising contacting the LRRK2 gene or regulatory element thereof with (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in the LRRK2 gene a regulatory element thereof.

63. The method of claim 62, wherein the A-to-G nucleobase alteration is at the SNP associated with Parkinson’s disease.

64. The method of claim 62 or 63, wherein the SNP associated with Parkinson Disease results ina A419V, aR1441C, a R1441H, or a G2019S amino acid mutation in a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof, encoded by the LRRK2 gene.

65. The method of any one of claims 62-64, wherein the A-to-G nucleobase alteration changes the SNP associated with Parkinson’s disease to a wild type nucleobase.

66. The method of any one of claims 62-64, wherein the A-to-G nucleobase alteration changes the SNP associated with Parkinson’s disease to a non-wild type nucleobase that results in one or more ameliorated symptoms of Parkinson’s disease.

67. The method of any one of claims 62-66, wherein the A-to-G nucleobase alteration changes a Cysteine or Histidine to an Arginine in a LRRK2 polypeptide encoded by the LRRK2 gene.

68. The method of any one of claims 62-66, wherein the A-to-G alteration changes a Serine to a Glycine in a LRRK2 polypeptide encoded by the LRRK?2 gene.

69. The method of any one of claims 62-66, wherein the A-to-G alteration replaces the Cysteine (C) or Histidine (H) with an Arginine (R) at position 144 or replaces the Serine with a Glycine (G) at position 2019 of a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof, encoded by the LRRK?2 gene.

70. A method of editing a leucine-rich repeat kinase-2 (LRRK2) gene or a regulatory element thereof, the method comprising contacting the LRRK2 gene or regulatory element thereof with (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration at a SNP in a LLRK2 gene, wherein the SNP does not encode a G2019S mutation in a LRRK?2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof.

71. The method of claim 70, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof.

72. The method of any one of claims 61-71, wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the LRRK?2 gene or regulatory element thereof comprising the SNP associated with Parkinson’s Disease.

73. The method of any one of claims 61-71, wherein the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the LRRK?2 gene or regulatory element thereof comprising the SNP associated with Parkinson Disease.

74. The method of claim 73, wherein the sgRNA comprises a nucleic acid sequence: 5'- AAGCGCAAGCCUGGAGGGAA -3'; or 5'-ACUACAGCAUUGCUCAGUAC-3".

75. The method of claim 60, wherein the target gene is an alpha-L-iduronidase (IDUA) gene and the neurological disease is Hurler syndrome.

76. A method of editing an alpha-L-iduronidase (IDUA) gene or a regulatory element thereof, the method comprising contacting the IDUA gene or regulatory element thereof with (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in the IDUA gene or a regulatory element thereof.

77. The method of any one of claims 75 or 76, wherein the IDUA gene or regulatory element thereof comprises a SNP associated with Hurler syndrome.

78. The method of any one of claims 75-77, wherein the A-to-G nucleobase alteration is at the SNP associated with Hurler syndrome.

79. The method of claim 77 or 78, wherein the SNP associated with Hurler syndrome results in a W402X or a W401X amino acid mutation in an IDUA polypeptide as numbered in SEQ ID NO: 4, or a variant thereof, encoded by the IDUA gene, wherein X is a stop codon.

80. The method of any one of claims 77-79, wherein the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a wild type nucleobase.

81. The method of any one of claims 77-79, wherein the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a non-wild type nucleobase that results in one or more ameliorated symptoms of Hurler syndrome.

82. The method of any one of claims 77-81, wherein the A-to-G alteration at the SNP associated with Hurler Syndrome changes a stop codon to a tryptophan in an IDUA polypeptide encoded by the IDUA gene.

83. The method of any one of claims 77-81, wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the JDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome.

84. The method of any one of claims 77-83, wherein the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the IDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome.

85. The method of claim 84, wherein the sgRNA comprises a nucleic acid sequence selected from the group consisting of: 5'- GACUCUAGGCAGAGGUCUCAA -3',5'- ACUCUAGGCAGAGGUCUCAA-3', 5'- CUCUAGGCCGAAGUGUCGC -3', and 5'- GCUCUAGGCCGAAGUGUCGC-3".

86. The method of claim 60, wherein the target gene is a methyl CpG binding protein 2 (MECP2) gene and the neurological disease is Rett syndrome.

87. A method of editing a methyl CpG binding protein 2 (MECP2) gene or regulatory element thereof, the method comprising administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in the MECP2 gene or a regulatory element thereof.

88. The method of claim 86 or 87, wherein the MECP2 gene or regulatory element thereof comprises a SNP associated with Rett syndrome.

89. The method of claim 88, wherein the A-to-G nucleobase alteration is at the SNP associated with Rett Syndrome.

90. The method of claim 88 or 89, wherein the SNP associated with Rett syndrome results in a R106W or a T158M amino acid mutation in a MECP2 polypeptide as numbered in SEQ ID NO: 5, or a variant thereof, encoded by the MECP2 gene.

91. The method of claim 88 or 89, wherein the SNP associated with Rett syndrome results in a R255X or a R270X amino acid mutation in a MECP2 polypeptide encoded by the MECP2 gene, wherein X is a stop codon.

92. The method of any one of claims 88-81, wherein the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a wild type nucleobase.

93. The method of any one of claims 88-91, wherein the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a non-wild type nucleobase that results in one or more ameliorated symptoms of Rett syndrome.

94. The method of any one of claims 88-91, wherein the A-to-G nucleobase alteration at the SNP associated with Rett Syndrome changes a stop codon to tryptophan in MECP2 polypeptide.

95. The method of any one of claims 88-94, wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the MECP2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome.

96. The method of any one of claims 88-94, wherein the adenosine base editor is in complex with a single guide RNA (sgRINA) comprising a nucleic acid sequence complementary to the MECP?2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome.

97. The method of claim 96, wherein the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of: 5’- CUUUUCACUUCCUGCCGGGG- 3’, 5’-AGCUUCCAUGUCCAGCCUUC-3’, 5’- ACCAUGAAGUCAAAAUCAUU-3’, and 5’- GCUUUCAGCCCCGUUUCUUG-3’.

98. The method of claim 60, wherein the target gene is an ATP-binding cassette subfamily member 4 (ABCA4) gene and the neurological disease is Stargardt disease.

99. A method of editing an ATP binding cassette subfamily member 4 (ABCA4) gene or regulatory element thereof, the method comprising contacting the ABCA4 gene or regulatory element thereof with (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in the ABCA4 gene or a regulatory element thereof.

100. The method of claim 98 or 99, wherein the administration ameliorates at least one symptom related to Stargardt disease.

101. The method of claim 100, wherein the administration results in faster amelioration of at least one symptom related to Stargardt disease as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase.

102. The method of any one of claims 98-101, wherein the ABCA4 gene comprises a SNP associated with Stargardt disease.

103. The method of claim 102, wherein the A-to-G nucleobase alteration is at the SNP associated with Stargardt disease.

104. The method of claim 102 or 103, wherein the SNP associated with Stargardt disease results in a A1038V, or a G1961E amino acid mutation in an ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof, encoded by the ABCA4 gene.

105. The method of claim 104, wherein the SNP associated with Stargardt disease results in a G1961E amino acid mutation in the ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof.

106. The method of any one of claims 103-105, wherein the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a wild type nucleobase.

107. The method of any one of claims 103-105, wherein the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a non-wild type nucleobase that results in one or more ameliorated symptoms of Stargardt disease.

108. The method of any one of claims 103-107, wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt Disease.

109. The method of any one of claims 103-108, wherein the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt Disease.

110. The method of claim 109, wherein the sgRNA comprises the sequence 5'- CUCCAGGGCGAACUUCGACACACAGC-3".

111. The method of any one of claims 60-110, wherein the contacting is in a cell.

112. The method of claim 111, wherein the contacting results in less than 10% indels in a genome in the cell, wherein indel rate is measured by mismatch frequency between sequences flanking the single nucleotide modification and an unmodified sequence.

113. The method of claim 111, wherein the contacting results in less than 5% indels in a genome in the cell, wherein indel rate is measured by mismatch frequency between sequences flanking the single nucleotide modification and an unmodified sequence.

114. The method of claim 111, wherein the contacting results in less than 1% indels in a genome in the cell, wherein indel rate is measured by mismatch frequency between sequences flanking the single nucleotide modification and an unmodified sequence.

115. The method of any one of claims 111-114, wherein the cell is a neuron.

116. The method of any one of claims 60-110, wherein the contacting is in a population of cells.

117. The method of claim 116, wherein the contacting results in the A-to-G nucleobase alteration in at least 40% of the population of cells after the contacting step.

118. The method of claim 116, wherein the contacting results in the A-to-G nucleobase alteration in at least 50% of the population of cells after the contacting step.

119. The method of claim 116, wherein the contacting results in the A-to-G nucleobase alteration in at least 70% of the population of cells after the contacting step.

120. The method of any one of claims 116-119, wherein at least 90% of the cells are viable after the contacting step.

121. The method of any one of claims 116-120, wherein the population of cells was not enriched after the contacting step.

122. The method of any one of claims 116-121, wherein the population of cells are neurons.

123. The method of any one of claims 111-122, wherein the contacting is in vivo or ex vivo. 124, The method of any one of claims 1-123, wherein the polynucleotide programmable DNA binding domain is a Cas9.

125. The method of claim 124, wherein the Cas9 is a SpCas9, a SaCas9, or a variant thereof.

126. The method of claim 124 or 125, wherein the polynucleotide programmable DNA binding domain comprises a modified SpCas9 having an altered protospacer-adjacent motif (PAM) specificity.

127. The method of claim 126, wherein the Cas9 has specificity for a PAM sequence selected from the group consisting of NGG, NGA, NGCG, NGN, NNGRRT, NNNRRT, NGCG, NGCN, NGTN, and NGC; wherein Nis A, G, C, or T; and wherein Ris A or G.

128. The method of any one of claims 124-127, wherein the polynucleotide programmable DNA binding domain is a nuclease inactive variant.

129. The method of any one of claims 124-127, wherein the polynucleotide programmable DNA binding domain is a nickase variant.

130. The method of claim 129, wherein the nickase variant comprises an amino acid substitution D10A or a corresponding amino acid substitution thereof.

131. The method of any one of claims 1-130, wherein the adenosine deaminase domain comprises a TadA domain.

132. The method of claim 131, wherein the adenosine deaminase comprises a TadA deaminase comprising a V82S alteration and / or a T166R alteration.

133. The method of any one of claims 1-132, wherein the adenosine deaminase further comprises one or more of the following alterations: Y147T, Y147R, Q154S, Y123H, Q154R, or a combination thereof.

134. The method of any one of claims 1-133, wherein the adenosine deaminase comprises a combination of alterations selected from the group consisting of: Y147R + Q154R +Y123H; Y147R + Q154R + 176Y; Y147R + Q154R + T166R; Y147T + Q154R; Y147T + Q154S; and Y123H + Y147R + Q154R + I76Y.

135. The method of any one of claims 1-134, wherein the adenosine base editor domain comprises an adenosine deaminase monomer.

136. The method of any one of claims 1-135, wherein the adenosine base editor comprises an adenosine deaminase dimer.

137. The method of any one of claims 131-136, wherein the TadA deaminase is a TadA*8 variant.

138. The method of claim 137, wherein the TadA*8 variant is selected from the group consisting of: TadA*8.1, TadA*8.2, TadA*8.3, TadA*8.4, TadA*8.5, TadA*8.6, TadA*8.7, TadA*8.8, TadA*8.9, TadA*8.10, TadA*8.11, TadA*8.12, and TadA*8.

13.

139. The method of claim 138, wherein the adenosine base editor is an ABES base editor selected from the group consisting of: ABE8.1, ABE8.2, ABES8.3, ABE8.4, ABES.S, ABES.6, ABES.7, ABES.8, ABES.9, ABES.10, ABES.11, ABES.12, and ABES.

13.

140. A cell produced by the method of any one of claims 111-115.

141. A population of cells produced by the method of any one of claims 116-122.

142. A base editor system comprising (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a target gene or a regulatory element thereof associated with the neurological disorder.

143. The base editor system of claim 142, wherein the target gene is a leucine-rich repeat kinase-2 (LRRK?2) gene and the neurological disease is Parkinson’s disease.

144. A base editor system comprising (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a LRRK2 gene a regulatory element thereof.

145. The base editor system of claim 144, wherein the A-to-G nucleobase alteration is at a SNP associated with Parkinson's disease in the LRRK2 gene or regulatory element thereof.

146. The base editor system of claim 144 or 145, wherein the SNP associated with Parkinson Disease results in a A419V, a R1441C, a R1441H, or a G2019S amino acid mutation in a LRRK2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof, encoded by the LRRK2 gene.

147. The base editor system of any one of claims 145 or 146, wherein the A-to-G nucleobase alteration changes the SNP associated with Parkinson's disease to a wild type nucleobase.

148. The base editor system of any one of claims 145 or 146, wherein the A-to-G nucleobase alteration changes the SNP associated with Parkinson’s disease to a non-wild type nucleobase that results in ameliorated Parkinson’s symptoms.

149. The base editor system of any one of claims 145-148, wherein the A-to-G nucleobase alteration changes a Cysteine or Histidine to an Arginine in a LRRK2 polypeptide encoded by the LRRK2 gene.

150. The base editor system of any one of claims 145-148, wherein the A-to-G alteration changes a Serine to a Glycine in a LRRK2 polypeptide encoded by the LRRK2 gene.

151. The base editor system of any one of claims 145-148, wherein the A-to-G alteration replaces the Cysteine (C) or Histidine (H) with an Arginine (R) at position 144 or replaces the Serine with a Glycine (G) at position 2019 of a LRRK?2 polypeptide as numbered in SEQ ID NO: 3, or a variant thereof, encoded by the LRRK2 gene.

152. The base editor system of claim 151, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof.

153. The base editor system of any one of claims 143-152, wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the LRRK?2 gene or regulatory element thereof comprising the SNP associated with Parkinson’s Disease.

154. The base editor system of any one of claims 143-152, wherein the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the LRRK?2 gene or regulatory element thereof comprising the SNP associated with Parkinson Disease.

155. The base editor system of claim 154, wherein the sgRNA comprises a nucleic acid sequence: 5'-AAGCGCAAGCCUGGAGGGAA -3" or 5'- ACUACAGCAUUGCUCAGUAC-3".

156. The base editor system of claim 142, wherein the target gene is an alpha-L-iduronidase (IDUA) gene and the neurological disease is Hurler syndrome.

157. A base editor system comprising (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in an alpha-L-iduronidase (IDUA) gene or a regulatory element thereof 158. The base editor system of claim 156 or 157, wherein the IDUA gene or regulatory element thereof comprises a SNP associated with Hurler syndrome.

159. The base editor system of any one of claims 156-158, wherein the A-to-G nucleobase alteration is at the SNP associated with Hurler syndrome.

160. The base editor system of claim 158 or 159, wherein the SNP associated with Hurler syndrome results in a W402X or a W401X amino acid mutation in an IDUA polypeptide as numbered in SEQ ID NO: 4, or a variant thereof, encoded by the IDUA gene, wherein X is a stop codon.

161. The base editor system of any one of claims 158-160, wherein the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a wild type nucleobase.

162. The base editor system of any one of claims 158-160, wherein the A-to-G nucleobase alteration changes the SNP associated with Hurler syndrome to a non-wild type nucleobase that results in one or more ameliorated symptoms of Hurler syndrome.

163. The base editor system of any one of claims 158-162, wherein the A-to-G alteration at the SNP associated with Hurler Syndrome changes a stop codon to a tryptophan in an IDUA polypeptide encoded by the IDUA gene.

164. The base editor system of any one of claims 158-162, wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the IJDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome.

165. The base editor system of any one of claims 158-164, wherein the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the IDUA gene or regulatory element thereof comprising the SNP associated with Hurler syndrome.

166. The base editor system of claim 165, wherein the sgRNA comprises a nucleic acid sequence selected from the group consisting of: 5- GACUCUAGGCAGAGGUCUCAA - 3' 5'- ACUCUAGGCAGAGGUCUCAA-3’, 5'- CUCUAGGCCGAAGUGUCGC -3', and 5S'-GCUCUAGGCCGAAGUGUCGC-3" 167. The base editor system of claim 142, wherein the target gene is a methyl CpG binding protein 2 (MECP2) gene and the neurological disease is Rett syndrome.

168. A base editor system comprising (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a methyl CpG binding protein 2 (MECP2) gene or regulatory element thereof.

169. The base editor system of claim 167 or 168, wherein the MECP2 gene or regulatory element thereof comprises a SNP associated with Rett syndrome.

170. The base editor system of claim 169, wherein the A-to-G nucleobase alteration is at the SNP associated with Rett Syndrome.

171. The base editor system of claim 169 or 170, wherein the SNP associated with Rett syndrome results in a R106W or a T158M amino acid mutation in a MECP2 polypeptide as numbered in SEQ ID NO: 5, or a variant thereof, encoded by the MECP2 gene.

172. The base editor system of claim 169 or 170, wherein the SNP associated with Rett syndrome results in a R255X or a R270X amino acid mutation in a MECP2 polypeptide encoded by the MECP2 gene, wherein X is a stop codon.

173. The base editor system of any one of claims 169-172, wherein the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a wild type nucleobase.

174. The base editor system of any one of claims 169-172, wherein the A-to-G nucleobase alteration changes the SNP associated with Rett syndrome to a non-wild type nucleobase that results in one or more ameliorated symptoms of Rett syndrome.

175. The base editor system of any one of claims 169-172, wherein the A-to-G nucleobase alteration at the SNP associated with Rett Syndrome changes a stop codon to tryptophan in MECP2 polypeptide.

176. The base editor system of any one of claims 169-175, wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the MECP?2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome.

177. The base editor system of any one of claims 169-175, wherein the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the MECP2 gene or regulatory element thereof comprising the SNP associated with Rett syndrome.

178. The base editor system of claim 177, wherein the guide polynucleotide comprises a nucleic acid sequence selected from the group consisting of: 5'- CUUUUCACUUCCUGCCGGGG-3', 5-AGCUUCCAUGUCCAGCCUUC-3', 5'- ACCAUGAAGUCAAAAUCAUU-3', and 5'- GCUUUCAGCCCCGUUUCUUG-3".

179. The base editor system of claim 142, wherein the target gene is an ATP binding cassette subfamily member 4 (ABCA4) gene and the neurological disease is Stargardt disease.

180. A base editor system comprising contacting (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises an amino acid substitution at amino acid position 82 or 166 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in an ATP binding cassette subfamily member 4 (ABCA4) gene or regulatory element thereof.

181. The base editor system of claim 179 or 180, wherein the administration ameliorates at least one symptom related to Stargardt disease.

182. The base editor system of claim 181, wherein the administration results in faster amelioration of at least one symptom related to Stargardt disease as compared to treatment with a base editor without the amino acid substitution in the adenosine deaminase.

183. The base editor system of any one of claims 179-182, wherein the ABCA4 gene comprises a SNP associated with Stargardt disease.

184. The base editor system of claim 183, wherein the A-to-G nucleobase alteration is at the SNP associated with Stargardt disease.

185. The base editor system of claim 183 or 184, wherein the SNP associated with Stargardt disease results in a A1038V, or a G1961E amino acid mutation in an ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof, encoded by the ABCA4 gene.

186. The base editor system of claim 185, wherein the SNP associated with Stargardt disease results in a G1961E amino acid mutation in the ABCA4 polypeptide as numbered in SEQ ID NO: 6, or a variant thereof.

187. The base editor system of any one of claims 184-186, wherein the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a wild type nucleobase.

188. The base editor system of any one of claims 184-186, wherein the A-to-G nucleobase alteration changes the SNP associated with Stargardt disease to a non-wild type nucleobase that results in ameliorated Stargardt disease symptoms.

189. The base editor system of any one of claims 184-188, wherein the guide polynucleotide comprises a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt Disease.

190. The base editor system of any one of claims 184-189, wherein the adenosine base editor is in complex with a single guide RNA (sgRNA) comprising a nucleic acid sequence complementary to the ABCA4 gene or regulatory element thereof comprising the SNP associated with Stargardt Disease.

191. The base editor system of claim 190, wherein the sgRNA comprises the sequence 5'- CUCCAGGGCGAACUUCGACACACAGC-3".

192. The base editor system of any one of claims 142-191, wherein the polynucleotide programmable DNA binding domain is a Cas9.

193. The base editor system of claim 192, wherein the Cas9 is a SpCas9, a SaCas9, or a variant thereof.

194. The base editor system of claim 192 or 193, wherein the polynucleotide programmable DNA binding domain comprises a modified SpCas9 having an altered protospacer- adjacent motif (PAM) specificity.

195. The base editor system of claim 194, wherein the Cas9 has specificity for a PAM sequence selected from the group consisting of NGG, NGA, NGCG, NGN, NNGRRT, NNNRRT, NGCG, NGCN, NGTN, and NGC, wherein Nis A, G, C, or T and wherein R isAorG.

196. The base editor system of any one of claims 192-195, wherein the polynucleotide programmable DNA binding domain is a nuclease inactive variant.

197. The base editor system of any one of claims 192-195, wherein the polynucleotide programmable DNA binding domain is a nickase variant.

198. The base editor system of claim 197, wherein the nickase variant comprises an amino acid substitution D10A or a corresponding amino acid substitution thereof.

199. The base editor system of any one of claims 142-198, wherein the adenosine deaminase domain comprises a TadA domain.

200. The base editor system of claim 199, wherein the adenosine deaminase comprises a TadA deaminase comprising a V82S alteration and / or a T166R alteration.

201. The base editor system of any one of claims 142-200, wherein the adenosine deaminase further comprises one or more of the following alterations: Y147T, Y147R, Q1548S, Y123H, Q154R, or a combination thereof.

202. The base editor system of any one of claims 142-201, wherein the adenosine deaminase comprises a combination of alterations selected from the group consisting of: Y147R + Q154R +Y123H; Y147R + Q154R +176Y; Y147R + Q154R + T166R; Y147T + Q154R; Y147T + Q154S; and Y123H + Y147R + Q154R + I76Y.

203. The base editor system of any one of claims 142-202, wherein the adenosine base editor domain comprises an adenosine deaminase monomer.

204. The base editor system of any one of claims 142-203, wherein the adenosine base editor comprises an adenosine deaminase dimer, 205. The base editor system of any one of claims 199-204, wherein the TadA deaminase is a TadA*8 variant.

206. The base editor system of claim 205, wherein the TadA*8 variant is selected from the group consisting of: TadA*8.1, TadA*8.2, TadA*8.3, TadA*8.4, TadA*8.5, TadA*8.6, TadA*8.7, TadA*8.8, TadA*8.9, TadA*8.10, TadA*8.11, TadA*8.12, and TadA*8.

13.

207. The base editor system of claim 206, wherein the adenosine base editor is an ABES base editor selected from the group consisting of: ABES.1, ABES.2, ABES8.3, ABES8.4, ABES.5, ABES.6, ABES.7, ABE8.8, ABES.9, ABES.10, ABES.11, ABES8.12, and ABES 13.

208. A vector comprising the nucleic acid sequence encoding the adenosine base editor of any one of claims 142-207.

209. A vector comprising the nucleic acid sequence encoding the adenosine base editor and the guide polynucleotide of any one of claims 142-207.

210. The vector of claim or 208 or 209, wherein the vector is a viral vector, a lentiviral vector, or an AAV vector.

211. A cell comprising the base editor system of any one of claims 142-207, or the vector of any one of claims 208-210, 212. The cell of claim 211, wherein the cell is a central nervous system cell.

213. The cell of claim 211, wherein the cell is a neuron.

214. The cell of claim 211, wherein the cell is a photoreceptor.

215. The cell of any one of claims 211-214, wherein the cell is in vitro, in vivo, or ex vivo.

216. A pharmaceutical composition comprising the base editor of any one of claims 142-207, the vector of any one of claims 208-210, or the cell of any one of claims 211-215 and a pharmaceutically acceptable carrier.

217. The pharmaceutical composition of claim 216, further comprising a lipid.

218. The pharmaceutical composition of claim 216, further comprising a virus.

219. A Kkit comprising the base editor of any one of claims 142-207 or the vector of any one of claims 208-210.

220. The method of any one of claims 1-139, wherein at least one nucleotide of the guide polynucleotide comprises a non-naturally occurring modification.

221. The method of any one of claims 14, 31, 45, 58, 74, 85, 97, or 110, wherein at least one nucleotide of the nucleic acid sequence comprises a non-naturally occurring modification.

222. The base editor system of any one of claims 155, 166, 178, or 191, wherein at least one nucleotide of the nucleic acid sequence comprises a non-naturally occurring modification.

223. The base editor system of claim 222, wherein the non-naturally occurring modification is a chemical modification.

224. The base editor system of claim 223, wherein the chemical modification is a 2’-O- methylation.

225. The base editor system of claim 223, wherein the nucleic acid sequence comprises a phosphorothioate.

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