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

3-5. (canceled)

12-13. (canceled)

15-23. (canceled)

25-38. (canceled)

40-59. (canceled)

A method of editing a target gene or regulatory element thereof associated with a neurological disorder selected from the group consisting of Hurler syndrome, Parkinson's disease, Rett syndrome and Stargardt disease, 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.

61-63. (canceled)

(canceled)

(canceled)

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 LRRK2 polypeptide as numbered in SEQ ID NO:

• 3, or a variant thereof.

71-75. (canceled)

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.

77-86. (canceled)

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.

88-89. (canceled)

91-98. (canceled)

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.

100-103. (canceled)

105-110. (canceled)

112-139. (canceled)

(canceled)

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 selected from the group consisting of LRRK2, IDUA, and ABCA4, or a regulatory element thereof associated with the neurological disorder.

143-207. (canceled)

(canceled)

212-215. (canceled)

217-225. (canceled)