Methods of editing nucleotide polymorphism using programmable base editor systems

A method of editing a methyl-CpG-binding protein 2 (MECP2) polynucleotide comprising a single nucleotide polymorphism (SNP) associated with Rett Syndrome (RTT), the method comprising contacting the MECP2 polynucleotide with a base editor in complex with one or more guide polynucleotides, wherein the base editor comprises a Streptococcus pyogenes Cas9 (SpCas9) domain having protospacer-adjacent motif (PAM) specificity for the nucleic acid sequence 5′-NGT-3′, and an adenosine deaminase domain, and wherein said one or more of said guide polynucleotides direct said base editor to effect an A-T to G-C alteration at the SNP associated with RTT, wherein the SpCas9 domain comprises an amino acid sequence with at least 90% identity to SEQ ID NO:

• 42, and wherein:
• the SpCas9 domain further comprises the following amino acid substitutions referenced to SEQ ID NO:
• 42:
• a) L1111R or 1111,
• b) D1135V or D1135L,
• c) G1218R or G1218S,
• d) E1219F or E1219V,
• e) A1322R,
• f) R1335V or R1335Q, and
• g) T1337R, T1337, T1337L, T1337Q, T13371, T1337V, T1337F, T1337S, T1337N, T1337K, T1337H, T1337Q, or T1337M;
• or
• the SpCas9 domain further comprises the following amino acid substitutions referenced to SEQ ID NO:
• 42:
• a) D1135L,
• b) S1136R,
• c) G1218S or G1218R,
• d) E1219V or E1219F,
• e) A1322R,
• f) R1335Q, and
• g) T1337, T1337L, T13371, T1337V, T1337F, T1337S, T1337N, T1337K, T1337R, T1337H, T1337Q, or T1337M.