IP Library › Granted Patent US 12,612,618
Granted Patent B2
US 12,612,618 · App. 17/427,410 · Granted Apr 28, 2026

Nucleobase editors having reduced non-target deamination and assays for characterizing nucleobase editors

Inventors: Ian Slaymaker (Cambridge, MA); Jason Michael Gehrke (Cambridge, MA); Nicole Gaudelli (Cambridge, MA); Yi Yu (Cambridge, MA)
Assignee: Beam Therapeutics Inc.
C12N15/102C12N9/22C12N9/80C12N15/111C12N15/62C40B40/10C12N2310/20C12N2320/11C12Y305/04005
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Quick Facts
Patent No.
US 12,612,618
App. No.
17/427,410
Filed
Jul 30, 2021
Granted
Apr 28, 2026
Kind
B2
Art Unit
1635
USPC
435/455
Abstract

The invention features base editors having reduced non-target deamination, methods of using the base editors, and assays for characterizing base editors as having decreased non-target deamination, e.g. compared to programmed, on-target deamination.

Claims (36)

1 . A fusion protein comprising a deaminase inserted within a flexible loop of a Cas9 polypeptide, wherein the fusion protein comprises the structure:

NH2-[N-terminal fragment of a Cas9]-[TadA adenosine deaminase]-[C-terminal fragment of a Cas9]-COOH,

wherein each instance of “]-[” is an optional linker, wherein the TadA adenosine deaminase is inserted between amino acid positions 768-769, 1022-1023, 1026-1027, 1040-1041, 1068-1069, or 1247-1248, as numbered in SEQ ID NO: 1, and wherein the TadA adenosine deaminase of the fusion protein deaminates a target nucleobase in a target DNA molecule and effects reduced deamination at non-target sites compared with an end-terminus fusion protein comprising the TadA adenosine deaminase fused to an N-terminus or C-terminus of a Cas9 polypeptide.

2 . The fusion protein of claim 1 further comprising a nuclear localization signal.

3 . The fusion protein of claim 1 , wherein the fusion protein is in complex with a guide nucleic acid to effect deamination of a target nucleobase.

4 . A cell comprising the fusion protein of claim 1 .

5 . A kit comprising the fusion protein of claim 1 .

6 . A method for base editing comprising contacting a polynucleotide sequence with the fusion protein of claim 1 , wherein the deaminase of the fusion protein deaminates a nucleobase in the polynucleotide, thereby editing the polynucleotide sequence.

7 . The method of claim 6 , wherein the contacting is performed in a cell.

8 . A fusion protein comprising a deaminase inserted within a Cas9 polypeptide, wherein the fusion protein comprises the structure:

NH2-[N-terminal fragment of a Cas9]-[TadA adenosine deaminase]-[C-terminal fragment of a Cas9]-COOH, wherein each instance of “]-[” is an optional linker,

wherein the Cas9 polypeptide comprises a deletion of amino acid positions 794-905, as numbered in SEQ ID NO: 1,

wherein the TadA adenosine deaminase is inserted at the deletion position, and wherein the TadA adenosine deaminase of the fusion protein deaminates a target nucleobase in a target DNA molecule and effects reduced deamination at non-target sites compared with an end-terminus fusion protein comprising the TadA adenosine deaminase fused to an N-terminus or C-terminus of a Cas9 polypeptide.

9 . A polynucleotide encoding a fusion protein, wherein the fusion protein comprises:

A) a TadA adenosine deaminase inserted within a flexible loop of a Cas9 polypeptide, wherein the fusion protein comprises the structure:

NH2-[N-terminal fragment of a Cas9]-[TadA adenosine deaminase]-[C-terminal fragment of a Cas9]-COOH,

wherein each instance of “]-[” is an optional linker, wherein the TadA adenosine deaminase is inserted between amino acid positions 768-769, 1022-1023, 1026-1027, 1040-1041, 1068-1069, or 1247-1248, as numbered in SEQ ID NO: 1; or

B) a deaminase inserted within a Cas9 polypeptide, wherein the fusion protein comprises the structure:

NH2-[N-terminal fragment of a Cas9]-[TadA adenosine deaminase]-[C-terminal fragment of a Cas91-COOH, wherein each instance of “1-” is an optional linker,

wherein the Cas9 polypeptide comprises a deletion of amino acid positions 794-905, as numbered in SEQ ID NO: 1,

wherein the TadA adenosine deaminase is inserted at the deletion position; and

wherein the TadA adenosine deaminase of the fusion protein deaminates a target nucleobase in a target DNA molecule and effects reduced deamination at non-target sites compared with an end-terminus fusion protein comprising the TadA adenosine deaminase fused to an N-terminus or C-terminus of a Cas9 polypeptide.

10 . An expression vector comprising the polynucleotide of claim 9 .

11 . A method for editing a target nucleobase in a target polynucleotide sequence, the method comprising: contacting the target polynucleotide sequence with a fusion protein comprising a TadA adenosine deaminase inserted within a Cas9 polypeptide, wherein the fusion protein comprises the structure:

NH2-[N-terminal fragment of a Cas9]-[TadA adenosine deaminase]-[C-terminal fragment of a Cas91-COOH, wherein each instance of “1-” is an optional linker,

wherein the Cas9 polypeptide comprises a deletion of amino acid positions 794-905, as numbered in SEQ ID NO: 1,

wherein the TadA adenosine deaminase is inserted at the deletion position, and wherein the TadA adenosine deaminase of the fusion protein effects reduced deamination at non-target sites compared with an end-terminus fusion protein comprising the TadA adenosine deaminase fused to an N-terminus or C-terminus of a Cas9 polypeptide.

12 . A method for editing a target nucleobase in a target polynucleotide sequence, the method comprising: contacting the target polynucleotide sequence with a fusion protein comprising a deaminase inserted within a flexible loop of a Cas9 polypeptide, wherein the fusion protein comprises the structure NH2-[N-terminal fragment of a Cas9]-[TadA adenosine deaminase]-[C-terminal fragment of a Cas9]-COOH, wherein each instance of “]-[” is an optional linker, wherein the TadA adenosine deaminase is inserted between amino acid positions 768-769, 1022-1023, 1026-1027, 1040-1041, 1068-1069, or 1247-1248, as numbered in SEQ ID NO: 1, and wherein the TadA adenosine deaminase of the fusion protein effects reduced deamination at non-target sites compared with an end-terminus fusion protein comprising the TadA adenosine deaminase fused to an N-terminus or C-terminus of a Cas9 polypeptide.

13 . A method for treating a genetic condition in a subject, the method comprising: administering to the subject a fusion protein comprising a TadA adenosine deaminase inserted within a Cas9 polypeptide, wherein the fusion protein comprises the structure:

NH2-[N-terminal fragment of a Cas91-[TadA adenosine deaminase]-[C-terminal fragment of a Cas9]-COOH, wherein each instance of “1-” is an optional linker,

wherein the Cas9 polypeptide comprises a deletion of amino acid positions 794-905, as numbered in SEQ ID NO: 1,

wherein the TadA adenosine deaminase is inserted at the deletion position, and a guide nucleic acid or a polynucleotide encoding the guide nucleic acid, wherein the guide nucleic acid directs the fusion protein to deaminate a target nucleobase in a target DNA molecule of the subject,

, wherein the genetic condition is caused by the target nucleobase, which comprises a single nucleotide polymorphism or point mutation at a single locus in the target DNA molecule of the subject, and wherein the TadA adenosine deaminase effects reduced deamination at non-target sites compared with an end-terminus fusion protein comprising the TadA adenosine deaminase fused to an N-terminus or C-terminus of a Cas9 polypeptide, wherein deamination of the target nucleobase ameliorates symptoms of the genetic condition, thereby treating the genetic condition.

14 . The method of claim 13 , wherein the deamination of the target nucleobase replaces the target nucleobase with a wild type nucleobase.

15 . The method of claim 13 , wherein the deamination of the target nucleobase replaces the target nucleobase with a non-wild type nucleobase.

16 . A method for treating a genetic condition in a subject, the method comprising: administering to the subject a fusion protein comprising a TadA adenosine deaminase inserted within a flexible loop of a Cas9 polypeptide, wherein the fusion protein comprises the structure NH2-[N-terminal fragment of a Cas9]-[TadA adenosine deaminase]-[C-terminal fragment of a Cas9]-COOH, wherein each instance of “]-[” is an optional linker, wherein the TadA adenosine deaminase is inserted between amino acid positions 768-769, 1022-1023, 1026-1027, 1040-1041, 1068-1069, or 1247-1248, as numbered in SEQ ID NO: 1, and a guide nucleic acid or a polynucleotide encoding the guide nucleic acid, wherein the guide nucleic acid directs the fusion protein to deaminate a target nucleobase in a target DNA molecule of the subject, wherein the genetic condition is caused by the target nucleobase, which comprises a single nucleotide polymorphism or point mutation at a single locus in the target DNA molecule of the subject, and wherein the TadA adenosine deaminase of the fusion protein effects reduced deamination at non-target sites compared with an end-terminus fusion protein comprising the TadA adenosine deaminase fused to an N-terminus or C-terminus of a Cas9 polypeptide, wherein deamination of the target nucleobase ameliorates symptoms of the genetic condition, thereby treating the genetic condition.

Assignments (4)
SECURITY INTEREST Recorded Mar 6, 2026
From: BEAM THERAPEUTICS INC.
To: SIXTH STREET LENDING PARTNERS, AS ADMINISTRATIVE AGENT
Reel/Frame 075021/0929 →
SECURITY INTEREST Recorded Feb 24, 2026
From: BEAM THERAPEUTICS INC.; GUIDE THERAPEUTICS, LLC; BBBR, LLC
To: SIXTH STREET LENDING PARTNERS, AS ADMINISTRATIVE AGENT
Reel/Frame 074955/0064 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 24, 2023
From: SLAYMAKER, IAN; GEHRKE, JASON MICHAEL; GAUDELLI, NICOLE; YU, YI
To: BEAM THERAPEUTICS INC.
Reel/Frame 063090/0172 →
CHANGE OF ADDRESS Recorded Mar 24, 2023
From: BEAM THERAPEUTICS INC.
To: BEAM THERAPEUTICS INC.
Reel/Frame 063163/0225 →
Continuity (2)
Provisional Application 62799702 · Jan 31, 2019
Related Publication 20220098572A1 · Mar 31, 2022
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