IP Library › Granted Patent US 12,516,308
Granted Patent B2
US 12,516,308 · App. 18/545,977 · Granted Jan 6, 2026

Suppression of pain by gene editing

Inventors: Juan Pablo Maianti (Cambridge, MA); David R. Liu (Cambridge, MA)
Assignee: President and Fellows of Harvard College
C12N9/78A61K9/0029A61K9/0053A61K31/7088A61K38/465A61K38/50C12N9/22C12N9/96C12N15/11C12Y305/04A61K48/00C07K2319/00C12N2310/20C12N2320/31C12N2320/32C12N2800/80
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Quick Facts
Patent No.
US 12,516,308
App. No.
18/545,977
Granted
Jan 6, 2026
Kind
B2
Abstract

Provided herein are systems, compositions, kits, and methods for the suppression of pain (e.g., chronic pain). Genes encoding ion channels (e.g., SCN9A) responsible for the propagation pain signals in neurons (e.g., DRG neurons) may be edited using a genome editing agent (e.g., a nucleobase editor). In some embodiments, loss-of-function ion channel mutants are generated, leading to pain suppression. In some embodiments, the genome editing agent is administered locally to the site of pain or to the nerves responsible for propagation of the pain signal.

Claims (28)

1 . A composition comprising:

(i) a fusion protein comprising: (a) a guide nucleotide sequence-programmable DNA binding protein domain; and (b) a cytosine deaminase domain; and

(ii) a guide nucleotide sequence targeting the fusion protein of (i) to a target cytosine (C) base in an ion channel-encoding polynucleotide; and

wherein when the fusion protein of (i) targets the cytosine (C) base in an ion channel-encoding polynucleotide,

(I) a premature stop codon is introduced in the ion channel-coding sequence that leads to a truncated or non-functional ion channel,

(II) a mutation occurs that destabilizes ion-channel protein folding,

(III) a C to T change occurs at a C base-paired with the G base in a start codon (AUG), and/or

(IV) a C to T change occurs in the non-coding region of the ion channel-encoding polynucleotide.

2 . The composition of claim 1 , wherein the guide nucleotide sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 339-1456 or 1504-2425.

3 . The composition of claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier.

4 . A method of suppressing pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 1 .

5 . The composition of claim 1 , wherein when the fusion protein of (i) targets the cytosine (C) base in an ion channel-encoding polynucleotide, a premature stop codon is introduced in the ion channel-coding sequence that leads to a truncated or non-functional ion channel.

6 . The composition of claim 1 , wherein when the fusion protein of (i) targets the cytosine (C) base in an ion channel-encoding polynucleotide, a mutation occurs that destabilizes ion-channel protein folding.

7 . The composition of claim 1 , wherein when the fusion protein of (i) targets the cytosine (C) base in an ion channel-encoding polynucleotide, a C to T change occurs at a C base-paired with the G base in a start codon (AUG).

8 . The composition of claim 1 , wherein when the fusion protein of (i) targets the cytosine (C) base in an ion channel-encoding polynucleotide, a C to T change occurs in the non-coding region of the ion channel-encoding polynucleotide.

9 . The composition of claim 1 , wherein the ion channel is selected from the group consisting of: NaV1.7, NaV1.8, NaV1.9, NaV1.3, CaV3.2, HCN1, HCN2, and Ano1.

10 . The composition of claim 1 , wherein the ion channel is NaV1.7 encoded by the SCN9A gene.

11 . The composition of claim 1 , wherein the guide nucleotide sequence-programmable DNA binding protein domain is selected from the group consisting of: nuclease inactive Cas9 (dCas9) domains, nuclease inactive Cpf1 domains, nuclease inactive Argonaute domains, and variants thereof.

12 . The composition of claim 1 , wherein the cytosine deaminase domain comprises an apolipoprotein B mRNA-editing complex (APOBEC) family deaminase.

13 . The composition of claim 1 , wherein the cytosine deaminase domain is selected from the group consisting of APOBEC1 deaminase, APOBEC2 deaminase, APOBEC3A deaminase, APOBEC3B deaminase, APOBEC3C deaminase, APOBEC3D deaminase, APOBEC3F deaminase, APOBEC3G deaminase, APOBEC3H deaminase, APOBEC4 deaminase, activation-induced deaminase (AID), and pmCDA1.

14 . The composition of claim 1 , wherein the cytosine deaminase domain comprises an amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 271-292, 303, and 2483-2494.

15 . The composition of claim 1 , wherein the fusion protein further comprises a uracil glycosylase inhibitor (UGI) domain.

16 . The composition of claim 15 , wherein the UGI domain comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 304.

17 . The composition of claim 1 , wherein the fusion protein comprises an amino acid sequence having at least 85% sequence identity to any one of SEQ ID NOs: 296-302 and 2495.

18 . A method of editing a polynucleotide encoding an ion channel in a dorsal root ganglion (DRG) neuron, the method comprising contacting the ion channel-encoding polynucleotide with the composition of claim 1 ; wherein the guide nucleic acid molecule is selected from the nucleic acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 339-1456; and

whereby the contacting results in deamination of the target C base by the fusion protein, resulting in a C to T change in the ion channel-encoding polynucleotide.

19 . The composition of claim 1 , wherein the cytosine deaminase domain comprises the amino acid sequence of any one of SEQ ID NOs: 271-292, 303, and 2483-2494.

20 . The composition of claim 1 , wherein the fusion protein comprises the amino acid sequence of any one of SEQ ID NOs: 296-302 and 2495.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 24, 2024
From: LIU, DAVID R.
To: HOWARD HUGHES MEDICAL INSTITUTE
Reel/Frame 067212/0674 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 24, 2024
From: HOWARD HUGHES MEDICAL INSTITUTE
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 067212/0677 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 24, 2024
From: MAIANTI, JUAN PABLO
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 067212/0681 →
Continuity (3)
Division 16492548
Provisional Application 62469408 · Mar 9, 2017
Related Publication 20240271116A1 · Aug 15, 2024
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