IP Library › Granted Patent US 12,746,294
Granted Patent B2
US 12,746,294 · App. 17/613,025 · Granted Sep 29, 2026

AAV delivery of nucleobase editors

Inventors: David R. Liu (Cambridge, MA); Jonathan Ma Levy (Cambridge, MA); Wei Hsi Yeh (Cambridge, MA)
Assignees: The Broad Institute, Inc.; President and Fellows of Harvard College
A61K48/005C12N9/22C12N15/111C12N15/113C12N15/86C12N2310/20
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Quick Facts
Patent No.
US 12,746,294
App. No.
17/613,025
Granted
Sep 29, 2026
Kind
B2
Abstract

Provided herein are methods of delivering “split” Cas9 protein or nucleobase editors into a cell, e.g., via a recombinant adeno-associated vims (rAAV), to form a complete and functional Cas9 protein or nucleobase editor. The Cas9 protein or the nucleobase editor is split into two sections, each fused with one part of an intein system (e.g., intein-N and intein-C encoded by the dnaE-n and dnaE-c genes, respectively). Upon co-expression, the two sections of the Cas9 protein or nucleobase editor are ligated together via intein-mediated protein splicing. Nucleic acid molecules encoding the N-terminal portion of a Cas9 protein or a nucleobase editor fused to an intein, and nucleic acid molecules encoding the C-terminal portion of a Cas9 protein or nucleobase editor, are provided. Recombinant AAV vectors (e.g, vectors comprising one or more of these nucleic acid molecules each comprising an intein) and particles for the delivery of the split Cas9 protein or nucleobase editor, compositions comprising such AAV vectors and particles, and methods of using such rAAV vectors and particles are also provided. Methods of administering such compositions and AAV particles to a subject are further provided. Cells and compositions comprising these nucleic acid molecules rAAV vectors, and rAAV particles are also provided.

Claims (24)

1 . A nucleic acid molecule comprising:

a first nucleic acid segment encoding a N-terminal portion of a nucleobase editor fused at its C-terminus to a first intein sequence, wherein the first nucleic acid segment is operably linked to a first promoter; and

a second nucleic acid segment encoding a guide RNA (gRNA) operably linked to a second promoter, wherein the direction of transcription of the second nucleic acid segment is reversed relative to the direction of transcription of the first nucleic acid segment; and

wherein the nucleic acid molecule comprises a sequence that is at least 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 642, 644, 646, 648, 650, and 652.

2 . The nucleic acid molecule of claim 1 , wherein the first intein sequence comprises the amino acid sequence as set forth in SEQ ID NO: 351.

3 . The nucleic acid molecule of claim 1 further comprising a transcriptional terminator.

4 . The nucleic acid molecule of claim 3 further comprising a woodchuck hepatitis posttranscriptional regulatory element (WPRE) inserted 5′ of the transcriptional terminator.

5 . The nucleic acid molecule of claim 3 , wherein the transcriptional terminator is the transcriptional terminator from a bGH gene, hGH gene, or SV40 gene.

6 . A composition comprising the nucleic acid molecule of claim 1 and a pharmaceutically acceptable carrier.

7 . The nucleic acid molecule of claim 1 , wherein the nucleic acid molecule comprises a sequence that is at least 95% a sequence selected from the group consisting of SEQ ID NOs: 642, 644, 646, 648, 650, and 652.

8 . The nucleic acid molecule of claim 1 , wherein the nucleic acid molecule comprises a sequence selected from the group consisting of SEQ ID NOs: 642, 644, 646, 648, 650, and 652.

9 . The nucleic acid molecule of claim 1 , wherein the first promoter is a Cbh promoter.

10 . The nucleic acid molecule of claim 1 , wherein the nucleobase editor comprises a cytosine deaminase.

11 . The nucleic acid molecule of claim 1 , wherein the nucleobase editor comprises an adenine deaminase.

12 . The nucleic acid molecule of claim 1 , wherein the nucleic acid molecule comprises a sequence that is at least 98% identical to a sequence selected from the group consisting of SEQ ID NOs: 642, 644, 646, 648, 650, and 652.

13 . The nucleic acid molecule of claim 1 , wherein the nucleic acid molecule comprises a sequence that is at least 99% identical to a sequence selected from the group consisting of SEQ ID NOs: 642, 644, 646, 648, 650, and 652.

14 . A recombinant AAV (rAAV) particle comprising the nucleic acid molecule of claim 1 .

15 . The rAAV particle of claim 14 , wherein the rAAV particle is an rAAV2 particle, rAAV6 particle, rAAV8 particle, rPHP.B particle, rPHP.eB particle, or rAAV9 particle.

16 . The rAAV particle of claim 14 , wherein the rAAV particle is an rAAV9 particle.

17 . A cell in vitro comprising the rAAV particle of claim 14 .

18 . The cell of claim 17 , wherein the cell is a human cell.

19 . A method comprising:

administering to a subject in need thereof a therapeutically effective amount of the rAAV particle of claim 14 , wherein the subject has a disease or disorder, and wherein the disease or disorder is Niemann-Pick type C (NPC) disease.

20 . The cell of claim 18 , wherein the human cell is a retinal cell, a cortical cell, or a cerebellar cell.

Assignments (5)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 26, 2022
From: HOWARD HUGHES MEDICAL INSTITUTE
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 061211/0439 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 26, 2022
From: YEH, WEI HSI
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 061211/0600 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 26, 2022
From: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
To: THE BROAD INSTITUTE, INC.
Reel/Frame 061211/0681 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 26, 2022
From: LEVY, JONATHAN MA
To: THE BROAD INSTITUTE, INC.
Reel/Frame 061211/0786 →
CONFIRMATORY ASSIGNMENT Recorded Sep 26, 2022
From: LIU, DAVID R.
To: HOWARD HUGHES MEDICAL INSTITUTE
Reel/Frame 061539/0495 →
Continuity (3)
Provisional Application 62949275 · Dec 17, 2019
Provisional Application 62850523 · May 20, 2019
Related Publication 20220249697A1 · Aug 11, 2022
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