IP Library › Granted Patent US 12,551,575
Granted Patent B2
US 12,551,575 · App. 17/402,233 · Granted Feb 17, 2026

Htt repressors and uses thereof

Inventors: Steven Froelich (Brisbane, CA); Jeffrey C. Miller (Brisbane, CA); David Paschon (Brisbane, CA); Edward J. Rebar (Brisbane, CA); Bryan Zeitler (Brisbane, CA); H. Steve Zhang (Brisbane, CA)
Assignee: Sangamo Therapeutics, Inc.
A61K48/0075A61K48/00C07K14/47C07K14/4702C07K14/4703C12N5/0619C12N5/0656C12N5/10C12N15/86C12N15/8645C07K2319/81
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Quick Facts
Patent No.
US 12,551,575
App. No.
17/402,233
Granted
Feb 17, 2026
Kind
B2
Abstract

Disclosed herein are Htt repressors and methods and compositions for use of these Htt repressors.

Claims (129)

1 . A method of modifying expression of a mutant Huntingtin (mHtt) gene having at least 35 expanded CAG repeats in a mouse or human cell in vitro, the method comprising administering to the cell one or more AAV9 vectors, the AAV9 vectors comprising one or more polynucleotides encoding one or more Htt repressors, the Htt repressors comprising a non-naturally occurring zinc finger protein transcription factor (ZFP-TF) comprising:

(a) a KRAB repression domain; and

(b) a zinc finger protein comprising 5 zinc finger domains ordered F1 to F5, wherein the zinc finger domains comprise the recognition helix regions sequences shown in a single row of the following table:

F1

F2

F3

F4

F5

45643

QSGDLTR

QSGDLTR

QSGDLTR

KHGNLSE

KRCNLRC

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

NO: 1)

NO: 1)

NO: 1)

NO: 2)

NO: 3 )

46025

CPSHLTR

QSGDLTR

KHGNLSE

KRCNLRC

RQFNRHQ

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

NO: 4)

NO: 1)

NO: 2)

NO: 3)

NO: 5).

2 . The method of claim 1 , wherein the ZFP-TF specifically targets SEQ ID NO: 6 of a mHtt gene.

3 . The method of claim 1 , comprising administering to the cell one or more AAV9 vectors each comprising the one or more polynucleotides each encoding an Htt repressor comprising a zinc finger protein comprising 5 zinc finger domains ordered F1 to F5, wherein the zinc finger domains comprise the recognition helix regions sequences shown in a single row of the following table:

F1

F2

F3

F4

F5

45643

QSGDLTR

QSGDLTR

QSGDLTR

KHGNLSE

KRCNLRC

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

NO: 1)

NO: 1)

NO: 1)

NO: 2)

NO: 3 )

46025

CPSHLTR

QSGDLTR

KHGNLSE

KRCNLRC

RQFNRHQ

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

NO: 4)

NO: 1)

NO: 2)

NO: 3)

NO: 5).

4 . The method of claim 1 , wherein a first AAV9 vector comprises a first polynucleotide encoding the ZFP-TF, and a second AAV9 vector comprises a second polynucleotide encoding a second ZFP-TF.

5 . The method of claim 1 , wherein the cell is a fibroblast or a neuron.

6 . The method of claim 5 , wherein the cell is a Huntington's Disease (HD) neuron.

7 . The method of claim 1 , wherein the mHtt gene has at least 48 CAG repeats.

8 . The method of claim 1 , the mHtt gene has at least 48 CAG repeats, and the cell is an HD neuron or fibroblast.

9 . The method of claim 1 , wherein the mHtt gene comprises SEQ ID NO: 6.

10 . The method of claim 1 , wherein the mHtt gene has 48 CAG repeats.

11 . A method of inhibiting expression of a mutant Htt (mHTT) gene with at least 35 expanded CAG repeats and treating a symptom of Huntington's Disease in a human subject comprising administering to the striatum of the human subject an AAV9 vector, the AAV9 vector comprising one or more polynucleotides encoding one or more Htt repressors, the Htt repressors comprising a non-naturally occurring zinc finger protein transcription factor (ZFP-TF) comprising:

(a) a KRAB repression domain; and

(b) a zinc finger protein comprising 5 zinc finger domains ordered F1 to F5, wherein the zinc finger domains comprise the recognition helix regions sequences shown in a single row of the following table:

F1

F2

F3

F4

F5

45643

QSGDLTR

QSGDLTR

QSGDLTR

KHGNLSE

KRCNLRC

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

NO: 1)

NO: 1)

NO: 1)

NO: 2)

NO: 3 )

46025

CPSHLTR

QSGDLTR

KHGNLSE

KRCNLRC

RQFNRHQ

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

(SEQ ID

NO: 4)

NO: 1)

NO: 2)

NO: 3)

NO: 5).

12 . The method of claim 11 , wherein the administration is bilateral stereotactic intrastriatal injection to the subject.

13 . The method of claim 11 , wherein the ZFP-TF specifically targets SEQ ID NO: 6 of a mHtt gene.

14 . The method of claim 11 , wherein the mHtt gene has at least 48 CAG repeats.

Continuity (4)
Continuation 16550949 · Aug 26, 2019
Continuation 15274357 · Sep 23, 2016
Provisional Application 62222588 · Sep 23, 2015
Related Publication 20210369872A1 · Dec 2, 2021
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