IP Library › Granted Patent US 12,351,837
Granted Patent B2
US 12,351,837 · App. 17/425,261 · Granted Jul 8, 2025

Supernegatively charged proteins and uses thereof

Inventors: Yongjoo Kim (Cambridge, MA); David R. Liu (Cambridge, MA); Kevin Tianmeng Zhao (Cambridge, MA)
Assignees: The Broad Institute, Inc.; President and Fellows of Harvard College
C12N9/22A61K9/5123C07K14/4702C07K14/4728C07K14/57581C12N9/78A61K38/00C07K2319/00
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Quick Facts
Patent No.
US 12,351,837
App. No.
17/425,261
Granted
Jul 8, 2025
Kind
B2
Abstract

Provided herein are compositions, systems, and methods for delivering an effector protein into a cell. The present disclosure, in some aspects, provide novel proteins delivering an effector protein into a cell. The novel proteins are supernegatively charged proteins derived from highly anionic proteins identified from the proteome (e.g., human proteome). The novel protein tags can be associated (e.g., covalently or nocovalently) with the protein to be delivered to facilitate delivery of the effector protein into a cell.

Claims (19)

1. A composition comprising a cationic lipid or a cationic polymer and a supernegatively charged protein associated with an effector protein, wherein the supernegatively charged protein is a prothymosin alpha (ProTα) fragment comprising an amino acid sequence of SEQ ID NO: 2 or 3.

2. The composition of claim 1 , wherein the effector protein is an enzyme, a transcriptional regulator, a therapeutic protein, or a diagnostic protein.

3. The composition of claim 2 , wherein the enzyme is a recombinase, a nuclease, or an epigenetic modifier.

4. The composition of claim 1 , wherein the cationic lipid comprises 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate (DOSPA), 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE), or a combination thereof.

5. A method comprising contacting a mammalian cell with the composition of claim 1 , whereby the contacting results in the delivery of the effector protein into the mammalian cell.

6. The composition of claim 1 , wherein the supernegatively charged protein consists of the amino acid sequence of SEQ ID NO: 2 or 3.

7. The composition of claim 1 , wherein the effector protein is a zinc-finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), or an RNA-guided nuclease.

8. The composition of claim 1 , wherein the effector protein comprises a CRISPR associated protein 9 (Cas9) protein.

9. The composition of claim 1 , wherein the effector protein is a transcriptional regulator.

10. The composition of claim 9 , wherein the transcriptional regulator is a transcriptional activator or a transcriptional repressor.

11. The composition of claim 10 , wherein the transcriptional activator is selected from the group consisting of VP16, VP64, and p65.

12. The composition of claim 10 , wherein the transcriptional repressor is a Krüppel associate box (KRAB) protein or a systemic RNA interference defective (SID) protein.

13. The composition of claim 1 , wherein the supernegatively charged protein is covalently associated with the effector protein.

14. The composition of claim 13 , wherein the supernegatively charged protein is covalently associated with the effector protein via a linker.

15. The composition of claim 14 , wherein the linker is a cleavable linker.

16. The composition of claim 1 , wherein the supernegatively charged protein is non-covalently associated with the effector protein.

17. The composition of claim 1 , wherein the effector protein is a recombinase.

18. The composition of claim 1 , wherein the supernegatively charged protein comprises the amino acid sequence of SEQ ID NO: 2.

19. The composition of claim 1 , wherein the supernegatively charged protein comprises the amino acid sequence of SEQ ID NO: 3.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 7, 2021
From: HOWARD HUGHES MEDICAL INSTITUTE
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 057401/0327 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 7, 2021
From: LIU, DAVID R.
To: HOWARD HUGHES MEDICAL INSTITUTE
Reel/Frame 057401/0343 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 7, 2021
From: KIM, YONGJOO; ZHAO, KEVIN TIANMENG
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 057401/0388 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 7, 2021
From: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
To: THE BROAD INSTITUTE, INC.
Reel/Frame 057401/0488 →
Continuity (2)
Provisional Application 62795912 · Jan 23, 2019
Related Publication 20230002745A1 · Jan 5, 2023
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