IP Library › Granted Patent US 12,409,207
Granted Patent B2
US 12,409,207 · App. 18/318,566 · Granted Sep 9, 2025

Cellular reprogramming to reverse aging and promote organ and tissue regeneration

Inventors: David A. Sinclair (Cambridge, MA); Yuancheng Lu (Cambridge, MA)
Assignee: President and Fellows of Harvard College
A61K38/1709A61K31/65C12N15/86C12N2750/14143
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Quick Facts
Patent No.
US 12,409,207
App. No.
18/318,566
Granted
Sep 9, 2025
Kind
B2
Abstract

Provided herein are engineered nucleic acids (e.g., expression vectors, including viral vectors, such as lentiviral vectors, adenoviral vectors, AV vectors, herpes viral vectors, and retroviral vectors) that encode OCT4; KLF4; SOX2; or any combination thereof that are useful, for example, in inducing cellular reprogramming, tissue repair, tissue regeneration, organ regeneration, reversing aging, or any combination thereof. Also provided herein are recombinant viruses (e.g., lentiviruses, alphaviruses, vaccinia viruses, adenoviruses, herpes viruses, retroviruses, or AAVs) comprising the engineered nucleic acids (e.g., engineered nucleic acids), engineered cells, compositions comprising the engineered nucleic acids, the recombinant viruses, engineered cells, engineered proteins, chemical agents that are capable of activating expression of OCT4; KLF4; SOX2; or any combination thereof, an engineered protein selected from the group consisting of OCT4; KLF4; SOX2; or any combination thereof, an antibody capable of activating expression of OCT4; KLF4; SOX2; or any combination thereof, and methods of treating a (e.g., ocular disease), preventing a disease (e.g., ocular disease), regulating (e.g., inducing or inducing and then stopping) cellular reprogramming, regulating tissue repair, regulating tissue regeneration, or any combination thereof).

Claims (31)

1. A syringe comprising a pharmaceutical composition, wherein the pharmaceutical composition comprises an expression vector comprising a polynucleotide encoding a human octamer-binding transcription factor 4 (OCT4) protein, a human sex determining region Y-box 2 (SOX2) protein, and a human Kruppel-like factor 4 (KLF4) protein, wherein the polynucleotide does not encode a Myc proto-oncogene (c-Myc) protein, wherein the polynucleotide does not encode a Nanog protein, wherein the polynucleotide is operably linked to at least one promoter, and wherein the pharmaceutical composition does not comprise a cytokine.

2. The syringe of claim 1 , wherein:

i) the OCT4 comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 41;

ii) the SOX2 comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 43; and

iii) the KLF 4 comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 45.

3. The syringe of claim 1 , wherein:

i) the OCT4 comprises the amino acid sequence of SEQ ID NO: 41;

ii) the SOX2 comprises the amino acid sequence of SEQ ID NO: 43; and

iii) the KLF4 comprises the amino acid sequence of SEQ ID NO: 45.

4. The syringe of claim 1 , wherein the polynucleotide does not encode a homolog of c-Myc and does not encode a homolog of Nanog.

5. The syringe of claim 1 , wherein the polynucleotide is comprised by an adeno-associated virus (AAV).

6. The syringe of claim 1 , wherein the expression vector is an adeno-associated virus (AAV) vector.

7. The syringe of claim 1 , wherein the expression vector is a lentiviral vector.

8. The syringe of claim 1 , wherein the at least one promoter comprises an inducible promoter.

9. The syringe of claim 8 , wherein the inducible promoter comprises:

a mifepristone-responsive promoter, or

a coumermycin-responsive promoter.

10. The syringe of claim 8 , wherein the inducible promoter comprises a tetracycline-responsive element (TRE).

11. The syringe of claim 10 , wherein the syringe comprises a polynucleotide encoding a reverse tetracycline-controlled transactivator (rtTA).

12. The syringe of claim 11 , wherein the expression vector comprises the polynucleotide encoding the rtTA.

13. The syringe of claim 8 , wherein the inducible promoter is a TRE3G promoter.

14. The syringe of claim 1 , wherein the polynucleotide comprises a polynucleotide sequence encoding a self-cleaving peptide.

15. The syringe of claim 8 , wherein the syringe comprises an inducing agent to induce expression of OCT4, SOX2, and/or KLF4.

16. The syringe of claim 15 , wherein the inducing agent is a tetracycline-class antibiotic.

17. The syringe of claim 15 , wherein the inducing agent is tetracycline.

18. The syringe of claim 15 , wherein the inducing agent is doxycycline.

19. The syringe of claim 15 , wherein:

i) OCT4 comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 41;

ii) SOX2 comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 43; and

iii) KLF4 comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 45.

20. The syringe of claim 1 , wherein the expression vector does not encode other transcription factors besides OCT4, SOX2, and KLF4.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 22, 2023
From: SINCLAIR, DAVID A.; LU, YUANCHENG
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 065644/0689 →
Continuity (6)
Continuation 17280384
Provisional Application 62738922 · Sep 28, 2018
Provisional Application 62792283 · Jan 14, 2019
Provisional Application 62865877 · Jun 24, 2019
Provisional Application 62880488 · Jul 30, 2019
Related Publication 20230338468A1 · Oct 26, 2023
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