IP Library › Granted Patent US 12,274,733
Granted Patent B2
US 12,274,733 · App. 17/280,384 · Granted Apr 15, 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 12,274,733
App. No.
17/280,384
Granted
Apr 15, 2025
Kind
B2
Abstract

Provided herein are engineered nucleic acids (e.g., expression vectors, including viral vectors, such as lentiviral vectors, adenoviral vectors, AAV 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 (125)

1. A method of treating glaucoma in a subject in need thereof comprising administering to an eye of the subject an adeno-associated virus (AAV) vector comprising a polynucleotide encoding OCT4, SOX2, and KLF4 operably linked to a promoter, flanked by inverted terminal repeat sequence (ITR) sequences, wherein the vector does not encode c-Myc and does not encode Nanog.

2. The method of claim 1 , wherein the vector is administered by intravitreal injection.

3. The method of claim 1 , wherein the vector is administered by sub-retinal injection.

4. The method of claim 1 , wherein the vector is an AAV2 vector.

5. The method of claim 1 , wherein the vector is an AAV9 vector.

6. The method of claim 1 , wherein the vector is an AAV.PHP.b vector.

7. The method of claim 1 , wherein the promoter comprises a comprises a tetracycline response element (TRE).

8. The method of claim 7 , wherein the promoter is a TRE3G promoter.

9. The method of claim 8 , wherein the polynucleotide comprises nucleic acid elements in the following order:

a. a first inverted terminal repeat sequence (ITR) sequence;

b. a TRE3G promoter sequence;

c. a multicistronic open reading frame encoding, in any order, OCT4, SOX2, and KLF4;

d. an SV-40-derived terminator sequence; and

e. a second inverted terminal repeat (ITR) sequence.

10. The method of claim 8 , wherein the TRE3G promoter comprises a minimal CMV promoter sequence.

11. The method of claim 10 , wherein the TRE3G promoter comprises a polynucleotide sequence at least 90% identical to SEQ ID NO: 7.

12. The method of claim 7 , wherein the method further comprises administering a second AAV vector comprising a second polynucleotide encoding a reverse tetracycline transactivator (rtTA) operably linked to a promoter, flanked by inverted terminal repeat sequence (ITR) sequences; and administering a tetracycline.

13. The method of claim 1 , wherein:

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

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

iii) KLF4 comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 45.

14. The method of claim 1 , wherein:

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

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

iii) KLF 4 comprises the amino acid sequence of SEQ ID NO: 45.

15. The method of claim 1 , wherein the polynucleotide comprises a polynucleotide sequence that is at least 90% identical to SEQ ID NO: 38 or a polynucleotide sequence that is at least 90% identical to SEQ ID NO: 121.

16. A method of rejuvenating an optic nerve in a subject in need thereof comprising administering to an eye of the subject an adeno-associated virus (AAV) vector comprising a polynucleotide encoding OCT4, SOX2, and KLF4 operably linked to a promoter, flanked by inverted terminal repeat sequence (ITR) sequences, wherein the vector does not encode c-Myc and does not encode Nanog.

17. The method of claim 16 , wherein the vector is administered by intravitreal injection.

18. The method of claim 16 , wherein the vector is administered by sub-retinal injection.

19. The method of claim 16 , wherein the vector is an AAV2 vector.

20. The method of claim 16 , wherein the vector is an AAV9 vector.

21. The method of claim 16 , wherein the vector is an AAV.PHP.b vector.

22. The method of claim 16 , wherein the promoter comprises a comprises a tetracycline response element (TRE).

23. The method of claim 22 , wherein the promoter is a TRE3G promoter.

24. The method of claim 23 , wherein the polynucleotide comprises nucleic acid elements in the following order:

a. a first inverted terminal repeat sequence (ITR) sequence;

b. a TRE3G promoter sequence;

c. a multicistronic open reading frame encoding, in any order, OCT4, SOX2, and KLF4;

d. an SV-40-derived terminator sequence; and

e. a second inverted terminal repeat (ITR) sequence.

25. The method of claim 23 , wherein the TRE3G promoter comprises a minimal CMV promoter sequence.

26. The method of claim 25 , wherein the TRE3G promoter comprises a polynucleotide sequence at least 90% identical to SEQ ID NO: 7.

27. The method of claim 22 , wherein the method further comprises administering a second AAV vector comprising a second polynucleotide encoding a reverse tetracycline transactivator (rtTA) operably linked to a promoter, flanked by inverted terminal repeat sequence (ITR) sequences; and administering a tetracycline.

28. The method of claim 16 , wherein:

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

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

iii) KLF4 comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 45.

29. The method of claim 16 , wherein:

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

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

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

30. The method of claim 16 , wherein the polynucleotide comprises a polynucleotide sequence that is at least 90% identical to SEQ ID NO: 38 or a polynucleotide sequence that is at least 90% identical to SEQ ID NO: 121.

31. A method of treating damage to retinal ganglion cells in optic neuropathy in a subject in need thereof comprising administering to an eye of the subject an adeno-associated virus (AAV) vector comprising a polynucleotide encoding OCT4, SOX2, and KLF4 operably linked to a promoter, flanked by inverted terminal repeat sequence (ITR) sequences, wherein the vector does not encode c-Myc and does not encode Nanog.

32. A method of treating decline in retinal ganglion cell function in a subject suffering from age-related visual acuity loss comprising administering to an eye of the subject an adeno-associated virus (AAV) vector comprising a polynucleotide encoding OCT4, SOX2, and KLF4operably linked to a promoter, flanked by inverted terminal repeat sequence (ITR) sequences, wherein the vector does not encode c-Myc and does not encode Nanog.

33. The method of claim 31 or 32 , wherein the vector is administered by intravitreal injection.

34. The method of claim 31 or 32 , wherein the vector is administered by sub-retinal injection.

35. The method of claim 31 or 32 , wherein the vector is an AAV2vector.

36. The method of claim 31 or 32 , wherein the vector is an AAV9vector.

37. The method of claim 31 or 32 , wherein the vector is an AAV.PHP.b vector.

38. The method of claim 31 or 32 , wherein the promoter comprises a comprises a tetracycline response element (TRE).

39. The method of claim 38 , wherein the promoter is a TRE3G promoter.

40. The method of claim 39 , wherein the polynucleotide comprises nucleic acid elements in the following order:

a. a first inverted terminal repeat sequence (ITR) sequence;

b. a TRE3G promoter sequence;

c. a multicistronic open reading frame encoding, in any order, OCT4, SOX2, and KLF4;

d. an SV-40-derived terminator sequence; and

e. a second inverted terminal repeat (ITR) sequence.

41. The method of claim 39 , wherein the TRE3G promoter comprises a minimal CMV promoter sequence.

42. The method of claim 41 , wherein the TRE 3 G promoter comprises a polynucleotide sequence at least 90% identical to SEQ ID NO: 7.

43. The method of claim 38 , wherein the method further comprises administering a second AAV vector comprising a second polynucleotide encoding a reverse tetracycline transactivator (rtTA) operably linked to a promoter, flanked by inverted terminal repeat sequence (ITR) sequences; and administering a tetracycline.

44. The method of claim 31 or 32 , wherein:

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

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

iii) KLF4 comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 45.

45. The method of claim 44 , wherein:

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

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

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

46. The method of claim 31 or 32 , wherein the polynucleotide comprises a polynucleotide sequence that is at least 90% identical to SEQ ID NO: 38 or a polynucleotide sequence that is at least 90% identical to SEQ ID NO: 121.

47. An adeno-associated virus (AAV) vector comprising a polynucleotide encoding OCT4, SOX2, and KLF4, flanked by inverted terminal repeats (ITRs), wherein the AAV vector does not encode c-Myc and does not encode Nanog, wherein the polynucleotide comprises nucleic acid elements in the following order:

a. a first inverted terminal repeat sequence (ITR) sequence;

b. a TRE3G promoter sequence;

c. a multicistronic open reading frame encoding, in any order, OCT4, SOX2, and KLF4;

d. an SV-40-derived terminator sequence; and

e. a second inverted terminal repeat (ITR) sequence.

48. The AAV vector of claim 47 , wherein the AAV vector is an AAV2vector.

49. The AAV vector of claim 47 , wherein the AAV vector is an AAV9vector.

50. The AAV vector of claim 47 , wherein the AAV vector is an AAV.PHP.b vector.

51. The AAV vector of claim 47 , wherein:

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

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

iii) KLF4 comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 45.

52. The AAV vector of claim 51 , wherein the AAV vector is an AAV2vector.

53. The AAV vector of claim 51 , wherein the AAV vector is an AAV9vector.

54. The AAV vector of claim 51 , wherein the AAV vector is an AAV.PHP.b vector.

55. The AAV vector of claim 47 , wherein:

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

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

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

56. The AAV vector of claim 55 , wherein the AAV vector is an AAV2vector.

57. The AAV vector of claim 55 , wherein the AAV vector is an AAV9vector.

58. The AAV vector of claim 55 , wherein the AAV vector is an AAV.PHP.b vector.

59. The AAV vector of claim 47 , wherein the AAV vector also does not encode homologs of c-Myc, and does not encode homologs of Nanog.

60. An adeno-associated virus (AAV) vector comprising a polynucleotide encoding OCT4, SOX2, and KLF4, but not c-Myc and not Nanog, the polynucleotide comprising nucleic acid elements in the following order:

a. a first inverted terminal repeat sequence (ITR) sequence;

b. a TRE3G promoter sequence;

c. an OCT4 sequence;

d. a P2A cleavage sequence;

e. a SOX2 sequence;

f. a T2A cleavage sequence;

g. a KLF4 sequence;

h. an SV-40-derived terminator sequence; and

i. a second inverted terminal repeat (ITR) sequence.

61. The AAV vector of claim 60 , wherein the AAV vector is an AAV2vector.

62. The AAV vector of claim 60 , wherein the AAV vector is an AAV9vector.

63. The AAV vector of claim 60 , wherein the AAV vector is an AAV.PHP.b vector.

64. The AAV vector of claim 60 , wherein:

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

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

iii) KLF4 comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 45.

65. The AAV vector of claim 60 , wherein:

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

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

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

66. The AAV vector of claim 60 , wherein the AAV vector also does not encode homologs of c-Myc, and does not encode homologs of Nanog.

Assignments (2)
CONFIRMATORY LICENSE Recorded Nov 22, 2023
From: HARVARD UNIVERSITY
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065666/0119 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 15, 2022
From: SINCLAIR, DAVID A.; LU, YUANCHENG
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 061102/0632 →
Continuity (5)
Provisional Application 62880448 · Jul 30, 2019
Provisional Application 62865877 · Jun 24, 2019
Provisional Application 62792283 · Jan 14, 2019
Provisional Application 62738922 · Sep 28, 2018
Related Publication 20230048010A1 · Feb 16, 2023
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