US 12,274,733 B2
Cellular reprogramming to reverse aging and promote organ and tissue regeneration
David A. Sinclair, Cambridge, MA (US); and Yuancheng Lu, Cambridge, MA (US)
Assigned to President and Fellows of Harvard College, Cambridge, MA (US)
Appl. No. 17/280,384
Filed by President and Fellows of Harvard College, Cambridge, MA (US)
PCT Filed Sep. 27, 2019, PCT No. PCT/US2019/053545
§ 371(c)(1), (2) Date Mar. 26, 2021,
PCT Pub. No. WO2020/069373, PCT Pub. Date Apr. 2, 2020.
Claims priority of provisional application 62/880,448, filed on Jul. 30, 2019.
Claims priority of provisional application 62/865,877, filed on Jun. 24, 2019.
Claims priority of provisional application 62/792,283, filed on Jan. 14, 2019.
Claims priority of provisional application 62/738,922, filed on Sep. 28, 2018.
Prior Publication US 2023/0048010 A1, Feb. 16, 2023
Int. Cl. A61K 48/00 (2006.01); A61K 31/65 (2006.01); A61K 38/17 (2006.01); C12N 15/86 (2006.01)
CPC A61K 38/1709 (2013.01) [A61K 31/65 (2013.01); C12N 15/86 (2013.01); C12N 2750/14143 (2013.01)] 66 Claims
 
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.
 
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.
 
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.
 
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.