Anti-apoptotic vector and method of using the same
The present invention provides vectors for delivery of an anti-apoptotic therapy. The vectors include a phosphoglycerate kinase (Pgk) promoter operably connected to a polynucleotide encoding an anti-apoptotic BCL2 protein (e.g., BCLX L ). The vectors may be used in methods of treating conditions associated with apoptosis, including glaucoma.
1 . A method of treating a subject having a condition associated with apoptosis of a cell, the method comprising administering a therapeutically effective amount of a vector to the subject, wherein the vector comprises a phosphoglycerate kinase (Pgk) promoter operably connected to a polynucleotide encoding an anti-apoptotic BCL2 protein, wherein the Pgk promoter comprises SEQ ID NO: 1, SEQ ID NO: 2, or a sequence having 90% identity to SEQ ID NO:1 or SEQ ID NO:2.
2 . The method of claim 1 , wherein the anti-apoptotic BCL2 protein is selected from SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO:20, or sequences 90% identical thereto.
3 . The method of claim 2 , wherein the anti-apoptotic BCL2 protein comprises SEQ ID NO: 16.
4 . The method of claim 3 , wherein the Pgk promoter comprises SEQ ID NO: 2.
5 . The method of claim 1 , wherein the vector is an adenovirus or adenovirus associated viral vector.
6 . The method of claim 5 , wherein the vector comprises an AAV2 or AAV8 vector.
7 . The method of claim 6 , wherein the AAV2 vector is an AAV2/2 vector.
8 . The method of claim 1 , wherein the vector is designed to be self-complementary.
9 . The method of claim 1 , wherein the condition is selected from the group consisting of glaucoma, multiple sclerosis, hereditary optic neuropathy, traumatic optic nerve injury, ischemic/reperfusion injury of the retina, anterior ischemic optic neuropathy, and other neurodegenerative conditions.
10 . The method of claim 9 , wherein the condition is glaucoma.
11 . The method of claim 10 , further comprising administering a therapeutically effective amount of a glaucoma therapeutic.
12 . The method of claim 11 , wherein the glaucoma therapeutic is selected from the group consisting of a prostaglandin or prostaglandin analog, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, a rho kinase inhibitor, and combinations thereof.
13 . The method of claim 1 , wherein the cells are retinal cells.
14 . The method of claim 13 , wherein the retinal cells are retinal ganglion cells.
15 . The method of claim 1 , wherein the vector is administered intraocularly.
16 . The method of claim 15 , wherein the intraocular administration is via intravitreal injection.
17 . The method of claim 1 , wherein administration of the vector to an eye of the subject reduces retinal ganglion cell loss after traumatic optic nerve damage in the eye as compared to a control subject not receiving the vector.
18 . The method of claim 1 , wherein administration of the vector to an eye of a subject with glaucoma reduces retinal ganglion cell degeneration as compared to a control subject not receiving the vector.
19 . The method of claim 1 , wherein administration of the vector to an eye of a subject with glaucoma reduces the loss of visual function as compared to a control subject not receiving the vector.
20 . The method of claim 1 , wherein the subject is a human or non-human mammal.