Delivery of NRF2 as therapy for protection against reactive oxygen species

12060,395

17/342120

June 08, 2021

The present invention provides methods and compositions for treating and/or preventing age related macular degeneration and other conditions involving macular degeneration, ocular neovascularization, or inflammation, including ocular inflammation. In some embodiments, the methods comprise administering an expression vector that delivers a secretable and cell penetrating Nrf2 to a subject in need thereof.

University of Florida Research Foundation, Incorporated (Gainesville, FL, US)

University of Florida Research Foundation, Incorporated (Gainesville, FL, US)

1. A method comprising administering a therapeutically effective amount of an AAV vector to the eye of a subject having an ocular disease or condition associated with oxidative stress or inflammation, wherein the AAV vector comprises an expression construct comprising a nucleotide sequence encoding a recombinant polypeptide, and wherein the recombinant polypeptide comprises an Nrf2 peptide, a cell penetrating peptide comprising a Tat peptide, and a secretion signal, and wherein the Nrf2 peptide comprises the amino acid sequence of LQLDEETGEFLPIQ (SEQ ID NO: 1), or a variant thereof that is capable of binding Keap-1 protein, wherein the variant has one, two, or three amino acid deletions or substitutions relative to SEQ ID NO: 1, and wherein the amino acid deletions are from the N and/or C terminus of SEQ ID NO: 1 and the amino acid substitutions within SEQ ID NO: 1 are conservative substitutions.

2. The method of claim 1 , wherein the Nrf2 peptide provides enhanced binding of the recombinant polypeptide to a Keap-1 protein in the eye, compared to a polypeptide lacking the Nrf2 peptide.

3. The method of claim 1 , wherein the AAV vector is encapsidated in a viral particle comprising a modified AAV2 capsid protein.

4. The method of claim 3 , wherein the modified AAV2 capsid protein comprises non-tyrosine residues corresponding to positions Y272, Y444, Y500, and Y730 of a wild-type AAV2 capsid.

5. The method of claim 1 , wherein the secretion signal is an Igκ signal.

6. The method of claim 1 , wherein the secretion signal comprises a sequence selected from SEQ ID NOs: 2-14.

7. The method of claim 1 , wherein the cell penetrating peptide comprises the amino acid sequence set forth as SEQ ID NO: 25.

8. The method of claim 1 , wherein the AAV vector is administered to the eye of the subject via any one of intravitreal injection, subretinal injection, injection into the anterior chamber of the eye, injection or application locally to the cornea, subconjunctival injection, subtenon injection, and eye drops.

9. The method of claim 1 , wherein the step of administering results in improvement of responses to light stimuli, improved visual field, increased thickness of the outer nuclear layer (ONL) of the retina, longer photoreceptor cell outer segments, reversal of loss of photoreceptor cell integrity, increased survival of photoreceptor cells, and/or reduction of inflammatory symptoms in the eye of the subject.

10. The method of claim 1 , wherein the step of administering results in secretion of the recombinant polypeptide from cells transfected with the AAV vector.

11. The method of claim 1 , wherein the recombinant polypeptide reduces secretion of IL-1β from cells in the eye.

12. The method of claim 1 , wherein the recombinant polypeptide further comprises a carrier protein.

13. The method of claim 12 , wherein the carrier protein is selected from opticin, human serum albumin, dihidrofolate reductase (DHFR) destabilization domain, and FK506 binding protein (FKBP) destabilization domain.

14. The method of claim 12 , wherein the carrier protein is opticin.

15. The method of claim 12 , wherein the carrier protein and cell penetrating peptide are linked to one another by a furin cleavage site.

16. The method of claim 1 , wherein the inflammation is retinal inflammation or retinal pigment epithelium (RPE) inflammation.

17. The method of claim 1 , wherein the ocular disease or condition is selected from the group consisting of macular degeneration, age-related macular degeneration (AMD), geographic atrophy, wet AMD, dry AMD, drusen formation, dry eye, diabetic retinopathy, vitreoretinopathy, corneal inflammation, uveitis, ocular hypertension, and glaucoma.

18. A method comprising administering at least one cell transfected with the AAV vector of claim 1 to the eye of a subject having an ocular disease or condition associated with oxidative stress or inflammation.

19. The method of claim 18 , wherein administration of the at least one cell results in improvement of responses to light stimuli, improved visual field, increased thickness of the outer nuclear layer (ONL) of the retina, longer photoreceptor cell outer segments, reversal of loss of photoreceptor cell integrity, increased survival of photoreceptor cells, and/or reduction of inflammatory symptoms in the eye of the subject.

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