Compositions and methods for treating and preventing macular degeneration
Inventors
Wadsworth, Samuel • Scaria, Abraham • Chan, Chi-Chao
Assignees
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Publication Number
US-12344842-B2
Publication Date
2025-07-01
Expiration Date
2034-04-17
Abstract
Compositions and methods for treating macular degeneration are disclosed. The methods utilize IL17 inhibitors, such as IL17 receptors, as well as fusion proteins including an IL17 receptor fused with a multimerization domain, and recombinant viral vectors encoding such fusions.
Core Innovation
The invention relates to compositions and methods for treating and preventing macular degeneration, specifically age-related macular degeneration (AMD), by using IL17 inhibitors such as IL17 receptors. The invention includes fusion proteins comprising an IL17 receptor fused with a multimerization domain, and recombinant viral vectors encoding such fusions providing a novel therapeutic approach to AMD.
The problem addressed is that AMD is the primary cause of irreversible blindness in the elderly, with pathogenesis involving aging, environmental, and genetic factors, but the molecular mechanisms responsible remain largely unknown. Existing observations link elevated IL17A cytokine levels with chronic inflammation and retinal degeneration, yet no treatment targeting this pathway was known.
The invention is based on the discovery that IL17A, a pro-inflammatory cytokine, plays a critical role in focal retinal degeneration. It was found that IL17A and IL17RC transcripts and protein are significantly elevated in AMD patient maculae compared to controls. Treatment with recombinant IL17A reduces viability of retinal pigment epithelial cells and induces apoptosis. Using a mouse model of focal retinal degeneration, it was shown that reducing or inhibiting IL17 activity significantly ameliorated photoreceptor and RPE degeneration by inhibiting MAPK-dependent signaling pathways. Thus, the invention provides methods for treating macular degeneration using compositions containing recombinant vectors encoding IL17 inhibitors, including recombinant adeno-associated virus vectors comprising nucleic acids encoding IL17 receptor fusion proteins.
Claims Coverage
The patent includes one independent claim focused on a method of reducing lipofuscin or glycogen deposits in a diseased eye of a mammalian subject using a specific recombinant vector and composition.
Method of reducing lipofuscin or glycogen deposits in a diseased eye
Intravitreal administration of a composition containing a recombinant adeno-associated virus serotype 2 (rAAV2) virion encoding a fusion protein comprising a soluble IL17A receptor capable of binding and modulating IL17A activity, fused with a multimerization domain, to reduce lipofuscin or glycogen deposits in the diseased eye.
Use of recombinant vector encoding an IL17A receptor fusion protein
The recombinant vector encodes a fusion protein comprising (a) an IL17A receptor and (b) an immunoglobulin constant region multimerization domain, where the fusion protein forms a multimer when expressed.
Multimerization domain derived from immunoglobulin Fc region
The multimerization domain is derived from the Fc region of an immunoglobulin, including specifically the CH3 domain, from IgG1, IgG2, IgG3, or IgG4, and more specifically from the constant region of an IgG1 heavy chain.
Production of multimeric fusion protein
When expressed, the fusion protein forms a multimer, such as a homodimer, which is an active form for modulating IL17A activity.
Formulation comprising an ophthalmologically acceptable vehicle
The administered composition further comprises an ophthalmologically acceptable vehicle suitable for intravitreal delivery to the diseased eye.
The claims cover a method of treating ocular deposits associated with macular degeneration by intravitreal administration of compositions containing recombinant rAAV2 vectors encoding fusion proteins of soluble IL17A receptors and multimerization domains derived from immunoglobulin Fc regions, forming multimeric proteins that inhibit IL17A activity.
Stated Advantages
IL17 inhibitors significantly ameliorate photoreceptor and retinal pigment epithelium (RPE) degeneration, reducing retinal degeneration associated with macular degeneration.
Neutralization of IL17 prevents MAPK-dependent phosphorylation events, indicating inhibition of a key disease pathway.
Treatment leads to reduction of lipofuscin, glycogen deposits, and mitochondrial damage in diseased eyes, improving cellular health in the retina.
Documented Applications
Methods for treating and preventing age-related macular degeneration using IL17 inhibitors, including recombinant viral vectors encoding IL17 receptor fusion proteins.
Treatment or reduction of retinal degeneration, RPE degeneration, RPE stress, RPE damage, photoreceptor degeneration, lipofuscin or glycogen deposits, A2E accumulation, and mitochondrial damage in diseased mammalian eyes.
Intravitreal administration of compositions comprising recombinant adeno-associated virus vectors expressing soluble IL17A receptor fusion proteins as a therapeutic approach for AMD, particularly dry AMD.
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