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-10640771-B2
Publication Date
2020-05-05
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 utilizing inhibitors of interleukin-17 (IL17), including IL17 receptors and fusion proteins comprising an IL17 receptor fused with a multimerization domain, and recombinant viral vectors encoding such fusions.
The problem being addressed is that AMD is the primary cause of central irreversible blindness in the elderly, involving degeneration of macular cells and atrophy of photoreceptors due to retinal pigment epithelial (RPE) degeneration. While genetic and environmental risk factors are known, including involvement of the complement system and IL17A cytokine, the precise molecular mechanism responsible for disease onset is largely unknown and no effective treatment targeting these pathways has been established.
The core innovation is the discovery that IL17 inhibitors can be used to treat macular degeneration by modulating the IL17 signaling pathway which is elevated in AMD patients' maculae. The methods involve administering compositions comprising recombinant vectors encoding IL17 inhibitors, such as soluble IL17A receptors or fusion proteins thereof, directly to the diseased eye, effectively reducing photoreceptor and RPE degeneration, lipofuscin and glycogen deposits, mitochondrial damage, and other pathological features related to AMD. The invention also includes recombinant adeno-associated virus (rAAV) vectors, particularly of serotype 2, for delivering these IL17 inhibitors intravitreally.
Claims Coverage
There is one independent claim described, focusing on a method for treating age-related macular degeneration using a specific recombinant viral vector approach. Two main inventive features are extracted from the claims.
Method of treating AMD using a recombinant viral vector encoding a fusion protein comprising a soluble IL17A receptor and a multimerization domain
The method comprises intravitreal administration of a composition containing a recombinant adeno-associated virus serotype 2 (rAAV2) virion encoding a fusion protein. The fusion protein includes an IL17 inhibitor which is a soluble IL17A receptor capable of binding and modulating IL17A activity, fused with a multimerization domain derived from an immunoglobulin component.
Multimerization domain specifics and fusion protein characteristics
The multimerization domain is derived from an immunoglobulin heavy chain constant region, specifically from the Fc region or the CH3 domain of IgG subclasses (IgG1, IgG2, IgG3, or IgG4). Upon expression, the fusion protein forms multimers, with embodiments including homodimers. The fusion protein may comprise the amino acid sequence of FIG. 3B (SEQ ID NO:4) or active variants thereof with at least 90% sequence identity. The rAAV vector includes AAV2 serotype capsid and AAV2 inverted terminal repeats (ITRs).
The claims cover a gene therapy method of treating age-related macular degeneration involving intravitreal delivery of an rAAV2 vector encoding a soluble IL17A receptor fused with an immunoglobulin-derived multimerization domain, producing multimeric fusion proteins to modulate IL17A activity and ameliorate AMD pathology.
Stated Advantages
IL17A signal blockade effectively arrests photoreceptor and retinal pigment epithelium (RPE) degeneration via a MAPK-dependent pathway in a mouse model of retinal degeneration.
Use of IL17 inhibitors provides a useful technique for treating and preventing macular degeneration, reducing several pathological features including photoreceptor and RPE degeneration, focal retinal degeneration, and accumulation of lipofuscin and glycogen deposits.
Recombinant viral vector-mediated delivery, specifically rAAV vectors, allows for effective local administration to the eye, limiting systemic side effects and enabling sustained therapeutic effects.
Documented Applications
Treating macular degeneration, particularly age-related macular degeneration (AMD), including dry AMD.
Reducing retinal degeneration, including focal retinal degeneration.
Reducing retinal pigment epithelium (RPE) degeneration, stress, or damage.
Reducing photoreceptor degeneration, including degeneration in inner segments (IS), outer segments (OS), or both.
Reducing lipofuscin or glycogen deposits in the diseased eye.
Reducing concentration of A2E (a lipofuscin fluorophore) in the diseased eye.
Reducing mitochondrial damage in the diseased eye.
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