Methods and compositions for preventing or treating ophthalmic conditions

Inventors

Liu, Liping • Tang, Shibo • Liang, Xiaoling

Assignees

Stealth Biotherapeutics Inc

Abstract

The disclosure generally describes methods of preventing or treating ophthalmic diseases or conditions in a mammalian subject, such as diabetic retinopathy, cataracts, retinitis pigmentosa, glaucoma, macular degeneration, choroidal neovascularization, retinal degeneration, and oxygen-induced retinopathy. The methods comprise administering an effective amount of an aromatic-cationic peptide to subjects in need thereof.

Core Innovation

The disclosure describes aromatic-cationic peptide therapeutics for prevention and treatment of ophthalmic disease in a mammalian subject. The therapeutics are based on a peptide represented by D-Arg-2′,6′-Dmt-Lys-Phe-NH2, including pharmaceutically acceptable salts, and associated peptides such as Phe-D-Arg-Phe-Lys-NH2. The ophthalmic disease context includes oxidative stress and mitochondrial dysfunction in conditions such as diabetic retinopathy, cataract, glaucoma, and macular degeneration, including choroidal neovascularization and retinal degeneration.

The problem addressed is ophthalmic damage linked to oxidative stress, reactive oxygen species, and impaired mitochondrial function, including mitochondrial membrane potential disruption and downstream apoptotic markers. The disclosure frames these dysfunctions as contributing to disease manifestations in ocular tissues, including effects on retinal cells, lens opacity, microvasculature and blood-retinal barrier integrity, and cell survival in glaucomatous conditions. The described therapeutic approach aims to improve cell survival and reduce oxidative stress-associated apoptosis pathways.

The disclosure further specifies peptide structural features and formulation-relevant characteristics, including an aromatic-cationic design with a net positive charge and relationships among aromatic groups and amino acid residues, with optional non-natural and D-amino acids. It also specifies C-terminal amidation and provides formula definitions with substituent meanings for peptide variants within the aromatic-cationic framework. The disclosure reports ophthalmic use in mammalian subjects, including administration and dosing as a therapeutically effective amount, and describes optional co-administration of an additional active agent.

Preclinical examples in retinal disease models are used to support the described therapeutic concept. The disclosure reports improved cell survival and reduced reactive oxygen species and apoptosis in high-glucose retinal cell models, reduced lens opacity and improved blood-retinal barrier and microvasculature in diabetic rat models, and protection of glaucomatous trabecular meshwork cells from oxidative stress with preserved mitochondrial membrane potential and reduced apoptosis. It also reports mouse model efficacy in choroidal neovascularization, oxygen-induced retinopathy, and retinal degeneration contexts, including protection of retinal layer and cone density outcomes.

Claims Coverage

The independent claim covers a method treating an ophthalmic condition (age-related macular degeneration, ARMD) in a mammalian subject by administering a therapeutically effective amount of a specific peptide represented by D-Arg-2′,6′-Dmt-Lys-Phe-NH2 or a pharmaceutically acceptable salt. Dependent claims further refine the ARMD subtype and expand coverage to additional administration routes and optional co-administration of a second active agent.

Overall, the claim set is centered on treating ARMD by administering a therapeutically effective amount of D-Arg-2′,6′-Dmt-Lys-Phe-NH2 (or a pharmaceutically acceptable salt), with coverage extended to dry and wet ARMD, multiple administration routes, and optional co-administration of a second active agent selected by specified categories or from an enumerated list of named compounds (including salts and combinations).

Stated Advantages

Documented Applications