Peptide compositions and methods of use

Inventors

BESIRLI, Cagri G. • Bridges, Alexander J. • FRESHLEY, John K. • Hunke, William A. • JOHNSON, Linda L. • Smith, Francis X. • SYLVAIN, Ethan • Zacks, David N.

Assignees

University of Michigan System • ONL Therapeutics Inc

Abstract

Provided herein are compositions including peptides, pharmaceutical preparations thereof, and methods of preventing photoreceptor death therewith and protecting of retinal cells, including, but not limited to, photoreceptors and retinal pigment epithelium, from Fas- or TRAIL-mediated apoptosis.

Core Innovation

The invention provides a peptide compound identified as Compound I, a C-terminally amidated Met-12-derived peptide, together with pharmaceutically acceptable salts, including triacetate and polyacetate salts. The compound is presented for use as an aqueous, ocularly deliverable formulation to address retinal cell damage and prevent apoptosis pathways implicated in retinal disease contexts.

The disclosure identifies prior Met-12 as associated with poor aqueous solubility, potency loss, and suboptimal intravitreal formulations, creating challenges for aqueous and ocular delivery. The therapeutic rationale is directed to extrinsic death-receptor pathways, including Fas- and/or TRAIL-mediated apoptosis, with downstream involvement such as FasL signaling and related apoptosis components. The intended protective effect is directed to retinal cells including photoreceptors, retinal pigment epithelium (RPE), and retinal ganglion cells.

The disclosed approach reports improved performance using Compound I in ocular delivery formulations, including pharmaceutically acceptable salt forms and ocular administration. It states improved potency versus Met-12 in 661W photoreceptor cells, enhanced in vivo efficacy in a rat retinal detachment model with reduced apoptosis based on TUNEL staining, and extended vitreous/retina exposure dependent on the formulation, including comparison between Poloxamer and Polysorbate/PG.

Claims Coverage

The claim set covers a compound of Formula I or a pharmaceutically acceptable salt, with dependent claims refining the compound form, pharmaceutical composition, ocular delivery configuration, target retinal cell types, and mechanistic protective indications. Across the claim family, the inventive features concentrate on specified acetate salt forms, an ocularly deliverable pharmaceutical composition, and use of the compound to prevent apoptosis or necroptosis involving Fas and/or TRAIL-related pathways in retinal cells.

Overall, the claims concentrate on a Formula I peptide compound in specified pharmaceutically acceptable acetate salt forms, combined into an ocularly deliverable pharmaceutical composition with a pharmaceutical carrier. The claims further specify ocular administration routes and tie the use to preventing apoptosis or necroptosis in retinal cell types, including retinal pigmented epithelium.

Stated Advantages

Documented Applications