Protective effect of RIPK1-inhibitory compound in in vivo models for retinal degenerative disease

Area of Science:

• Ophthalmology
• Molecular Biology
• Pharmacology

Background:

• Receptor interacting protein kinase 1 (RIPK1) is implicated in necroptosis, a cell death pathway involved in ocular diseases like glaucoma and dry age-related macular degeneration (AMD).
• A distinct RIPK1-inhibitory compound (RIC) was previously developed, showing protective effects on retinal ganglion cells against glaucomatous injury.

Purpose of the Study:

• To evaluate the protective effect of RIC on retinal pigment epithelium (RPE) against sodium iodate (SI)-induced insult, a model relevant to dry AMD pathogenesis.
• To assess the efficacy and safety of topical RIC administration for treating dry AMD.

Main Methods:

• RIC was administered as eye drops to induce topical retinal delivery.
• SI-induced retinal degeneration models in rabbits and iodoacetic acid-induced models in mini-pigs were used to assess RPE protection.
• Funduscopy, electroretinogram analyses, and retinal toxicity assessments in rats were performed.

Main Results:

• Topical administration of RIC prevented RPE loss in SI-induced retinal degeneration.
• RIC demonstrated consistent retinal protection in both rabbit and mini-pig models.
• RIC's in vivo efficacy surpassed that of ACU-4429 and doxycycline, with no observed retinal toxicity in rats.

Conclusions:

• RIC exhibits excellent retinal penetration and potent protective effects against RPE degeneration.
• RIC represents a promising therapeutic candidate for dry AMD, offering superior efficacy and safety profiles.