Small Molecules that Protect Against Lipofuscin Toxicity to Prevent Blindness

Background & Unmet Need

• Lipofuscin is a variable mixture of proteins and lipids that accumulates in lysosomes of many cell types, with age or due to genetic mutations
• Lipofuscin is a universal marker of aging but is also a risk factor in pathologic processes, including the most common forms of macular degeneration
• Ocular lipofuscin accumulates in the retinal pigment epithelium (RPE), where it interferes with the support of the neuroretina
• Retinal lipofuscin is directly linked to RPE cell death in Stargardt disease, but the role in age-related macular degeneration (AMD) is unclear
• Ongoing clinical trials to treat lipofuscin-associated pathologies target the formation of lipofuscin, and therefore do not treat established deposits
• Unmet Need: Improved understanding of lipofuscin toxicity is necessary to inform the development of novel therapeutic strategies to prevent blindness

Technology Overview

• The Technology: Identification of compounds that protect the retina against lipofuscin toxicity
• The Discovery: Lipofuscin promotes retinal degeneration via a light-independent atypical necroptotic cascade
• Lipofuscin was shown to form aggregates in lysosomes, triggering lysosomal membrane permeabilization (LMP) and subsequent atypical necroptosis
• Necrosulfonamide, necrostatin-7, and arimoclomol were all shown to effectively block lipofuscin toxicity, by targeting different steps in the necroptotic cascade
• PoC Data: The identified compounds successfully protected against cell death induced by A2E accumulation and LMP induced by the lysosomotropic peptide LLOMe

Technology Applications

• Treatment of genetic and age-related causes of blindness (e.g., Stargardt disease, Age-related macular degeneration (AMD))

Technology Advantages

• Protects against further damage to the retina by lipofuscin
• Applicable to multiple causes of blindness
• Arimoclomol is already in clinical trials for separate indications, which may enable an accelerated development pathway for ophthalmic diseases