Our Science

Background

Age-related macular degeneration (AMD) and Stargardt’s macular degeneration (SMD) are thought to arise from the gradual loss of retinal pigmented epithelial (RPE) cells of the macula, the area of the eye responsible for central vision. The accumulation of toxic vitamin A aggregates, including the bis-retinoid A2E, have been implicated in these diseases.

Recent research suggests that A2E is capable of binding native lysosomal enzymes, inhibiting their function. As A2E accumulation reaches a critical threshold, lysosomal impairment leads to the accumulation of intracellular lipofuscin, extracellular drusen deposition, and eventually RPE cell death.

LYSOCLEAR is a recombinant enzyme product under development by Ichor Therapeutics that is able to selectively localize to the lysosomes of RPE cells where A2E accumulates, and destroy it.

Mechanism of Action

Lysosomal storage diseases (LSDs) are a class of rare congenital illnesses that result from defects in endogenous lysosomal enzymes. Many LSDs are effectively treated in the clinic with recombinant forms of the defective enzyme. When “decorated” with mannose sugars, the recombinant enzyme is efficiently shuttled to the lysosomes of target cells, restoring function.

LYSOCLEAR operates identically to existing LSD therapies. However, instead of replacing a defective enzyme, a new enzyme is introduced that upgrades RPE cells with the ability to degrade A2E and other lipofuscin components.

The pH of the eye (~7) differs significantly from that of RPE lysosomes (~5). LYSOCLEAR has been designed to only be active at the lysosomal pH where it needs to function, avoiding off-target effects.

Research Status

LYSOCLEAR has been extensively studied in buffer systems, cell culture models, and in vivo. Preliminary findings have shown that LYSOCLEAR is safe and effective at destroying A2E, removing up to 10% with each dose. Dose escalation studies, PK/PD, and toxicology studies are ongoing.