In 2017, Ichor Life Sciences, then known as Ichor Therapeutics, announced the launch of LYSOCLEAR, a therapeutic approach that proposes to prevent, arrest, or reverse age-related macular degeneration (ARMD), the leading cause of blindness in persons over the age of 65, and the mechanistically related genetic disease Stargardt macular degeneration, by degrading the key intracellular waste product A2E.
Key to the development of ARMD is metabolic toxicity in retinal pigmented epithelial (RPE) cells, which are macrophage-like waste-clearing cells that “eat” the damaged membranes of photoreceptors. The photoreceptors’ light-sensing function, however, depends on a chemical flip-flop between two forms of vitamin A — a flip-flop whose more reactive side can generate a range of aggregated molecules including A2E. As RPE engulf and digest dying photoreceptor debris, they eventually become poisoned by A2E and its cousins, and they become dysfunctional, die, and decompose. The end result is ARMD.
LYSOCLEAR is both the spinout company and the engineered enzyme candidate originally identified at SENS Research Foundation, one of the two founding organizations of Lifespan Research Institute. The starting enzyme behind LYSOCLEAR was a peroxidase that was effective in destroying A2E in vitro. Kelsey Moody and his colleagues at Ichor Life Sciences selected the best of these (the common enzyme manganese peroxidase, or MnP) and engineered it to allow it to pass harmlessly through the circulation, penetrate cells, and reach the lysosome, where it could degrade A2E.
When tested in RPE cells that were pre-loaded with A2E, the engineered enzyme broke down A2E and several related compounds with limited toxic effects. Ichor scientists then tested it in mice with a genetic form of macular degeneration. Six weekly doses of LYSOCLEAR eliminated nearly a third of the A2E and rekated wastes in the mice’s eyes.
Investigational New Drug application and Phase 1 clinical trials were slated for 2018, and they aim to test this new therapy in humans to identify the optimal dosages and regimen of application. Unfortunately, Ichor tried manufacturing LYSOCLEAR at the quality standards required for human drug testing, they found that the branching of the sugars that allow the enzyme to enter cells and be directed to the lysosome was too inconsistent for use as a human therapy. Even when Ichor tried an entirely new biomanufacturing technique to produce the enzyme, they still could not get the branching pattern consistent.
So despite its promise, these “Chemistry, Manufacturing, and Controls” (CMC) problems spelled the end for the original LYSOCLEAR enzyme. Ichor has moved on to looking at alternative enzymes that might do the essential task (safely breaking down A2E) but be free of this limitation.
Importantly, current therapies for ARMD are only effective against the relatively rare “wet” form of the disease. 80-90% of the people suffering from ARMD are afflicted with the “dry” form. Clearing A2E from aging RPE would potentially prevent and arrest both forms.
