Modified vitamin A slows lipofuscin formation: a step towards a clinical trial to prevent vision loss in Stargardt disease

Ilyas Washington, PhD
Columbia University Medical Center (CUMC) (New York, NY)
Year Awarded:
2010
Grant Duration:
April 1, 2010 to March 31, 2013
Disease:
Macular Degeneration
Award Amount:
$100,000
Grant Reference ID:
M2010096
Award Type:
Standard
Award Region:
US Northeastern
Recipient of the Ernest R. Kuykendall award for AMD research

Deuterium enrichment of vitamin A slows lipofuscin formation

Summary

The big picture: to determine the extent to which lipofuscin, a naturally occurring pigment soluble in fat and found in aging tissues, contributes to vision loss. The objectives for our proposed research are to gather data in order to be able to proceed with a clinical trial designed to evaluate the extent to which C20-D3-vitamin A can impede the formation of ocular lipofuscin as well as to aid in the development of diagnostic methods to evaluate treatment compliance during future clinical trials.

Details

This research investigates a method to slow the formation of ocular lipofuscin, a naturally occurring pigment soluble in fat and found in aging tissues. The development of lipofuscin correlates with the progression of various macular dystrophies and degenerations. As such, methods to halt or reverse the formation of ocular lipofuscin are highly sought after as means to better understand the link between lipofuscin and macular degenerations or dystrophies and as clinical interventions for their treatment. The objectives for our proposed research are to gather data in order to be able to proceed with a clinical trial designed to evaluate the extent to which C20-D3-vitamin A can impede the formation of ocular lipofuscin as well as to aid in the development of diagnostic methods to evaluate treatment compliance during the trial. This trial will help to determine the extent to which lipofuscin contributes to vision loss. The most innovative aspect of this research is that it involves a method to slow down the formation of ocular lipofuscin without interrupting the visual cycle or normal vitamin A metabolism, which can result in poor night vision. At the completion of our study, we anticipate that we will be able to: 1) determine whether treatment with C20-D3-vitamin A would be practical in humans; 2) evaluate the ability of C20-D3-vitamin A to slow lipofuscin formation in another animal model; 3) determine the time it would take for the vitamin to start working in order to better estimate proper dosing in future clinical studies; 4) evaluate whether urine analysis can be used as a potential method to measure treatment compliance in future clinical studies; and 5) elucidate how vitamin A is dynamically used in the body to promote vision and health.

Research Updates

Preliminary results from this research helped attract further support for the development of a drug, called ALK-001, for the prevention of vision loss due to certain types of macular degeneration. ALK-001 is designed to slow the formation of toxic vitamin A aggregates and deposits, called lipofuscin, in the retina. Dr. Washington’s team showed that ALK-001 could reach the retina at levels sufficient to bring about a therapeutic effect. Before obtaining this research grant, existing data could predict how quickly ALK-001 would reach the retina in humans. In general, poor drug pharmacokinetics and delivery to the tissue of interest is responsible for disqualify drug candidates in about 80% of cases, despite promising animal results. As such, the team’s demonstration that ALK-001 rapidly reaches the retina in an appropriate swine (pig) model is a major step in ALK-001's development. This research has helped provide data critical in the clinical development of ALK-001, taken over by the biotechnology company, Alkeus Pharmaceuticals. Dr. Washington is the Scientific Founder of Alkeus Pharmaceuticals.