Genetic and clinical variability of the Stargardt disease gene ABCA4, and the implications for treatment

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A huge thank you to our Professor Rando Allikmets who recently joined our Zoom session to talk to us about genetic and clinical variability of the Stargardt disease gene ABCA4, and the implications for treatment.

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Both of these approaches try to reduce the accumulation of lipofuscin (and its major component, A2E, which is an aggregate of two vitamin A molecules), in two different ways. Both approaches are scientifically sound, the question is if these would work and how efficient would they be.

ALK001 tries to replace all vitamin A in a patient with a modified form of vitamin A, which forms A2E ~5X less efficiently. The approach suggests a patient to take an oral pill of the modified vitamin A daily. The approach worked well in mice (especially if started very early), but it would be much harder to have an effect in humans due to starting much later in life and the disease process and much more complicated dietary control.

Emixustat is a compound which slows down the most important protein in the visual cycle, RPE65, so the visual cycle will work slower and the amount of accumulated lipofuscin will be lower. Again, it will have some effect, but here the main issue is the proper dosing. If the dose is too high, the drug will cause, not prevent, vision loss. As a reminder, mutations in RPE65 cause early onset retinitis pigmentosa, a much more severe disease than Stargardt. So again, the approach is scientifically sound (I tried myself similar approach at Columbia about 15 years ago) but it has to be applied with great caution. I assume this has been addressed since the drug is already in Phase III clinical trial.

So, both of these approaches are valid, but the effect on the disease has to be seen. Both of these are also “indefinite” approaches, one has to take the drug for the rest of their lives, as opposed to gene therapy (if that would be available), which is usually a one-time treatment. As a reminder, there is approved gene therapy available for the aforementioned RPE65 gene and it seems to be working.