Drug Screening for Potential Adrenoleukodystrophy Treatments Using a Zebrafish Disease Model

Adrenoleukodystrophy (ALD) is a disease characterized by degradation of myelin in the central nervous system (CNS), and there are virtually no treatments. We have created a disease model for ALD in the small vertebrate organism zebrafish (Danio rerio). The mutant ALD zebrafish develop disease characteristics similar to human ALD patients. This includes motor dysfunction, very long chain fatty acid (VLCFA) accumulation, as well as CNS apoptosis and demyelination. Our goal is to identify possible treatments that slow or prevent disease progression in the ALD mutant zebrafish. We tested a library of 2560 FDA-approved drugs (Microsource Spectrum Collection). Drugs were administered to fish as mixtures of four compounds and behavior was measured to assess motor function recovery. Promising compounds were then tested in a secondary behavior screen, consisting of testing individual compounds at a lower concentration. We identified four promising compounds for further testing. For each compound, we will measure VLCFA levels by administering drugs then testing whole fish extracts using tandem mass spectrometry. We will conduct TUNEL staining for apoptosis and Olig2:dsRed staining to count the number of oligodendrocyte precursor cells, which are indicative of myelin levels. Our intention is to take the most promising compound forward towards clinical trials.