Preclinical testing of a candidate Angelman syndrome therapeutic
$200,000 – 2-years
This grant represents a continuation of funding for this investigator’s laboratory which was instrumental in identifying that a class of topoisomerase inhibitors can unsilence the paternal UBE3A gene. The investigator now plans to extend this work by additional experiments on topoisomerase inhibitors in the animal mouse model to determine how persistent the silencing effect is. They will also determine drug administration parameters by evaluating intracerebral, intrathecal and IV administration of topoisomerase inhibitor agents. They will also study tissue distribution, drug toxicity and pharmacokinetic data in the mouse model. Finally, the rescue effects of the inhibitor medications will be studied by brain slice physiology, in vivo neuro-plasticity studies and by studies of the behavioral recovery/rescue using customary behavioral tests. These additional studies are hoped to lay the groundwork for development of an Angelman syndrome therapeutic agent that may be available for subsequent human trials, provided issues of toxicity and efficacy are established in the mouse model.
This study was published in Nature and PNAS. See an overview and FAQs.