Identification and validation of targets for therapeutic intervention in rare diseases of intermediary metabolism

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Fast-Track SBIR: Identification and validation of targets for therapeutic intervention in rare diseases of intermediary metabolism defects. ABSTRACT There are very few reliable methods to study and understand the biology of liver rare diseases in the laboratory for the purpose of drug discovery and development, which contributes to a dismal record for development of new treatments. First, genetic mouse models do not faithfully mimic human rare diseases. Second, modeling liver diseases in vitro is challenging on account of the rapid loss of the liver-like phenotype of primary hepatocytes in vitro. For these reasons, target ID, validation and prioritization can be misleading and costly. In 2014, HemoShear, LLC and Children's National Health System formed a strategic partnership to systematize and accelerate discovery and treatments for rare diseases of the liver. HemoShear is an early stage biotechnology company with a patented technology for recreating human liver disease biology in the laboratory using human primary cells. The Division of Genetics and Metabolism at Children's is a premier research center with the nation's largest clinical program that studies and treats patients with liver rare diseases. Under this partnership, we have already shown that biomaterial from patients treated at Children's can be used to validate the rare disease system developed at HemoShear for the identification of targets for therapeutic development [Chapman et al, Mol. Gen. Metab., 2015]. This study will focus on the biochemical group of diseases called organic acidemias, specifically propionic acidemia and methylmalonic acidemia. These rare diseases have high early and late mortality rates, there are no primary therapies for these conditions and patients often undergo liver transplant to control symptoms. The purpose of this FastTrack SBIR is to identify, validate and prioritize targets for the future development of therapies to treat patients with intermediary metabolism defects in the liver.