Treating AT Deficiency with Drugs that Modulate the Proteostasis Network

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Project Summary The classical form of α1antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease. Liver transplantation represents the only treatment currently available. The liver disease associated with ATD is characterized by a stereotypical chronic fibrosis leading to cirrhosis and hepatocyte hyper-proliferation that predisposes to hepatocellular carcinoma. This pathology is attributed to the gain-of-function, proteotoxic effect of mutant AT Z that accumulates in the endoplasmic reticulum (ER) of liver cells. My lab has elucidated the potential mechanisms by which liver cells cope with the proteotoxic effects of ATZ accumulation in the ER including a distinct set of intracellular degradation pathways (proteasomal and autophagic) and a distinct set of signaling pathways that are specifically activated (autophagy, NFκB, ER- and mitochondrial-caspases but not the unfolded protein response). Our working hypothesis is that pharmacological strategies which capitalize on these naturally occurring, presumably protective proteostasis regulatory mechanisms will have a therapeutic effect on the liver disease caused by ATD. Recently, we validated this hypothesis by showing that an autophagy enhancer drug, carbamazepine (CBZ), promotes degradation of ATZ, reduces the hepatic ATZ load and hepatic fibrosis in vivo in a mouse model. In the work proposed here we will pursue this hypothesis further by investigating other drug candidates with putative actions specifically on the autophagy system, including FDA-approved drugs, cyclodextrins and mucolipin agonists. The project will also capitalize on a C. elegans ATD model-based high content screening platform (Proj 2) together with computational pharmacological analyses (core B) to discover additional therapeutic candidates. Finally, we will investigate several sequence variants that are candidate genetic modifiers arising from whole exome sequencing of a unique family and cohort populations. These variants will be tested for validity in model systems (Proj 3, Cores A and C), hopefully to move into diagnostic platforms and as novel targets for drug development that would enable state- of-the art personalized medicine approaches.