Identification of Pharmacological Chaperones for the Treatment of Hereditary Protein Conformational Disorders

A number of genetic disorders are caused by inheritance of mutations that alter the conformation of proteins translated from a mutated gene. These disorders are collectively known as protein conformational disorders (PCDs). PCDs range from congenital conditions such as alpha-1 antitrypsin (AAT) deficiency and the early-onset juvenile form of primary open angle glaucoma (POAG), to neurodegenerative diseases such as Huntington's disease. One common pathological hallmark among PCDs is the accumulation of aggregated proteins caused by mutation-induced changes in protein conformation. In many cases, these aggregated proteins are toxic to the host cells due to mechanisms such as overloading of protein degradation machinery and the subsequent apoptotic response. In addition, the sequestration of proteins into aggregates inevitably depletes the supply of functional protein, causing a loss-of-function phenotype. Using the myocilin related POAG and AAT deficiency as disease models, our laboratory is endeavoring to identify and explore the potential use of pharmacological chaperones to correct abnormal protein folding in an effort to prevent protein aggregate formation, alleviate cytoxicity and restore normal protein function. To detect specific protein-chemical binding and to perform high-throughput screening of chemical libraries, we have applied the Corning Epic system which is a new, unique platform designed to sensitively measure surface plasmon resonance changes during micro-binding events. From one of our FDA approved drug libraries, we have identified potential leads that interact with recombinant myocilin and, more importantly, reduce aggregation and increase secretion of disease-related myocilin mutants in cultured cell models. Currently, we are validating these lead compounds in an in vivo model of POAG caused by mutant myocilin. The identification of pharmacological chaperones for myocilin not only will increase our understanding on the disease mechanism, but also potentially reveal a new class of therapeutics for myocilin-related POAG and other PCDs.