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Sravan PenchalaSravan Penchala is a Ph.D. student in the drug targeting and delivery track at University of the Pacific, Department of Pharmaceutics & Medicinal Chemistry. He is mentored by Assistant Professor Mamoun Alhamadsheh.

Diseases that affect a small percentage of the population (< 200,000) are known as “rare diseases.” Several federal laws (Rare Diseases Act of 2002 and Orphan Drug Act of 1983) are already in place to encourage drug discovery for such diseases. The National Institutes of Health has created a separate but focused discipline, Therapeutics for Rare and Neglected Diseases (TRND), which aims to encourage and speed up the development of new drugs for rare and neglected diseases. The interest in rare diseases and orphan drugs from big pharma stems from the fact that FDA has designated a special “fast track drug development” status for these diseases. This typically reduces the approval time frame to about 3–5 years in comparison to about 10–12 years for a regular drug.

Transthyretin amyloidoses are rare and fatal diseases that are caused by aggregation of the serum protein transthyretin (TTR). In the elderly, wild-type TTR can aggregate and form amyloid plaques in the heart tissue, leading to senile systemic amyloidosis. Mutations in the TTR gene (such as the Val122Ile) accelerate the aggregation of TTR, leading to familial amyloid cardiomyopathy (FAC). The Val122Ile mutation is present in about 4% of the African-American population, and it is estimated that the prevalence of FAC in this population is about 50,000 people.

Unfortunately, the only treatment option currently available for FAC is liver transplantation, which removes the source of the mutated TTR protein. Combined liver and heart transplantation is also performed as a palliative measure for a subset of patients with FAC. It has been shown that a number of small molecules can bind and stabilize TTR and prevent its aggregation. Recently, clinical trials of tafamidis (Pfizer’s Vyndaqel) indicated that it slows the progression of early stage TTR familial amyloid polyneuropathy (FAP), a disease that is similar to FAC but affects the peripheral nervous system. However, tafamidis was rejected by the FDA in 2012 because there was little data supporting its efficacy.

Our team at University of the Pacific discovered the small molecule drug AG10 that effectively stabilized mutant TTR when tested in serum samples obtained from patients with FAC.

Structure of TTR bound to AG10

Structure of TTR bound to AG10

This research could potentially lead to preventative treatment for heart failure and other forms of TTR diseases, including FAP. Another potential treatment for FAC is siRNA therapeutics. These potential treatments are in various stages of preclinical and clinical development. Despite the progress made so far, more research focused on rare diseases is needed in order to find therapeutics for the millions of people affected by these diseases.

Have you or your colleagues done any research on rare diseases?