UMass Pilot Grant Program for Rare Disease Research Awards Funds to Two UMMS Researchers

Two research scientists from UMass Chan Medical School have been awarded funds for research on much-needed therapies for certain rare diseases that have a devastating impact on patients and for which there are currently no effective treatments. The awards were made through the Pilot Grant Program for Rare Disease Research, which was initiated by the Co-Directors of the Li Weibo Institute for Rare Diseases Research — Michael Green, MD, PhD, and Guangping Gao, PhD. These awards are intended to advance research into a rare disease and lead to follow-on extramural research funding. Each award provides a one-year pilot grant of $70,000.

Finding therapies for interferonopathies

One of the selected awardees, Katherine Fitzgerald, PhD, professor of medicine, is exploring a potential therapy for a rare autoinflammatory disease called SAVI (STING-associated vasculopathy with onset in infancy), which is part of a group of diseases collectively referred to as interferonopathies. Interferonopathies are associated with abnormally high production of type I interferons (IFNs), a class of proteins that help regulate the immune system’s response to infections. Previous work from Dr. Fitzgerald’s lab had established some of the basic principles of type I IFN gene regulation in response to viruses’ nucleic acids (i.e., DNA and RNA). This work paved the way for greater understanding of the immune system’s earliest responses to viruses. 

Mutations in certain genes can cause SAVI, particularly mutations that activate molecular pathways that sense nucleic acids. In order to further understand the disease process in SAVI, Dr. Fitzgerald’s lab has created mouse models bearing individual gene mutations characteristic of the disease. Her lab is defining how these mutations lead to tissue damage and disease, using a combination of molecular, genetic, and biochemical approaches. Importantly, Dr. Fitzgerald’s lab identified a new small-molecule inhibitor of STING (a naturally occurring protein that acts as a stimulator of IFN genes). The awarded pilot project will study this small-molecule inhibitor in mice in order to understand the feasibility of blocking STING signaling as a potential treatment for SAVI. This research will help to determine whether blocking STING activity is beneficial therapeutically in preventing tissue damage and disease. Dr. Fitzgerald’s long-term goal is to translate these findings to humans by studying the effect of STING inhibition in samples from human patients.

Finding therapies for nemaline rod myopathies

Also selected as an awardee is Miguel Sena Esteves, PhD, associate professor of neurology, who is investigating a potential therapy for nemaline rod myopathy (NRM), a neuromuscular disease. Although NRM is rare, it is the most common of the muscle diseases (known as myopathies) that are present at birth, with an incidence of 1 in 50,000 births. Mutations in ten different genes have been associated with different forms of NRM. The awarded project from Dr. Esteves’ lab focuses on NRM caused by mutations in one gene in particular, the TNNT1 gene. This gene expresses a protein called troponin T, which is critical for the ability of muscles to contract. Troponin T is expressed in a subset of muscle cells that are especially abundant in energy-efficient muscles used to control posture and breathing. (For example, the leg muscles of long-distance runners have a higher percentage of these particular muscle cells than non-athletes.) In the case of NRM, mutations in the TNNT1 gene eliminate expression of troponin T in muscle cells, impairing the ability of muscles to contract. Children affected with TNNT1-associated NRM lose most acquired motor skills by 12 months of age, and the disease is fatal in the majority of patients (76%) before 2 years of age, due to eventual suffocation. And because children with this disease are cognitively normal, they are likely to have some understanding of their impending fatality.

The goal of Dr. Esteves’ awarded project is to develop a treatment to restore expression of TNNT1 in the subset of muscle cells that require it to function normally. His lab aims to accomplish this by identifying a gene delivery vector, known as a recombinant adeno-associated virus (AAV) vector, that is capable of restoring TNNT1. They will then determine whether injection of the vector into the bloodstream is efficacious and safe in an animal model of TNNT1 deficiency. These studies will be the foundation for translation into a clinical trial with human patients who have TNNT1-associated NRM. Dr. Esteves believes that developing a therapy for NRM that is associated specifically with TNNT1 paves the way for development of gene therapies for NRMs that are associated with other genes and builds on his lab’s continued commitment to develop gene therapies for rare diseases regardless of the number of patients in the United States or worldwide.