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Pilot Grant Program

The Pilot Grant Program for Rare Disease Research is open to UMass Chan Medical School faculty who are members of The Li Weibo Institute for Rare Diseases Research. These one-year awards are intended to advance research into a rare disease and lead to follow-on extramural research funding. Funding announcements are typically sent out in December.

2021

Kevin Donahue, MD
Developing Gene Therapy Methods for Familial Atrial Fibrillation

Dr. Donahue is exploring gene therapy methods for familial atrial fibrillation (AF), a rare inherited condition that disrupts the heart’s normal rhythm. Familial AF increases the risk for having a stroke and severe heart failure, and can ultimately be fatal. The condition is typically caused by rare mutations in genes regulating the electrical impulses that control heartbeat rhythm and the muscle fibers that enable heart contractions, in the top chambers of the heart known as the atria.

Familial AF is difficult to treat — there is currently a lack of safe and effective treatment options. Dr. Donahue’s awarded pilot project would explore the first gene therapy–based strategy to treat familial AF. Dr. Donahue has had longstanding interests and successes in developing innovative gene therapy methods and novel animal models of heart disease. His pilot project aims to improve the way that genes are delivered and transferred to the atria, with the ultimate goal of using these improved gene transfer methods in the treatment of familial AF. To facilitate this goal, Dr. Donahue will be collaborating with Phillip Tai, PhD, who has considerable expertise in developing gene therapy vectors, which are essentially the vehicles needed to carry and deliver the therapeutic genes into cells of the atria. Drs. Donahue and Tai plan to increase both the specificity and the intensity of gene expression in the atria by manipulating critical parts of the vectors that they use for gene transfer. The potential resulting improvement in efficacy and safety of the gene transfer process could set the stage for future clinical trials with patients affected by familial AF. Ultimately, the gene transfer methods developed in this pilot project could be applied to the development of treatment strategies for not only other rare inherited heart diseases but also for the more common forms of AF.

Marian Walhout, PhD
Exploring the Molecular Mechanisms Underlying 2-Hydroxyglutarate Accumulation Disorders

Metabolism is essentially a collection of chemical reactions that convert dietary nutrients into building blocks for growth as well as energy for cellular activities. But when mutations occur in genes involved in metabolism, the body cannot properly break down nutrients and convert them into energy, leading to rare diseases known as inborn errors of human metabolism. Dr. Walhout has made great strides in developing and studying animal models of human inborn errors of metabolism, using the roundworm Caenorhabditis elegans as a model system. Her awarded pilot project will build on this previous body of work by focusing on a rare metabolic disease called 2-hydroxyglutaric aciduria, which is characterized by toxic accumulation of the metabolite D-2-hydroxyglutarate (2-HG) in body fluids. There are approximately 150 known cases of patients with D-2-hydroxyglutaric aciduria worldwide. It develops in early life and can cause a wide range of symptoms, including psychomotor and developmental retardation, hypotonia (weak muscle tone), encephalopathy (brain disease or damage), seizures, and early death. Although the cause of D-2-hydroxyglutaric aciduria is known (a mutation in the D2HGDH gene), there is currently no treatment. Interestingly, toxic buildup of 2-HG is also found in a rare and usually fatal brain cancer known as glioblastoma, which is most often caused by mutations in the IDH1 gene. In both of these diseases — 2-hydroxyglutaric aciduria and glioblastoma — the mechanisms by which toxic 2-HG accumulation leads to disease or contributes to cancer are poorly understood.

Dr. Walhout’s project aims to characterize the genetic and dietary mechanisms of 2-HG accumulation, toxicity, and its ability to cause disease. She will use C. elegans models that her lab has created for 2-hydroxyglutaric aciduria and for the cancer-associated mutation in IDH1. Working with two models instead of one presents a unique opportunity to compare and contrast the traits (phenotypes) related to 2-HG accumulation, ultimately leading to a better understanding of the underlying mechanisms of these rare diseases.

Past Awardees

2020

Katherine Fitgerald, PhD
Finding Therapies for Interferonopathies

Dr. Fitzgerald 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.

Miguel Sena Esteves, PhD
Finding Therapies for Nemaline Rod Myopathies

Dr. Sena Esteves 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 ses regardless of the number of patients in the United States or worldwide.