Coalition to Cure Calpain 3 (C3) is driving LGMD2A/R1 research by awarding a new grant to Dr. Elisabeth Barton, Dr. Lan Wei-LaPierre, and Dr. Siobhan Malany of the University of Florida. The project is titled “Store-operated calcium entry modulation as a potential therapeutic for LGMD2A/R1.” This research is co-funded with the Muscular Dystrophy Association (MDA).
Setting the stage
LGMD2A/R1 is caused by defects in Calpain 3, a protein that has multiple roles in maintaining muscle health. In 2022, C3 awarded Dr. Barton and colleagues a research grant to investigate how Calpain 3 contributes to store-operated calcium entry (SOCE), a process that brings calcium into muscle cells when they need it for generated force, such as during prolonged activity. The group found that in a mouse model of LGMD2A/R1, SOCE is abnormally high at rest and does not appropriately respond to exercise.
The next phase
The new grant award allows the University of Florida group to continue their research into SOCE activity in LGMD2A/R1. They will now test SOCE normalization as a potential therapeutic target by evaluating chemical inhibitors that reduce SOCE activity. They will test these inhibitors in mouse models of LGMD2A/R1 as well as muscle cells isolated from individuals living with LGMD2A/R1 to determine if this will improve muscle function at rest and during exercise. If successful, this could lead to the development of new treatments.
“Dr. Barton and colleagues recently showed that SOCE is abnormal in muscles from a Calpain 3-null mouse model. C3 is excited to support the current grant, which will determine if SOCE modulation could be a therapeutic approach for LGMD2A/R1. This collaboration with MDA will enable us to accelerate progress and bring hope to the LGMD2A/R1 community.”
-- Jennifer Levy, PhD, Scientific Director, Coalition to Cure Calpain 3
“This project represents exactly the type of translational science the Muscular Dystrophy Association is dedicated to supporting. The University of Florida team has uncovered important abnormalities in calcium handling that may be central to LGMD2A/R1, and testing targeted SOCE modulation could move the field closer to therapeutic development. We are encouraged by the scientific rigor behind this work and optimistic about the potential impact for patients as we deepen our understanding of how to restore muscle function in LGMD2A/R1.”
-- Angela Lek, PhD, Chief Research Officer, Muscular Dystrophy Association
“Our research supported by C3 set the stage by enabling us to identify SOCE abnormalities in the absence of Calpain 3. This new collaborative venture by MDA and C3 provides a unique opportunity for us to perform rigorous preclinical evaluation of already available compounds. We are thrilled to begin testing a new strategy that may improve strength and endurance for people living with LGMD2A/R1.”
-- Elisabeth Barton, PhD, Molecular Physiology of Muscle Laboratory, University of Florida