Two new research projects have been funded by the Coalition to Cure Calpain 3 (C3), a nonprofit patient advocacy organization, to develop gene therapies for limb-girdle muscular dystrophy type 2A (LGMD2A).
LGMD2A, also known as calpainopathy, is the most common subtype of limb girdle muscular dystrophy (LGMD), a progressive muscle-wasting disease resulting from genetic defects. Caused by mutations in the calpain-3 (CAPN3) gene, it accounts for 30 percent of all LGMD cases.
LGMD is characterized by muscle shrinkage in the limb-girdle regions of the body — the bony structure surrounding the shoulder and hip joints — or in the muscles around the shoulders and hips.
C3’s focus is on supporting the development and advancement of potential treatments for LGMD2A, one of which is gene therapy. In fact, the organization launched an initiative last year to fund research projects specifically testing gene therapy approaches.
“Gene therapy has shown tremendous promise in numerous diseases caused by a single malfunctioning gene, including in more common forms of muscular dystrophy and other LGMD subtypes,” Jennifer R. Levy, PhD, scientific director at C3, said in a press release.
“Because LGMD2A is caused by a malfunctioning calpain 3 gene, we believe that gene therapy holds great promise to treat this debilitating disease for which there is currently no treatment or cure. Our gene therapy initiative is designed to study a number of gene therapy techniques with the goal of advancing potential treatments toward the clinic as quickly as possible.”
Gene therapies work by targeting the gene(s) that cause a disease, using various approaches — replacing the mutated gene with a healthy gene; deleting or inactivating the mutated gene; or introducing a new gene that helps fight the disease.
One of the two recently funded projects, called “Calpain and animal models: towards therapy,” is aimed at first developing a new model to study LGMD2A and then developing an adeno-associated viral (AAV)-mediated gene therapy. AAVs are non-disease-carrying viruses, which are used as vehicles to deliver a copy of a normal gene.
Researchers will administer the gene therapy to determine the lowest dose needed to effectively improve skeletal muscle function. Isabelle Richard, PhD, a researcher at Généthon in Paris, is the lead investigator of the project.
The other project, titled “Pre-clinical studies for gene therapy in LGMD2A,” will also evaluate an AAV-mediated CAPN3 gene therapy, which will be delivered to the whole body of a mouse model of the disease.
Led by Zarife Sahenk, MD, PhD, a professor of pediatrics and neurology at Nationwide Children’s Hospital, in Columbus, Ohio, researchers will assess the therapy’s safety and effectiveness.
Previous work by Sahenk’s lab showed that LGMD2A is characterized by an impairment in muscle regenerative capacity and that AAV-calpain 3 gene therapy can correct the gene defect.
These projects are the second wave of C3’s funded gene therapy research. In 2017, the nonprofit funded two other projects — one, led by Michele Calos, PhD, a professor of genetics at Stanford University, is testing the effectiveness of using genetic material (specifically DNA) to deliver a healthy CAPN3 gene to muscle cells. Calos’ team is evaluating if the therapy, injected into the vein, is able to reach the muscle fibers and lead to the production of a healthy calpain 3 protein.
The other project funded in 2017 is evaluating a gene-editing tool called CRISPR-CAS9 to edit the CAPN3 gene or, in other words, to correct the mutations in the gene in cells from LGMD2A patients. Led by Rita Perlingeiro, PhD, the Lillihei Professor in Stem Cell Medicine at the Lillihei Heart Institute at the University of Minnesota, the outcomes of this research will determine the potential of gene editing as a treatment strategy for LGMD2A.
“As our Gene Therapy Initiative research projects near their first milestones, we are excited to soon learn which approaches have the potential to ultimately benefit patients with this serious disease,” Levy said.