Plasmid-mediated Gene Therapy Shows Promise for LGMD2A/R1 Patients

PUBLISHED RESEARCH ALERT: Plasmid-Mediated Gene Therapy in Mouse Models of LGMD

Coalition to Cure Calpain 3 (C3) is pleased to announce the publication of a new research paper from the group of Dr. Michele Calos, Stanford University School of Medicine. The paper, titled “Plasmid-mediated gene therapy in mouse models of LGMD,” was published in Molecular Therapy: Methods & Clinical Development. This study delivered plasmid DNA encoding therapeutic genes to the muscles of mouse models of LGMD2A/R1, LGMD2B/R2, and LGMD2D/R3.

Plasmid-mediated gene therapy delivers a healthy gene into muscle cells by using DNA. The DNA is injected into the muscles and then an electrical field is applied (called electroporation) which causes the DNA to enter the muscle cells. Inside the muscle fibers, the cellular machinery generates the protein that is defective in a genetic disease. In the case of LGMD2A/R1, a healthy version of the calpain 3 gene was delivered to the muscles of a mouse that is calpain 3 deficient. Results from this study show (1) successful delivery of calpain 3 and (2) expression was retained throughout the 3-month length of the experiment. Similar results were obtained with mouse models of LGMD2B/R2 (injected with the gene for dysferlin) and LGMD2D/R3 (injected with the gene for alpha-sarcoglycan). In LGMD2B/R2 and LGMD2D/R3 mice, which have leaky muscle membranes, the researchers measured improved membrane permeability in treated animals.

Gene therapy using plasmid DNA differs from adeno-associated virus (AAV)-mediated gene therapy in that it does not require viruses to transport genes to muscle cells. This method has several potential advantages over AAV-mediated therapy, including a lack of immune response (allowing for re-dosing if needed) and inexpensive manufacturing. It is possible that, in the future, LGMD patients who are not candidates for AAV-mediated gene therapy may benefit from plasmid-mediated gene therapy. Alternatively, patients could be treated with a combination of multiple types of gene therapy.

Click here to access the article on the journal’s website.

This work was funded in part by the C3 Gene Therapy Initiative.