Promising Insights into Safety of LGMD2A/R1 Gene Therapy Approach

Published research alert: Titin splicing regulates cardiotoxicity associated with Calpain-3 gene therapy for LGMD2A/R1

Coalition to Cure Calpain 3 (C3) is pleased to announce the publication of research undertaken by Dr. Isabelle Richard, Head of the Progressive Dystrophy Laboratory, Généthon, and colleagues. The paper, titled “Titin splicing regulates cardiotoxicity associated with Calpain-3 gene therapy for LGMD2A/R1,” was published in Science Translational Medicine. The main purpose of the study was to perform animal testing of AAV-mediated transfer of the Calpain-3 (CAPN3) gene as a potential therapeutic for LGMD2A/R1 patients.

A previous study by the group showed gene therapy in a mouse model of LGMD2A/R1 causes toxicity in the heart muscles. In the current study, the researchers sought to understand the cardiac toxicity by administering CAPN3 gene therapy to healthy macaques. They found that the gene therapy was well-tolerated and caused no deleterious effects to the heart. Importantly, the doses used for the safety study in macaques led to Calpain-3 expression levels similar to those shown to have a therapeutic effect in a mouse model of disease.

The researchers delved further into the problem of cardiac effects of Calpain-3 expression by examining the protein Titin, which binds to Calpain-3. They found that the mode of Calpain-3-Titin binding is species-specific and that this is likely the reason why cardiac toxicity was observed in mice but not macaques. Human Titin is similar to macaque, suggesting that humans, like macaques, will not develop cardiac toxicity in response to Calpain-3 gene therapy.

Click here to view the abstract on PubMed.gov

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