Gene editing therapeutics for LMNA cardiomyopathy – Correct-LMNA

Dilated cardiomyopathy, a myocardial disorder defined by ventricular chamber enlargement and systolic dysfunction, is the second leading cause of advanced heart failure, accounting for almost 50% of all heart transplantations. In about 25-50% of patients with dilated cardiomyopathy, monogenic causative mutations are identified, with LMNA gene one of the most frequently reported in 5-10% of cases. Compared to other causes of cardiomyopathies, laminopathies - caused by mutations in LMNA encoding nuclear A-type lamins - are characterized by a remarkably high cardiovascular mortality. Despite optimization of conventional therapeutic strategies, terminal heart failure and post transplantation complications represent by far the most frequent cause of death. These trends highlight a particular need for alternative treatment modalities for this population, such as gene editing as proposed in this grant.

Genome editing has been made a reality for human gene therapy by the recent development of transformative technologies that use engineered enzymes to cut DNA sequences at specific sites in the genome. Within “CORRECT-LMNA” network, we aim to develop a “genome editing correction package” that will deliver CRISPR/Cas9 and a corrective donor DNA to LMNA mutated cardiac myocytes. The overall objective of this research proposal is to develop methods to perform LMNA gene correction in vivo thereby abrogating mutated A-type lamins expression in LMNA cardiomyopathy. The central hypothesis is that nuclease-mediated gene correction will lead proper A-type lamins expression and function in mouse models of LMNA cardiomyopathy. “CORRECT-LMNA” proposal will test the technique from patient-specific human iPSC (induced pluripotent stem cells) platform to mice models, thus obtaining the technological proof-of-concept and fostering the translation to patients. We will first applied hiPSC-CMs to the study of LMNA cardiomyopathy, to recapitulate basic mechanisms of the disease. The French Registry on laminopathies, OPALE – the largest worldwide-, will be used to identify patients and families with cardiomyopathy carrying specific mutations at potential interest for gene editing therapy and facilitate their inclusion in this program. Next, we will achieve genome editing to correct point mutations in hiPSC-CMs carrying LMNA mutations. We will design specific tools and define the optimal recombination strategy to obtain an efficient and specific gene repair in this model. We next aim to investigate, for the first time, the utility of genome editing in vivo, in cardiac muscle of LMNA mutated model of the disease.

“CORRECT-LMNA” is innovative because it capitalizes on the unfulfilled potential of the CRISPR genome editing technology to address the fundamental limitations of conventional gene therapies and the unmet need for a safe and effective permanent cure to LMNA cardiomyopathy. “CORRECT-LMNA” emerged from a cross-disciplinary collaboration between partners, coordinating the French network of diseases related to LMNA mutations (the Coordinator), an expert of cardiac gene therapy and CRISPR genome editing technology (Partner 1), an expert of translational research in LMNA cardiomyopathy (Partner 2) and cardiologists specialists of the disease (Partners 1&3). Furthermore, this project has a great potential of success due to the skills of the groups involved, with major potential spin-offs in terms of insights into innovative therapies in monogenic cardiomyopathies.