Abstract Body (Do not enter title and authors here): Background: LMNA-related Dilated Cardiomyopathy (LMNA-related DCM) is an aggressive type of DCM caused by pathogenic mutations in the LMNA gene that comprises 5-6% of genetic DCM cases. NVC-001 is an adeno-associated virus (serotype 9) gene-therapy vector encoding a truncated form of the naturally occurring human SUN1 protein (dnSUN1) that is being developed as a new treatment for LMNA-related DCM patients. Here we report the results of preclinical pharmacology, safety and biodistribution studies of NVC-001 that support a first-in-human clinical trial of NVC-001, which is a multicenter, non-randomized, open-label, ascending-dose Phase 1/2 study to assess the safety, tolerability and preliminary efficacy of NVC-001 in LMNA-related DCM patients.
Methods: In vitro proof-of-concept studies were performed in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes harboring the N195K pathogenic LMNA mutation. In vivo proof of concept studies were performed in a high-fidelity Lmna conditional deletion mouse model of LMNA DCM. Nonclinical biodistribution and safety of NVC-001 were assessed in both diseased and healthy mice, as well as in non-human primates.
Results: NVC-001 successfully targeted the LINC complex in iPSC-derived human cardiomyocytes and rescued the arrhythmia phenotype of the N195K mutation. In the Lmna-deletion mouse model of LMNA DCM, NVC-001 treatment led to 8-fold longer survival in treated LMNA DCM mice (>300 days) compared to untreated mice (< 40 days), accompanied by halting of disease progression as indicated by stabilization of left ventricular function, rescue of conduction-system disease, and reduction in myocardial fibrosis. In biodistribution and safety studies in diseased and healthy mice and in cynomolgus monkeys, dnSUN1 transgene expression was restricted to the myocardium as intended with minimal to no expression in other tissues. No NVC-001-related clinical or histopathological adverse findings were observed at any dose level tested in diseased and healthy mice, or in cynomolgus monkeys.
Conclusion: Collectively, these studies confirmed the transduction, target engagement and potential disease-modifying efficacy of NVC-001 in human target cells and in a LMNA DCM disease model. These data, together with the absence of adverse findings in multiple species, support investigation of NVC-001 in human LMNA-related DCM patients in a first-in-human adaptive-design Phase 1/2 clinical trial to be conducted in the US and in Europe.