Abstract 13927: AAV Gene Therapy to Treat Underlying Cardiac Biomechanical Defects in Lmna Dilated Cardiomyopathy Improves Lifespan and Preserves Ejection Fraction in Lmna DCM Mouse Model

Mutations in the LMNA gene are the second most common cause of genetic dilated cardiomyopathies (DCMs) with a prevalence of ~1/12500. Adeno-associated virus (AAV) gene therapies are a promising treatment modality for genetic disease. However, the autosomal dominant, gain-of-function mutations underlying LMNA DCM preclude standard gene replacement approaches. To understand LMNA DCM, we previously generated a mouse model that exhibits reduced ejection fraction, dilation of ventricular inner dimensions and increased cardiac fibrosis, surviving for only ~40 days after cardiac-specific deletion of the Lmna gene. We propose that the mutant LMNA gene weakens the structural integrity of the nucleus, making it vulnerable to biomechanical forces generated by contracting cardiomyocytes, which ultimately results in nuclear damage and a decline in cardiac function. Our gene therapy, AAV9-cTnT-GSLA01, prevents nuclear damage and disease in our Lmna DCM model by reducing biomechanical forces transmitted to the nucleus. To determine if we can treat, rather than prevent, Lmna DCM, we injected animals with AAV9-cTnT-GSLA01 at 1x10 14 vg/kg at different timepoints (21, 17, 14 and 1 day(s)) after induction of Lmna deletion. Treatment with AAV9-cTnT-GSLA01 17 days post Lmna deletion resulted in lifespan extension to 108 days (P= 0.0002), while earlier intervention at day 14 or day 1, improved lifespan to 122 and 208 days respectively (P = 0.0002, P= 0.0035). To address dose dependency of AAV9-cTnT-GSLA01, we delivered the vector at 5x10 13 vg/kg, 1x10 14 vg/kg, and 2x10 14 vg/kg at 17 days after Lmna deletion. Lifespan was extended from 40 days in untreated mice to 51.5 (P = 0.0135), 67.5 (P < 0.0001), and 103.5 days (P < 0.0001) respectively. The progressive decline of ejection fraction in these mice was attenuated in a dose-dependent manner. Thus, the positive effect of AAV9-cTnT-GSLA01 on lifespan and cardiac function in Lmna DCM mice is enhanced with increasing dose and transgene expression. Initial optimisation of the therapeutic expression cassette appears to improve lifespan extension significantly. AAV9-cTnT-GSLA01 is a novel gene therapy approach that promises to address the underlying cause of LMNA DCM.