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

• DOI: 10.1161/circ.146.suppl_1.13927
• Publication Date: 2023-06-15T16:25:16Z
• Authors: Hendrikje Werner; Esther S Gan; Connie Y Loh; Nyein Thet Khaing; Jinqiu Zhang; Mervyn Ong; Brian Burke; Yann Chong Tan; Colin L Stewart; Yin Loon Lee
• Keywords: LMNA; Dilated Cardiomyopathy

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