Why the study?
Loss-of-function mutations in MYBPC3 are the most common genetic cause of HCM, typically resulting in haploinsufficiency, prompting development of an optimized AAV9 gene therapy to restore cardiac MYBPC3.
Does AAV9-mediated MYBPC3 gene therapy improve cardiac function and survival in MYBPC3-deficient cardiomyopathy models?
Does AAV9-mediated MYBPC3 gene therapy improve cardiac function and survival in MYBPC3-deficient cardiomyopathy models?
AAV9-mediated MYBPC3 gene therapy reverses cardiac hypertrophy and systolic dysfunction while prolonging survival in a symptomatic murine model of hypertrophic cardiomyopathy.
Hypothesis-generating for AAV9-MYBPC3 restoration in HCM; human trials needed before any clinical consideration.
Hypertrophic cardiomyopathy (HCM) affects approximately 600,000 people in the United States. Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of HCM, with the majority of mutations resulting in haploinsufficiency. To restore cardiac MYBPC3, we use an adeno-associated virus (AAV9) vector and engineer an optimized expression cassette with a minimal promoter and cis-regulatory elements (TN-201) to enhance packaging efficiency and cardiomyocyte expression. Rather than simply preventing cardiac dysfunction preclinically, we demonstrate in a symptomatic MYBPC3-deficient murine model the ability of AAV gene therapy to reverse cardiac hypertrophy and systolic dysfunction, improve diastolic dysfunction, and prolong survival. Dose-ranging efficacy studies exhibit restoration of wild-type MYBPC3 protein levels and saturation of cardiac improvement at the clinically relevant dose of 3E13 vg/kg, outperforming a previously published construct. These findings suggest that TN-201 may offer therapeutic benefits in MYBPC3-associated cardiomyopathy, pending further validation in clinical settings. Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of hypertrophic cardiomyopathy. Here, the authors present an AAV9-based gene therapy system with an optimized expression cassette with minimal promoter and cis-regulatory elements that can ameliorate cardiac functions and prolong survival in a murine MYBPC3-deficient model.
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Greer-Short et al. (2025) studied this question.
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