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AAV9-mediated MYBPC3 gene therapy with optimized expression cassette enhances cardiac function and survival in MYBPC3
Amara Greer-Short1, Anna Greenwood1, Elena C Leon1
1Tenaya Therapeutics, South San Francisco, CA, USA.
Insights
Gene therapy using AAV9 successfully reversed cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy (HCM). This approach restored MYBPC3 protein levels, improving heart function and survival in symptomatic animals.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Hypertrophic cardiomyopathy (HCM) affects ~600,000 people in the US.
- Loss-of-function mutations in MYBPC3 are the most common genetic cause of HCM, often leading to haploinsufficiency.
- Current treatments focus on managing symptoms rather than addressing the genetic root cause.
Purpose of the Study:
- To develop and evaluate an AAV9-based gene therapy (TN-201) for MYBPC3-associated HCM.
- To assess the efficacy of TN-201 in reversing cardiac dysfunction in a symptomatic murine model.
- To determine the optimal therapeutic dose for AAV gene therapy in this condition.
Main Methods:
- Engineered an optimized AAV9 vector (TN-201) with a minimal promoter and cis-regulatory elements for enhanced cardiac expression.
- Administered TN-201 to a symptomatic MYBPC3-deficient murine model of HCM.
- Conducted dose-ranging studies to evaluate therapeutic effects on cardiac structure, function, and survival.
Main Results:
- AAV gene therapy reversed cardiac hypertrophy and systolic dysfunction.
- Diastolic dysfunction was improved, and survival was prolonged in treated mice.
- Restoration of wild-type MYBPC3 protein levels was observed, with maximal efficacy at 3E13 vg/kg.
Conclusions:
- TN-201 gene therapy demonstrates significant therapeutic potential for MYBPC3-associated cardiomyopathy.
- The study provides preclinical evidence for reversing established cardiac dysfunction in HCM.
- Further clinical validation is warranted to explore TN-201's benefits in human patients.
Abstract:
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.
