AAV9-mediated MYBPC3 gene therapy with optimized expression cassette enhances cardiac function and survival in MYBPC3 cardiomyopathy models

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.

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Publication Details

Journal
Nature Communications
Published
2025-03-04
DOI
https://doi.org/10.1038/s41467-025-57481-7
Citations
24
Primary Topic
Cardiomyopathy and Myosin Studies
Type
article
Field-Weighted Citation Impact
33.32
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article

AAV9-mediated MYBPC3 gene therapy with optimized expression cassette enhances cardiac function and survival in MYBPC3 cardiomyopathy models

Amara Greer-Short, Kathryn N. Ivey, Jaclyn J. Ho, Marie Cho et al.
24 citations
Nature Communications
Cardiomyopathy and Myosin Studies
33.32
article

AAV9-mediated MYBPC3 gene therapy with optimized expression cassette enhances cardiac function and survival in MYBPC3 cardiomyopathy models

Amara Greer-Short, Kathryn N. Ivey, Jaclyn J. Ho, Marie Cho, Frank Jing, Jun Liu, Ana Budan, Charles Feathers, Elena C. Leon, Emilee Easter, Laura M. Lombardi, Tawny Neal Qureshi, William S. Prince, Christopher M. Reid, Konor von Kraut, Jonathan H. Tsui, Timothy Hoey, Stephanie Steltzer, Olga Cisne-Thompson, Justin Wong, Jin Yang, Rishikesan Chandrakumar, Chris Alleyne-Levy, Anna Greenwood, Samantha W. Jones, Ze Cheng, Whittemore G. Tingley, Neshel Rodriguez, Jianmin Lin, Tae Won Chung
article en
24 citations

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.

Nature CommunicationsVol. 16(1)
Tenax Therapeutics (United States) (US)
Openalex Percentile: Top 0%
Cardiomyopathy and Myosin Studies
33.32
DOIOpen Access PDFOpenAlex
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