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

Amara Greer-Short, Anna Greenwood, Elena C. Leon, Tawny Neal Qureshi, Konor Kraut, Justin Wong, Jonathan H. Tsui, Christopher A. Reid, Ze Cheng, Emilee Easter, Jin Yang, Jaclyn Ho, Stephanie Steltzer, Ana Budan, Marie Cho, Rishikesan Chandrakumar, Olga Cisne-Thompson, Charles Feathers, Tae Won Chung, Neshel Rodriguez, Samantha Jones, Chris Alleyne-Levy, Jun Liu, Frank Jing, William S. Prince, JianMin Lin, Kathryn N. Ivey, Whittemore G. Tingley, Timothy Hoey and Laura M. Lombardi ()
Additional contact information
Amara Greer-Short: Tenaya Therapeutics
Anna Greenwood: Tenaya Therapeutics
Elena C. Leon: Tenaya Therapeutics
Tawny Neal Qureshi: Tenaya Therapeutics
Konor Kraut: Tenaya Therapeutics
Justin Wong: Tenaya Therapeutics
Jonathan H. Tsui: Tenaya Therapeutics
Christopher A. Reid: Tenaya Therapeutics
Ze Cheng: Tenaya Therapeutics
Emilee Easter: Tenaya Therapeutics
Jin Yang: Tenaya Therapeutics
Jaclyn Ho: Tenaya Therapeutics
Stephanie Steltzer: Tenaya Therapeutics
Ana Budan: Tenaya Therapeutics
Marie Cho: Tenaya Therapeutics
Rishikesan Chandrakumar: Tenaya Therapeutics
Olga Cisne-Thompson: Tenaya Therapeutics
Charles Feathers: Tenaya Therapeutics
Tae Won Chung: Tenaya Therapeutics
Neshel Rodriguez: Tenaya Therapeutics
Samantha Jones: Tenaya Therapeutics
Chris Alleyne-Levy: Tenaya Therapeutics
Jun Liu: Tenaya Therapeutics
Frank Jing: Tenaya Therapeutics
William S. Prince: Tenaya Therapeutics
JianMin Lin: Tenaya Therapeutics
Kathryn N. Ivey: Tenaya Therapeutics
Whittemore G. Tingley: Tenaya Therapeutics
Timothy Hoey: Tenaya Therapeutics
Laura M. Lombardi: Tenaya Therapeutics

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57481-7

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