SHORT DESCRIPTION
A precision cardiac gene‑regulation platform that deletes a MYH7 enhancer to shift ventricular myosin isoform balance toward faster α‑MHC and activates upstream MYH6 enhancers to increase MYH6 expression and improve contractility, creating a dual toolkit for disease‑modifying therapy in cardiomyopathy and heart failure.
NU Tech ID: NU 2020-154, NU 2022-044
IP STATUS
Multiple US (18/265,135; 18/880,416) and OUS patents (21901505.4) pending
DEVELOPMENT STAGE
TRL-3 Experimental Proof-of-Concept: Initial in vitro studies confirm effective modulation of gene expression in cardiac cells.
BACKGROUND Cardiomyopathies, especially dilated cardiomyopathy (DCM), are major causes of heart failure, arrhythmias, and sudden cardiac death, accounting for substantial morbidity, mortality, and transplant/LVAD utilization across all ages. More than 100 genes, including sarcomeric myosin heavy chain genes MYH7 and MYH6, and nuclear‑envelope genes such as LMNA, are now recognized as drivers of inherited cardiomyopathies with age‑dependent penetrance and highly variable clinical expression. Current management relies on guideline‑directed medical therapy (ACEI/ARB/ARNI, beta‑blockers, MRAs, SGLT2 inhibitors), device therapy (ICD/CRT), and, for end‑stage disease, transplant or LVAD. While these approaches improve symptoms and survival, they do not correct disease‑causing imbalances in gene expression such as the maladaptive shift toward higher MYH7 and lower MYH6 seen in advanced heart failure. Emerging myosin modulators (e.g., cardiac myosin inhibitors and activators) and early gene‑editing approaches show that directly targeting myosin function or correcting pathogenic MYH7 variants can reverse disease in preclinical models, but there are no approved therapies that durably re‑program ventricular MYH6/MYH7 expression by acting on upstream regulatory DNA. This creates a clear unmet need for in vivo genetic medicines that directly target the underlying genetic factors in heart dysfunction to safely and specifically modulate ventricular myosin heavy chain isoform balance at the enhancer level, improve contractility, and alter the trajectory of cardiomyopathy and heart failure.
ABSTRACT Northwestern researchers have developed a unified epigenome-engineering strategy to therapeutically rebalance myosin heavy chain expression in cardiomyopathy and heart failure by combining two complementary genome-editing modalities. The first technology uses CRISPR-mediated deletion of disease-relevant enhancer elements within the MYH7/MYH6 regulatory locus to suppress MYH7 while inducing a compensatory increase in MYH6, leveraging enhancer loss-of-function to remodel the myosin program. The second leverages CRISPR-activation technology to deploy nuclease-defective Cas9 fused to transcriptional activators and targeted guide RNAs to engage MYH6 enhancer regions and selectively drive MYH6 upregulation, with data in human cardiomyocyte models showing the potential to lower MYH7 as well. Together, these enhancer-targeting approaches are designed to shift the MYH6/MYH7 balance toward a faster, more energetically favorable contractile phenotype, providing a precision, locus-specific platform that can be delivered via AAV or lipid nanoparticles and positioned for combination with existing heart failure and cardiomyopathy standards of care.
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PUBLICATIONS
KEYWORDS Cardiology, cardiomyopathy, heart failure, MYH7, MYH6, gene editing, cardiac gene therapy, epigenetics, heart function, regenerative medicine