Modulating cardiac myosin heavy chain isoform expression for treating cardiomyopathies
Grant Award Details
Grant Type:
Grant Number:
DISC2-16590
Investigator(s):
Disease Focus:
Human Stem Cell Use:
Award Value:
$2,772,000
Status:
Active
Grant Application Details
Application Title:
Modulating cardiac myosin heavy chain isoform expression for treating cardiomyopathies
Public Abstract:
Research Objective
To discover CRISPR-based genetic strategies that will directly and therapeutically modify cardiac myosin heavy chain isoform expression to treat HF and cardiomyopathies.
Impact
Heart Failure and Cardiomyopathies
Major Proposed Activities
To discover CRISPR-based genetic strategies that will directly and therapeutically modify cardiac myosin heavy chain isoform expression to treat HF and cardiomyopathies.
Impact
Heart Failure and Cardiomyopathies
Major Proposed Activities
- Validate CRISPR-based MYH6/MYH7 gene regulation and switching strategy as a genetic therapy for cardiomyopathy in human ventricular cardiomyocytes
- Identify key sequences/nucleotides that control MYH6/MYH7 expression and switching using CRISPR-based base editing (BE) screening strategy
- Investigate whether regulating/switching MYH6/MYH7 expression using dCasMINI-based effectors (CRISPR activator, interference, BE) can therapeutically modify heart disease in hPSC cardiomyopathy models
- Investigate and validate that MYH6/MYH7 gene regulation therapeutic strategies are broadly applicable across a genetically diverse population
- Test AAV dCasMINI effector MYH6/MYH7 genetic therapy dosing and safety in in vivo mouse models
- Test AAV dCasMINI effector MYH6/MYH7 genetic therapy efficacy in vivo in a mouse model of cardiomyopathy
Statement of Benefit to California:
Heart failure is a growing global epidemic and one of the major causes of morbidity and mortality worldwide, and its prevalence among U.S. adults ranges from ~1.9-2.6%. California also has the highest overall age-adjusted mortality rate associated with hypertrophic cardiomyopathy. Our proposed research will deliver a genetic-based therapy that will directly increase cardiac function to treat heart failure and cardiomyopathy patients, thus benefitting the State of California and its citizens.
