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RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes

ABSTRACT: RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes

PROVIDER: PRJNA883694 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21684802_1.fastq.gz	Fastqsanger.gz
	SRR21684802_2.fastq.gz	Fastqsanger.gz
	SRR21684803_1.fastq.gz	Fastqsanger.gz
	SRR21684803_2.fastq.gz	Fastqsanger.gz
	SRR21684804_1.fastq.gz	Fastqsanger.gz

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Project description:BACKGROUND: Cardiac reprogramming is a technique to directly convert non-myocytes into myocardial cells using genes and/or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use. METHODS: Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single AAV. We also created a novel AAV capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating post-translationally modified capsid residues. Since a constitutive promoter was needed to drive high expression of these cell-fate altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3’ UTR of the expression cassette that limits expression to non-myocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid / cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models. RESULTS: We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model two weeks after MI, showing that cardiac reprogramming, when delivered in a single, clinically relevant AAV vector, can support functional improvement in the post-remodeled heart. This benefit was not observed with GFP or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism. CONCLUSION: Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury.

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RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes

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