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Adeno-Associated Virus-Mediated Delivery of CRISPR for Cardiac Gene Editing in Mice

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Published on: August 2, 2018

Regional Variation in Cardiovascular Genes Enables a Tractable Genome Editing Strategy.

Vikki A Krysov^1,2, Rachel H Wilson¹, Nicholas S Ten¹

¹Division of Cardiovascular Medicine (V.A.K., R.H.W., N.S.T., N.Y., H.N.D.J., S.S., Y.H., C.M.R., M.T.W., E.A.A., V.N.P.).

Circulation. Genomic and Precision Medicine

|March 20, 2024

Summary

Genome engineering strategies can target clustered pathogenic variants in cardiovascular disease genes. This approach enables efficient prime editing therapeutics for genetic heart conditions, balancing personalized treatment with broad applicability.

Keywords:

cluster analysis feasibility studies gene editing genetics mutagenesis

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Area of Science:

Genetics
Molecular Biology
Cardiovascular Medicine

Background:

Developing genome engineering therapeutics requires balancing personalized medicine with off-the-shelf solutions.
Pathogenic variants in cardiovascular disease genes often exhibit regional clustering, offering a potential therapeutic design strategy.

Purpose of the Study:

To investigate the regional clustering of pathogenic variants in cardiovascular disease genes.
To demonstrate the feasibility of a prime editing strategy targeting these variant hotspots for therapeutic development.

Main Methods:

Collation of 2435 pathogenic/likely pathogenic variants in 82 cardiovascular disease genes from ClinVar.
Assessment of variant regional density using a clustering index.
In vitro demonstration of prime editing efficiency at pathogenic hotspots.

Main Results:

Pathogenic variants in cardiovascular disease genes show higher regional density compared to general population variants.
Missense pathogenic variants exhibit higher regional density than truncating variants.
Prime editing achieved a mean efficiency of 57±27% at introduced variants within a pathogenic hotspot.

Conclusions:

Targeting pathogenic hotspots can address both known and novel variants, particularly missense mutations.
Prime editing is a valuable tool for dominant-negative cardiovascular diseases due to variant clustering.
This study presents a strategy for targeting key genomic regions in inherited cardiovascular diseases using prime editing.