CRISPR Activation Reverses Haploinsufficiency and Functional Deficits Caused by <i>TTN</i> Truncation Variants.

ABSTRACT:

Background

TTN truncation variants (TTNtvs) are the most common genetic lesion identified in individuals with dilated cardiomyopathy, a disease with high morbidity and mortality rates. TTNtvs reduce normal TTN (titin) protein levels, produce truncated proteins, and impair sarcomere content and function. Therapeutics targeting TTNtvs have been elusive because of the immense size of TTN, the rarity of specific TTNtvs, and incomplete knowledge of TTNtv pathogenicity.

Methods

We adapted CRISPR activation using dCas9-VPR to functionally interrogate TTNtv pathogenicity and develop a therapeutic in human cardiomyocytes and 3-dimensional cardiac microtissues engineered from induced pluripotent stem cell models harboring a dilated cardiomyopathy-associated TTNtv. We performed

SUBMITTER: Ghahremani S 

PROVIDER: S-EPMC11031707 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature