An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair.

The efficacy and safety of gene-therapy strategies for indications like tissue damage hinge on precision; yet, current methods afford little spatial or temporal control of payload delivery. Here, we find that tissue-regeneration enhancer elements (TREEs) isolated from zebrafish can direct targeted, injury-associated gene expression from viral DNA vectors delivered systemically in small and large adult mammalian species. When employed in combination with CRISPR-based epigenome editing tools in mice, zebrafish TREEs stimulated or repressed the expression of endogenous genes after ischemic myocardial infarction. Intravenously delivered recombinant AAV vectors designed with a TREE to direct a constitutively active YAP factor boosted indicators of cardiac regeneration in mice and improved the function of the injured heart. Our findings establish the application of contextual enhancer elements as a potential therapeutic platform for spatiotemporally controlled tissue regeneration in mammals.

Duke Scholars

Author Charles Gersbach Biomedical Engineering

Author Aravind Asokan Surgery, Surgical Sciences

Author Ravi Karra Medicine, Cardiology

Author Nenad Bursac Biomedical Engineering

Author Gurpreet Baht Orthopaedic Surgery

Author Dawn Elizabeth Bowles Surgery, Surgical Sciences

Author Adam Richard Williams Surgery, Cardiovascular and Thoracic Surgery

Author Kenneth Daniel Poss Cell Biology