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.
CITATION STYLE
Yan, R., Cigliola, V., Oonk, K. A., Petrover, Z., DeLuca, S., Wolfson, D. W., … Poss, K. D. (2023). An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair. Cell Stem Cell, 30(1), 96-111.e6. https://doi.org/10.1016/j.stem.2022.11.012
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