|Title||An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair.|
|Publication Type||Journal Article|
|Year of Publication||2023|
|Authors||R Yan, V Cigliola, KA Oonk, Z Petrover, S DeLuca, DW Wolfson, A Vekstein, MA Mendiola, G Devlin, M Bishawi, MP Gemberling, T Sinha, MA Sargent, AJ York, A Shakked, P DeBenedittis, DC Wendell, J Ou, J Kang, JA Goldman, GS Baht, R Karra, AR Williams, DE Bowles, A Asokan, E Tzahor, CA Gersbach, JD Molkentin, N Bursac, BL Black, and KD Poss|
|Journal||Cell Stem Cell|
|Pagination||96 - 111.e6|
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.
|Short Title||Cell Stem Cell|