Cell stem cell · 2022
An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Yan Ruorong, Cigliola Valentina, Oonk Kelsey A, Petrover Zachary, DeLuca Sophia, Wolfson David W, Vekstein Andrew, Mendiola Michelle A, Devlin Garth, Bishawi Muath, Gemberling Matthew P, Sinha Tanvi, Sargent Michelle A, York Allen J, Shakked Avraham, DeBenedittis Paige, Wendell David C, Ou Jianhong, Kang Junsu, Goldman Joseph A, Baht Gurpreet S, Karra Ravi, Williams Adam R, Bowles Dawn E, Asokan Aravind, Tzahor Eldad, Gersbach Charles A, Molkentin Jeffery D, Bursac Nenad, Black Brian L, Poss Kenneth D
Аннотация
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.