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

Ruorong Yan, Valentina Cigliola, Kelsey A. Oonk, Zachary Petrover, Sophia DeLuca, David W. Wolfson, Andrew Vekstein, Michelle A. Mendiola, Garth Devlin, Muath Bishawi, Matthew P. Gemberling, Tanvi Sinha, Michelle A. Sargent, Allen J. York, Avraham Shakked, Paige DeBenedittis, David C. Wendell, Jianhong Ou, Junsu Kang, Joseph A. GoldmanGurpreet S. Baht, Ravi Karra, Adam R. Williams, Dawn E. Bowles, Aravind Asokan, Eldad Tzahor, Charles A. Gersbach, Jeffery D. Molkentin, Nenad Bursac, Brian L. Black, Kenneth D. Poss

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)96-111.e6
JournalCell Stem Cell
Volume30
Issue number1
DOIs
StatePublished - 5 Jan 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • YAP
  • cardiomyocyte proliferation
  • enhancers
  • gene therapy
  • heart regeneration
  • mouse
  • pig
  • tissue regeneration
  • zebrafish

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