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 Goldman; Gurpreet 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

doi:10.1016/j.stem.2022.11.012

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

Cell Stem Cell. 2023 Jan 5;30(1):96-111.e6. doi: 10.1016/j.stem.2022.11.012. Epub 2022 Dec 13.

Authors

Ruorong Yan¹, Valentina Cigliola¹, Kelsey A Oonk¹, Zachary Petrover², Sophia DeLuca³, David W Wolfson⁴, Andrew Vekstein⁵, Michelle A Mendiola⁵, Garth Devlin⁵, Muath Bishawi⁶, Matthew P Gemberling⁷, Tanvi Sinha⁸, Michelle A Sargent⁹, Allen J York⁹, Avraham Shakked², Paige DeBenedittis¹⁰, David C Wendell¹¹, Jianhong Ou¹², Junsu Kang¹³, Joseph A Goldman¹⁴, Gurpreet S Baht¹⁵, Ravi Karra¹⁰, Adam R Williams⁵, Dawn E Bowles⁵, Aravind Asokan¹⁶, Eldad Tzahor², Charles A Gersbach¹⁷, Jeffery D Molkentin⁹, Nenad Bursac¹⁸, Brian L Black⁸, Kenneth D Poss¹⁹

Affiliations

¹ Duke Regeneration Center, Duke University, Durham, NC, USA; Department of Cell Biology, Duke University Medical School, Durham, NC, USA.
² Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
³ Department of Cell Biology, Duke University Medical School, Durham, NC, USA; Department of Biomedical Engineering, Duke University, Durham, NC, USA.
⁴ Duke Regeneration Center, Duke University, Durham, NC, USA; Department of Cell Biology, Duke University Medical School, Durham, NC, USA; Department of Surgery, Duke University School of Medicine, Durham, NC, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA.
⁵ Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
⁶ Department of Biomedical Engineering, Duke University, Durham, NC, USA; Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
⁷ Department of Biomedical Engineering, Duke University, Durham, NC, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA.
⁸ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
⁹ Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
¹⁰ Department of Medicine, Duke University Medical Center, Durham, NC, USA.
¹¹ Duke Cardiovascular Magnetic Resonance Center, Duke University Medical Center, Durham, NC, USA.
¹² Duke Regeneration Center, Duke University, Durham, NC, USA.
¹³ Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹⁴ Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, OH, USA.
¹⁵ Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA; Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, USA.
¹⁶ Duke Regeneration Center, Duke University, Durham, NC, USA; Department of Biomedical Engineering, Duke University, Durham, NC, USA; Department of Surgery, Duke University School of Medicine, Durham, NC, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA.
¹⁷ Duke Regeneration Center, Duke University, Durham, NC, USA; Department of Cell Biology, Duke University Medical School, Durham, NC, USA; Department of Biomedical Engineering, Duke University, Durham, NC, USA; Department of Surgery, Duke University School of Medicine, Durham, NC, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA; Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, USA.
¹⁸ Department of Biomedical Engineering, Duke University, Durham, NC, USA.
¹⁹ Duke Regeneration Center, Duke University, Durham, NC, USA; Department of Cell Biology, Duke University Medical School, Durham, NC, USA; Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA. Electronic address: ken.poss@duke.edu.

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.

Keywords: YAP; cardiomyocyte proliferation; enhancers; gene therapy; heart regeneration; mouse; pig; tissue regeneration; zebrafish.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation
Enhancer Elements, Genetic*
Genetic Therapy* / methods
Heart* / physiology
Mice
Myocardial Infarction* / genetics
Myocardial Infarction* / therapy
Myocytes, Cardiac* / metabolism
Regeneration* / genetics
Zebrafish / genetics

Abstract

Publication types

MeSH terms

Grants and funding