. 2023 Jan 5;30(1):96-111.e6.

doi: 10.1016/j.stem.2022.11.012. Epub 2022 Dec 13.

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

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.

PMID: 36516837
PMCID: PMC9830588
DOI: 10.1016/j.stem.2022.11.012

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

Ruorong Yan et al. Cell Stem Cell. 2023.

. 2023 Jan 5;30(1):96-111.e6.

doi: 10.1016/j.stem.2022.11.012. Epub 2022 Dec 13.

Authors

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.

PMID: 36516837
PMCID: PMC9830588
DOI: 10.1016/j.stem.2022.11.012

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests R.Y., J.K., J.A.G., V.C., and K.D.P. are listed as inventors on a patent application filed by Duke University on methods for enhancing tissue regeneration. C.A.G. is an inventor on patents and patent applications related to epigenome editing, is a co-founder/advisor of Tune Therapeutics and Locus Biosciences, and is an advisor to Sarepta Therapeutics.

Figures

**Figure 1.. Zebrafish TREE regulatory sequences direct injury-induced gene expression in adult mouse tissues.**
(A) Transgene constructs to evaluate the ability of individual zebrafish TREEs to direct expression of a permissive promoter (*Hsp68*) in adult mouse tissues upon injury. (B) Whole-mount images of X-gal-stained adult mouse hearts, with staining (arrowheads) appearing in the area of LCA ligation (asterisks) but not in uninjured hearts. a, atrium; v, ventricle. *LEN-Hsp68::LacZ*: n = 9, 11, and 6, *REN-Hsp68::LacZ*: n = 7, 6, and 5, for uninjured, 3, and 7 dpi, respectively. Scale bar, 2 mm. (C) Section images of X-gal-stained adult mouse hearts, with staining appearing in the infarcted area and restricted to the injured site (asterisks). High-magnification view (right) of box in left. Scale bar, 200 μm. (D) Whole-mount images of X-gal-stained digits of adult *LEN-Hsp68::LacZ* or *REN-Hsp68::LacZ* mice. Staining (arrows) is evident in amputated digit tips only (asterisks). n = 6 (3), and 8 (4) for *LEN-Hsp68::LacZ* and *REN-Hsp68::LacZ* digits (animals), respectively. Scale bar, 2 mm. (E) Whole-mount images of X-gal-stained tibia of adult *LEN-Hsp68::LacZ* mice 2 days and 21 days after tibia fracture. Staining (arrowhead) is evident in fractured site (asterisks) at 21 dpi. n = 5, and 7 for 2, and 21 dpi, respectively. Scale bar, 2 mm. (F) Whole-mount images of X-gal-stained tibialis anterior (TA) muscles of adult *REN-Hsp68::LacZ* mice 1 day and 3 days after BaCl₂-induced injury. Staining (arrowheads) is evident in injured TA muscles. n = 5, and 3 for 1 dpi and 3 dpi, respectively. Scale bar, 2 mm.

**Figure 2.. Zebrafish TREE constructs direct gene expression in injured murine cardiac tissue when delivered by AAV pre- or post MI.**
(A) Left, Schematic for virus delivery and ligation of LCA. Right, Experimental design in (B and C). (B) Section images of hearts after sham or MI injury, from adult mice infected pre-injury with AAV9 harboring a zebrafish TREE, an *Hsp68* minimal promoter, and an *EGFP* cassette. Fluorescence is induced by injury and restricted to CMs near the MI (asterisks). Tnnt antibody shows non-specific background in injury site when stained with fixed heart samples, which is not observed in unfixed heart samples (see Figure 5B). *LEN-Hsp68::EGFP*: n = 6, 4, 5, 5, and 3, *REN-Hsp68::EGFP*: n = 6, 4, 4, 3, and 3 for sham, 3, 7, 14, and 50 dpi, respectively. *2ankrd1aEN-Hsp68::EGFP*: n = 4, 3, 5, 3, and 3 for sham, 3, 7, 15 and 70 dpi, respectively. *LEN-Hsp68::EGFP*, *REN-Hsp68::EGFP*, and *2ankrd1aEN-Hsp68::EGFP* are detectable in MI injury. Scale bar, 500 μm. (C) TREE-driven EGFP fluorescence co-localizes with Tnnt⁺ cardiomyocytes. Scale bar, 50 μm. (D) Experimental design in (E). (E) Section images of hearts after MI, from adult mice transduced 1 day post-MI with AAV9 harboring *TREE-Hsp68::EGFP* or control *Hsp68::EGFP*. EGFP fluorescence is detectable in the injury sites (asterisks) in each *TREE-Hsp68::EGFP* group. n = 5, 3, 3, and 4 for *LEN-Hsp68::EGFP*, *REN-Hsp68::EGFP*, *2ankrd1aEN-Hsp68::EGFP*, and *Hsp68::EGFP*, respectively. Box from top image is magnified in bottom. Scale bar, 500 μm.

**Figure 3.. Zebrafish TREEs direct injury-associated expression in porcine cardiac muscle cells.**
(A) Experimental design in (B-G), in which pigs are transduced by intracoronary (IC) perfusion or 10–15 intramyocardial (IM) injections throughout the ventricles, prior to ischemia/reperfusion injury (I/R). Regions of the ventricle sampled for histology are indicated by (i-v). n = 1. (B) Section images of hearts after I/R injury, from pig infected pre-injury with AAV9 harboring a zebrafish TREE *LEN*, an *Hsp68* minimal promoter, and an *EGFP* (IC perfusion) cassette. Fluorescence is induced by injury and restricted to CMs near the ischemic injury. White dashed lines indicate injured area. Scale bars, 200 μm (left) and 100 μm (right). (C) Quantified EGFP expression of injured hearts from pig in (B). Graph indicates mean ± SEM. (D) Section images of liver and skeletal muscle after I/R injury, from pig infected as above. Fluorescence is negligible in liver and skeletal muscle. Scale bar, 100 μm. (E) Section images of hearts after I/R injury, from pig transduced pre-injury with AAV9 harboring a zebrafish TREE *LEN*, an *Hsp68* minimal promoter, and an *mCherry* (IM injection) cassette. Fluorescence is induced by injury and restricted to CMs near the MI. White dashed lines indicate injured area. Scale bars, 200 μm (left) and 100 μm (right). (F) Quantified *mCherry* expression of injured hearts from pig in (E). Graph indicates mean ± SEM. (G) Section images of liver and skeletal muscle after I/R injury, from pig transduced by IM injection as above. Fluorescence is negligible in liver and skeletal muscle. Scale bar, 100 μm. (H) Experimental design in (I-K), in which pigs are transduced by intracoronary (IC) perfusion 1 week post I/R injury. Regions of the ventricle sampled for histology are indicated by (i-v). n = 1. (I) Section images of hearts after I/R injury, from pig transduced post-injury with AAV9 harboring a zebrafish TREE *2ankrd1aEN*, an *Hsp68* minimal promoter, and an *EGFP* cassette. Fluorescence is induced by injury and restricted to CMs near the MI. Scale bars, 200 μm (left) and 100 μm (right). (J) Quantified EGFP expression of injured hearts from pig in (I). Graph indicates mean ± SEM. (K) Section images of liver and skeletal muscle after I/R injury, from pig transduced as above. Fluorescence is negligible in liver and skeletal muscle. White dashed lines indicate injured area. Scale bar, 100 μm.

**Figure 4.. Zebrafish TREEs paired with epigenome editing tools can activate expression of endogenous genes in injured murine hearts.**
(A and B) Experimental design for *in vivo* modulation of endogenous gene expression, involving transgenic mice enabling Cre-based expression of dCas9-based epigenome editors, and AAVs containing TREE- controlled Cre and a U6-gRNA expression cassette. (C and D) Section images from ventricle of *Rosa26;:LSL-dCas9*^p300 (in C) or *Rosa26:;LSL-dCas9*^KRAB (in D) mice injected with AAV9 carrying a zebrafish TREE, an *Hsp68* minimal promoter, and a Cre recombinase. Cas9 protein (green) is detected in CMs (red, Tnnt) near the injury site (asterisks). n = 3. Scale bars, 500 μm and 100 μm (magnified areas). (E) Representative Western blot images of AGRN and GAPDH protein levels in hearts of *Rosa26:;LSL-dCas9*^p300 mice injected with *AAV9-2ankrd1aEN-Hsp68:;Cre* containing a control non-targeting gRNA or *Agrn* gRNA and sacrificed at 14 dpi. Each lane represents sampling of one animal. (F) Quantification of AGRN protein levels from 3 independent experiments; all samples are included in the graph and color-coded for each experiment. Each point represents one mouse. Mann-Whitney rank sum test; n = 10 for scramble gRNAs and n = 17 for *Agrn* gRNAs. Solid line on violin plot indicates the median. (G) Representative Western blot images of SAV1 and GAPDH protein levels from hearts of *Rosa26:LSL-dCas9*^KRAB mice injected with *AAV9-LEN-Hsp68:Cre* containing a scramble or *Sav1* gRNA and sacrificed at 14 dpi. (H) Quantification of SAV1 protein levels from 3 independent experiments; all samples are included in the graph and color coded for each experiment. Each point represents one mouse. Unpaired t-test with Welch’s correction; n = 9 for control non-targeting gRNAs and n = 15 for *Sav1* gRNAs. Solid line on violin plot indicates the median.

**Figure 5.. TREE-mediated YAP5SA delivery boosts CM cycling.**
(A) Experimental design in (B-I). An AAV with *LEN* directing *EGFP* or a *YAP5SA* cassette is delivered one week before myocardial infarction. (B and C) Section images of 14 dpi hearts from adult mice transduced pre-injury with AAV9 harboring *LEN-Hsp68::EGFP* or *LEN-Hsp68::HA-YAP5SA*. EGFP or HA is induced at the site of injury (asterisks) in *LEN-Hsp68::EGFP* or *LEN-Hsp68::HA-YAP5SA* hearts, respectively. High-magnification view of box in left. Scale bars, 500 μm (B) and 50 μm (C). (D) Left, Quantified CM Ki67 indices in the border zone. Mann-Whitney test. Right, Section images of border zone stained for the CM marker Tnnt (red), WGA (white) and cycling marker Ki67 (green). Arrows indicate Ki67⁺ CM nuclei. Scale bar, 20 μm. Lines on violin plots indicate the median and quartiles. (E) Quantified CM Ki67 indices in distal myocardium. Mann-Whitney test. Lines on violin plots indicate the median and quartiles. (F) Left, Quantified CM EdU incorporation indices in the border zone. Mann-Whitney test. Right, Section images of border zone stained for CM marker Tnnt (red), WGA (white) and EdU (green). Arrows indicate EdU⁺ CM nuclei. Scale bar, 20 μm. Lines on violin plots indicate the median and quartiles. (G) Quantified CM EdU incorporation indices in distal myocardium. Mann-Whitney test. Lines on violin plots indicate the median and quartiles. (H) Left, Quantified CM dedifferentiation indices in the border zone. Mann-Whitney test. Right, Section images of border zone stained for CM marker Tnnt (red), and dedifferentiation marker αSMA (green). αSMA marks vascular smooth muscle and immature CMs, and CM αSMA staining is greater in the border zones of experimental animals. Arrows indicate αSMA⁺ CMs. Scale bar, 50 μm. Lines on violin plots indicate the median and quartiles. (I) Quantified CM dedifferentiation indices in distal myocardium. Mann-Whitney test. Values in (D-I) are from 2 independent experiments. Each point represents one mouse and each color represent samples of an independent experiment. Lines on violin plots indicate the median and quartiles.

**Figure 6.. TREE-mediated YAP5SA delivery improves indicators of cardiac function.**
(A) Experimental design for AAV introduction, I/R injury, echocardiographic monitoring, and collection for histology. (B and C) Ejection fractions (EF) and fractional shortening (FS) were calculated pre- and post-I/R. Shown are normalized mean +/− SEM for animals from each group that displayed a loss in EF of relative 10% or more at 3 dpi as compared with the previous measurement at Baseline prior to injury. (D and E) Left ventricular anterior wall dimensions during systole (LVAW;s) (D) and diastole (LVAW;d) (E) were calculated pre- and post-I/R. Shown are normalized mean +/− SEM for animals described in (A). (F and G) Left ventricular posterior wall dimensions during systole (LVPW;s) (F) and diastole (LVPW;d) (G) were calculated pre- and post-I/R. Shown are normalized mean +/− SEM for animals described in (A). (H and I) Left ventricular internal diameter end systole (LVID;s) (H) and diastole (LVID;d) (I) were calculated pre- and post-I/R. Shown are normalized mean +/− SEM for animals described in (A). (J) Wald’s tests were used for statistical comparisons of functional indicators among groups from 7 dpi to 42 dpi, which preserved individual animal performance over time. p values for the Wald’s tests are shown in the table. Graphs and statistical analysis of pooled actual (rather than normalized) values are shown in Figure S6. (K) Transverse section images from hearts at 42 days post-I/R, stained by Masson’s Trichrome to highlight collagen (blue). One representative section from a *LEN-Hsp68::EGFP*, a *LEN-Hsp68::HA-YAP5SA* heart, and a *LEN-Hsp68::HA-YAP5SA* post I/R injection heart are shown. n = 8, 7, 8, and 7–8 for Sham, *LEN-Hsp68::EGFP*, *LEN-Hsp68::HA-YAP5SA,* and *LEN-Hsp68::HA-YAP5SA* post I/R injection, respectively (One animal died between 36 and 42 dpi in the *LEN-Hsp68::HA-YAP5SA* post I/R injection group). Scale bar, 500 μm. Representative sections from each heart are shown in Figure S6.

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Regrowing the heart, one TREE at a time.
Steimle JD, Martin JF. Steimle JD, et al. Cell Stem Cell. 2023 Jan 5;30(1):1-2. doi: 10.1016/j.stem.2022.12.004. Cell Stem Cell. 2023. PMID: 36608673

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

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

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