# Development of a Polymeric Delivery System for Efficient in vivo Cellular Reprogramming for Cardiac Regeneration

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $45,520

## Abstract

PROJECT SUMMARY
The goal of this study is to develop a targeted, injectable plasmid delivery system that is capable of efficient
direct reprogramming of cardiac fibroblasts to cardiomyocytes (CMCs) in vivo, aiding in cardiac tissue
regeneration following a myocardial infarction (MI) or ‘heart attack’. Cardiovascular disease (CVD) is the
leading cause of death worldwide and resulted in 17.9 million deaths in 2016 alone. Cardiac fibrosis, a major
contributor to CVD is which results from traumatic injury such as MI. A promising treatment avenue is direct
reprogramming of cardiac fibroblasts into CMCs to regenerate the myocardial tissue and regain functional
post-infarct heart tissue. Several recent studies have demonstrated that a combination of transcription factors,
Gata4, Mef2c, and Tbx5 delivered simultaneously can directly reprogram cardiac fibroblasts to CMCs and
induce CMC phenotype in vitro and in vivo. Unfortunately, while cardiac fibroblast to CMC differentiation is now
a possibility, implementation of this approach as a CVD treatment has not been viable. The gene delivery
vehicles (polyplexes) developed in the Ma Lab have been shown to drive bone tissue regeneration in vivo,
setting an important precedent on which this study is based. Preliminary data using an improved polyplex has
thus far driven in vitro reprogramming of cardiac fibroblasts into CMCs, a promising proof-of-concept result. In
the proposed study, researchers will be further improving the recently developed system by improving the gene
expression through nuclear targeting using a Nuclear Localization Signal (NLS). Preliminary results indicate
this improves gene expression compared to polyplexes alone. Further, researchers will be driving direct
reprogramming in vivo using a newly developed hydrogel scaffold to implement sustained delivery of the
polyplexes. The hypothesis is that through addition of a NLS and sustained delivery of plasmid DNA using an
injectable hydrogel, the nuclear localization and amount of plasmid delivered will be increased, resulting in an
increase in in vivo reprogramming of fibroblasts into CMCs. This will be evaluated using PCR and
immunohistochemistry to compare gene expression and later MRI to evaluate functional changes in the heart.
This research aims to establish the first regenerative treatment option for patients who have suffered a heart
attack. This work may likely lay the framework for an effective non-viral gene delivery system for use in
treatment of other lost or diseased tissues, especially the fibrosis of other tissue/organ systems.

## Key facts

- **NIH application ID:** 10063433
- **Project number:** 5F31HL149249-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Laura Elisabeth Saunders
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-09-29 → 2021-09-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063433

## Citation

> US National Institutes of Health, RePORTER application 10063433, Development of a Polymeric Delivery System for Efficient in vivo Cellular Reprogramming for Cardiac Regeneration (5F31HL149249-02). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10063433. Licensed CC0.

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