# Injectable Hydrogels to Deliver Gene Therapy for Myocardial Infarct

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $396,347

## Abstract

Following myocardial infarction (MI), local tissue remodeling leads to chronically worsening heart function that is
a major cause of death in the US. Several preclinical studies have shown that local delivery of growth factors or
growth factor-encoding genes can significantly improve cardiac function. Unfortunately, effective delivery of
therapeutics to the beating heart remains a formidable challenge, impeding clinical translation of novel drug
therapeutics. The ideal MI drug-delivery system would be catheter injectable, would prevent extrusion out of the
contractile myocardium, and would provide sustained delivery of an effective therapeutic dosage. Unfortunately,
most catheter-injectable biomaterials are weak hydrogels that are rapidly extruded out of contractile heart tissue.
To overcome this clinical challenge, we propose the design of injectable gels that are crosslinked by dynamic
covalent chemistry (DCC) bonds that are strong yet reversible. Thus, these DCC hydrogels combine the clinically
desired properties of being injectable and having the mechanical integrity required for retention in the beating
heart. Specifically, our gels are formed through DCC hydrazone bonds between a chemically modified hyaluronic
acid and a recombinant, elastin-like protein. The resulting gel is enzymatically biodegradable and fully chemically
defined for future potential in FDA studies. In Aim 1, a family of 20 gels with distinct viscoelastic mechanical
properties will be synthesized and characterized for ease of catheter injection and retention in the contracting
heart. We will modulate the viscosity of the gels by altering the molecular weight of hyaluronic acid and the yield
stress of the gel by varying the concentration of a DCC crosslink competitor and perform in vitro and in vivo
quantifications of injectability. In parallel in Aim 2, we evaluate the hypothesis that sustained release of a
regenerative payload can be achieved through combinatorial mixing of drug tethers with distinct cleavage
kinetics. Specifically, our payload is minicircle genes encoding stromal cell-derived factor-1α (SDF-1α), which is
known to induce angiogenesis and improved heart function following MI. This payload is tethered to the injectable
gel via DNA hybridization with peptide nucleic acid (PNA)-peptides. In Aim 3, the gel formulation from Aim 1 with
optimal in vivo retention properties and the drug tether design from Aim 2 with sustained gene release will be
combined into an injectable MI therapy. Functional performance will be evaluated in a preclinical rat MI model
using minicircle genes carrying both SDF-1α and a firefly luciferase reporter gene. Following induction of MI
through ligation of the left anterior descending (LAD) artery, animals will be randomly assigned into either sham
or treatment groups. Treatment animals will receive a 60-μL intramyocardial injection of saline only, hydrogel
only, untethered genes in saline, untethered genes in gel, or tethered genes in ...

## Key facts

- **NIH application ID:** 10163255
- **Project number:** 5R01HL151997-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Sarah C Heilshorn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,347
- **Award type:** 5
- **Project period:** 2020-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163255

## Citation

> US National Institutes of Health, RePORTER application 10163255, Injectable Hydrogels to Deliver Gene Therapy for Myocardial Infarct (5R01HL151997-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10163255. Licensed CC0.

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