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Injectable Hydrogels to Deliver Gene Therapy for Myocardial Infarct

可注射水凝胶为心肌梗塞提供基因治疗

基本信息

批准号：
10396051
负责人：
Sarah C Heilshorn
金额：
$ 39.63万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396051
关键词：
Address Animals Anterior Arteries Biocompatible Materials Blood capillaries Cardiac Cardiac Myocytes Catheters Cause of Death Chemicals Chemistry Chronic Clinical Contracts DNA Diffuse Diffusion Dose Drug Delivery Systems Echocardiography Elastin Elements Exertion Family Female Firefly Luciferases Formulation Future Gel Gene Delivery Gene Expression Gene Expression Profiling Genes Geometry Growth Factor Heart Heart Contractilities Histologic Hyaluronic Acid Hydrazones Hydrogels Immune response In Situ In Vitro Infarction Inflammation Injectable Injections Kinetics Left Ligation Matrix Metalloproteinases Measurement Mechanics Modeling Molecular Weight Myocardial Infarction Myocardium Necrosis Operative Surgical Procedures Peptide Nucleic Acids Performance Pharmaceutical Preparations Plasmids Property Proteins Randomized Rattus Recombinants Recovery of Function Reporter Genes Rheology Saline Site Stress Stromal Cells Surgeon Surgical sutures Therapeutic Thinness Tissues Validation Variant Ventricular Viscosity Wistar Rats angiogenesis base bioluminescence imaging biomaterial compatibility chemokine clinical translation clinically relevant combinatorial crosslink density design dosage endothelial stem cell experimental group fluorescence imaging gene therapy healing heart function hemodynamics improved in vivo local drug delivery male mathematical model mechanical properties minimally invasive novel therapeutics placebo group pre-clinical preclinical study pressure prevent programs protein aminoacid sequence regenerative repaired therapeutic gene therapeutic protein therapeutically effective tissue regeneration treatment group treatment strategy viscoelasticity

项目摘要

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 gel. Bioluminescence imaging (days 0, 1, 4, 7, 21, 42, 60, and 90) will be used to monitor gene expression. Functional recovery after MI will be assessed using echocardiography (days 7, 21) and hemodynamic measurements (day 90). Finally, heart explants will be analyzed for evidence of necrosis, inflammation, angiogenesis, and tissue regeneration (day 90).

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