Although angioplasty and coronary bypass grafting are commonly used to treat coronary heart disease, many patients are not candidates for these procedures. Transmyocardial revascularization (TMR), which induces revascularization by creating multiple small wounds in the ischemic heart, offers promise as an alternative treatment. Therapeutic angiogenesis, in which angiogenic growth factors are used to pharmacologically stimulate revascularization of ischemic tissues, is also under investigation. Clinical trials, however, suggest that both approaches can benefit from further refinement. We therefore propose to augment TMR's effectiveness by the addition of a gene therapy approach to therapeutic angiogenesis, in which angiogenic genes are immobilized in a biocompatible matrix.
Specific Aim #1 will expand upon preliminary data to compare fibroblast growth factor (FGF) genes for their ability to induce angiogenesis and muscle regeneration in rodent skeletal muscle.
Specific Aim #2 will use the most effective of these genes in conjunction with TMR to induce revascularization and repair of chronically ischemic canine myocardium. Quantitative measures of cellular proliferation, angiogenesis, and blood flow will be performed to demonstrate efficacy. The data generated will establish the groundwork required for the future application of this therapeutic approach in Phase II studies and clinical trials.
Coronary heart disease is the major cause of death in the United States, and its major symptom, angina, is estimated to affect 6.2 million in this country. The primary treatments, angioplasty and coronary bypass grafting, are unsuitable for many patients, and therefore new approaches are required. The proposed studies will permit us to develop such novel therapeutic approaches, and therefore increase the treatment options for coronary heart disease.
| Doukas, John; Blease, Kate; Craig, Darren et al. (2002) Delivery of FGF genes to wound repair cells enhances arteriogenesis and myogenesis in skeletal muscle. Mol Ther 5:517-27 |
