HYALURONAN SYNTHASE GENE TRANSFER TO PREVENT RESTENOSIS

DESCRIPTION (Verbatim From Applicant's Abstract): Stent implantation markedly reduces the observed frequency of restenosis (a phenomenon of cell proliferation after coronary angioplasty). However, in-stent restenosis is more difficult to treat than post angioplasty restenosis. No systemic pharmacological treatment has hitherto been shown to convincingly reduce the restenosis incidence in patients. It has been observed in animal studies that saturation of RHAMM and CD44 receptors by hyaluronan significantly reduces neointimal formation without cellular destruction. The applicant proposes to investigate the feasibility of using a biodegradable, biocompatible and nonthrombogenic hyaluronic acid hydrogel (HA)(crosslinked and rendered insoluble), as a metallic stent coating, for sustained transfer of plasmid DNA encoding a hyaluronan synthase gene (HASyn). This HA hydrogei will be gradually hydrolyzed, releasing HA and thus the therapeutic gene into the surrounding environment. Steady transfer of the HASyn gene to the arterial wall and the subsequent expression will theoretically sustain the high localized HA concentration. In this Phase I program, we will initially optimize the in vitro DNA release characteristics of the HA stent coating and study the longevity of its gene transfer in A10 (aortic smooth muscle cell) culture. The program will be concluded by a pilot scale efficacy study in a porcine coronary model to assess the efficiency of gene transfer and the potential for inhibition of neointimal formation following stent implantation. PROPOSED COMMERCIAL APPLICATION: In-stent restenosis have significant socioeconomic impact. Almost all the gene delivery stents currently under investigation target the destruction of proliferating smooth muscle cells. This Phase I application is to demonstrate the feasibility of using a biodegradable hydrogel metallic stent coating as a new sustained delivery therapeutic modality for delivering a therapeutic gene NOT targeting the destruction of proliferating cells (a distinct contrast to other gene delivery stents under investigation). Promising results obtained will expand this study into Phase II and thereafter clinical trial. This could result in a gene therapy stent with a unique and nondestruction mode of action.