Research Project
6950267
[unreadable] DESCRIPTION (provided by applicant): The most widely prescribed treatment for multiple sclerosis (MS) is prolonged therapy requiring frequent administration of recombinant interferon-beta (IFN-beta). While effective in reducing disease progression and exacerbation rate in relapsing MS patients, the therapy has important limitations including high cost, need for repeated injections, frequent side effects, and development of neutralizing antibodies in some patients. The intramuscular delivery of gene sequences encoding therapeutic proteins is a potential alternate approach to direct administration of the protein itself. The principle benefit of a gene-based approach is that a single administration is capable of providing relatively stable, sustained production of the protein for several months. The long-term goal of this project is to develop a gene-based method for delivery of IFN-beta that significantly reduces both the cost and injection frequency, with clinical efficacy and side effects comparable to or better than the current recombinant protein therapies. In Phase I, Ichor demonstrated the basic feasibility of electroporation mediated intramuscular delivery of the IFN-beta3 gene. The procedure induced sustained expression of IFN-beta in mice for at least 3 months with no evidence of toxicity. The IFN-beta was biologically active as indicated by significant upregulation of an IFN-beta inducible biomarker in spleen. Notably, IFN-beta biomarker induction was significantly higher following gene transfer than after recombinant IFN-beta administration. Thus, the magnitude and duration of gene expression achieved with this gene based delivery plus the lack of significant toxicity indicate that further investigation and development of this approach is warranted. The aims of the proposed Phase II studies are to: [unreadable] 1) Develop an IFN-beta expression vector appropriate for clinical use; 2) Demonstrate that IFN-beta gene therapy inhibits the progression of murine EAE, an animal model of MS, as effectively as recombinant IFN-beta; 3) Demonstrate that IFN-beta gene transfer can be scaled up to rats and pigs and establish clinical dosage levels, and 4) Evaluate specific safety/toxicology issues relevant to therapeutic protein delivery via intramuscular gene transfer. These studies will set the stage for formal safety/toxicology evaluations and Phase I human studies, with the ultimate goal of providing an effective gene-based IFN-beta therapy for MS. [unreadable] [unreadable]
