Electroporation-Mediated Gene Therapy with IFN-b for MS

描述（由申请人提供）：多发性硬化症（MS）最广泛的处方治疗是需要频繁给药重组干扰素- β (ifn - β)的长期治疗。虽然在减少复发性MS患者的疾病进展和恶化率方面有效，但该疗法有重要的局限性，包括成本高、需要反复注射、副作用频繁以及在一些患者中产生中和抗体。肌肉内递送编码治疗性蛋白质的基因序列是直接给药蛋白质本身的潜在替代方法。基于基因的方法的主要好处是，单次给药能够在几个月内提供相对稳定、持续的蛋白质生产。该项目的长期目标是开发一种基于基因的ifn - β递送方法，显著降低成本和注射频率，临床疗效和副作用与目前的重组蛋白疗法相当或更好。在I期研究中，Ichor证明了电穿孔介导的ifn - β 3基因肌内递送的基本可行性。该过程在小鼠中诱导ifn - β持续表达至少3个月，无毒性证据。脾脏中ifn - β诱导的生物标志物显著上调表明，ifn - β具有生物活性。值得注意的是，基因转移后ifn - β生物标志物的诱导率明显高于重组ifn - β给药后。因此，这种基于基因的递送所实现的基因表达的规模和持续时间，加上缺乏显著的毒性，表明这种方法的进一步研究和发展是有必要的。拟议第II期研究的目的是：

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: 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.