Electroporation-Mediated Gene Therapy with IFN-b for MS

描述（由申请人提供）：多发性硬化症（MS）的最广泛处方治疗是需要频繁给予重组干扰素-β（IFN-β）的长期治疗。虽然在复发性MS患者中有效降低疾病进展和恶化率，但该疗法具有重要的局限性，包括高成本、需要重复注射、频繁的副作用和在一些患者中产生中和抗体。肌内递送编码治疗性蛋白质的基因序列是直接施用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，单次给药能够提供相对稳定的，持续数月的蛋白质生产。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，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。该程序诱导小鼠中IFN-β的持续表达至少3个月，没有毒性证据。IFN-β具有生物活性，如脾中IFN-β诱导型生物标志物的显著上调所示。值得注意的是，基因转移后IFN-β生物标志物诱导显著高于重组IFN-β给药后。因此，用这种基于基因的递送实现的基因表达的幅度和持续时间加上缺乏显著的毒性表明，有必要对这种方法进行进一步的研究和开发。拟议的第二阶段研究的目的是： 1)开发适合于临床使用的IFN-β表达载体; 2)证明IFN-β基因治疗与重组IFN-β一样有效地抑制小鼠EAE（MS的动物模型）的进展; 3)证明IFN-β基因转移可以扩大到大鼠和猪，并建立临床剂量水平， 4)评价与通过肌内基因转移递送治疗性蛋白质相关的特定安全性/毒理学问题。这些研究将为正式的安全性/毒理学评估和I期人体研究奠定基础，最终目标是为MS提供有效的基于基因的IFN-β治疗。

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.