Electroporation-Mediated Gene Therapy with IFN-b for MS

电穿孔介导的 IFN-b 基因治疗多发性硬化症

• 批准号: 6950267
• 负责人: CLAIRE Frances EVANS
• 金额: $ 70.39万
• 依托单位: ICHOR MEDICAL SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6950267
• 关键词: biomarker; drug design /synthesis /production; electroporation; gene delivery system; gene expression; gene therapy; interferon beta; intramuscular injections; laboratory mouse; laboratory rat; multiple sclerosis; neutralizing antibody; nonhuman therapy evaluation; swine; technology /technique development

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.

描述（由申请人提供）：多发性硬化症（MS）的最广泛规定的治疗方法是延长治疗，需要经常服用重组干扰素β（IFN-β）。虽然有效地降低了疾病进展和复发性MS患者的恶化率，但该疗法具有重要的局限性，包括高成本，需要重复注射，频繁的副作用以及某些患者中和抗体的发展。编码治疗蛋白的基因序列的肌内递送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，单个管理能够在几个月内提供相对稳定的持续产生蛋白质。该项目的长期目标是开发一种基于基因的IFN-β的方法，可显着降低成本和注入频率，其临床功效和副作用与当前的重组蛋白质疗法相当或更好。在第一阶段，Ichor证明了电穿孔介导的IFN-BETA3基因的肌内递送的基本可行性。该程序在小鼠中引起IFN-β至少3个月的持续表达，而没有毒性的证据。 IFN-β具有生物学活性，如脾脏中IFN-β诱导性生物标志物的显着上调所表明的。值得注意的是，基因转移后IFN-β生物标志物诱导比重组IFN-β给药后明显高。因此，基于基因的递送达到的基因表达的大小和持续时间加上缺乏显着毒性表明，这种方法的进一步研究和发展是有必要的。拟议的第二阶段研究的目的是： 1）开发适合临床使用的IFN-β表达载体； 2）证明IFN-β基因治疗抑制了MS的动物模型Mirine Eae的进展，就像重组IFN-BETA一样有效。 3）证明IFN-β基因转移可以缩放到大鼠和猪，并建立临床剂量水平，并且 4）评估通过肌内基因转移与治疗蛋白递送有关的特定安全/毒理学问题。这些研究将奠定正式安全/毒理学评估和I期人类研究的阶段，最终目的是为MS提供有效的基于基因的IFN-β疗法。