Electroporation-mediated Gene-based Interferon-beta

电穿孔介导的基因干扰素-β

• 批准号: 7154249
• 负责人: CLAIRE Frances EVANS
• 金额: $ 13.4万
• 依托单位: ICHOR MEDICAL SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154249
• 关键词: CD40 molecule; antihypercholesterolemic agent; apolipoprotein E; atherosclerosis; atherosclerotic plaque; biotechnology; cardiovascular disorder prevention; combination therapy; disease /disorder model; dosage; electroporation; gene delivery system; gene therapy; genetically modified animals; immunomodulators; inflammation; interferon beta; intramuscular injections; laboratory mouse; metalloendopeptidases; nonhuman therapy evaluation; recombinant proteins; therapy adverse effect; therapy design /development; transforming growth factors

DESCRIPTION (provided by applicant): Cardiovascular disease associated with atherosclerosis takes an enormous toll on human life and is responsible for a major portion of health care costs in the U.S. Although the advent of statin therapies has reduced the risk of mortality from coronary heart disease through both cholesterol-lowering and immunomodulatory effects, heart disease remains a major cause of death in this country. Thus, there is a critical need for new interventions capable of altering the underlying biochemical and cellular events that promote atherosclerosis. Recombinant interferon-beta (IFN-beta) is an approved immunomodulatory drug with an excellent safety record that has been used to safely treat thousands of patients with multiple sclerosis (MS). Based on its purported mechanisms of action in the treatment of multiple sclerosis (MS), IFN-beta appears to have promise as an anti-atherosclerotic agent. In preliminary studies, recombinant IFN-beta was shown to reduce aortic lesion size and inflammation in a mouse model of atherosclerosis. However, the high cost, frequent side effects, and inconvenient administration schedule associated with recombinant IFN-beta protein therapy is likely to preclude its widespread use in the cardiovascular disease setting. In order to realize the potential benefits of IFN-beta therapy in atherosclerosis, this proposal will evaluate an alternative method of delivery based on electroporation (EP)-mediated intramuscular transfer of plasmid DNA encoding the IFN-beta gene. The basic feasibility of the proposed DNA-based IFN-beta product as a treatment for atherosclerosis is dependent on demonstrating that gene-based IFN-beta delivery is capable of reducing the severity of atherosclerosis. Thus, the first aim of these studies will evaluate the ability of EP-mediated gene-based IFN-beta therapy to attenuate plaque formation in a well characterized mouse model of atherosclerosis. For a successful product, it will be necessary to demonstrate that the combination of gene-based IFN-beta and conventional statin therapy are superior to statin therapy alone; this will be addressed in the second Aim. Additionally, these studies will characterize any adverse events associated with gene-based IFN-beta administration, either alone or in combination with statin therapy. If efficacy and initial safety studies indicate that a gene-based IFN-beta therapy for atherosclerosis is feasible, further non-clinical testing will be completed and a Phase I human clinical study will be initiated in SBIR Phase II. Atherosclerosis is a chronic inflammatory process that occurs within the cardiovascular system and leads to a thickening of artery walls and the formation of plaques that restrict blood flow. Atherosclerosis is linked to nearly 75% of all deaths from cardiovascular diseases, and there is a great need for new therapies that will slow its progression. The proposed studies will evaluate the potential of a gene-based interferon-beta therapy for atherosclerosis, and thus will address a very critical need in current medical care.

描述（由申请人提供）：与动脉粥样硬化相关的心血管疾病对人类生命造成巨大损失，并且占美国医疗保健费用的很大一部分。尽管他汀类药物疗法的出现通过以下方式降低了冠心病的死亡风险：由于具有降低胆固醇和免疫调节作用，心脏病仍然是这个国家的主要死亡原因。因此，迫切需要能够改变促进动脉粥样硬化的潜在生化和细胞事件的新干预措施。重组干扰素-β (IFN-β) 是一种经批准的免疫调节药物，具有出色的安全记录，已用于安全治疗数千名多发性硬化症 (MS) 患者。根据其据称治疗多发性硬化症 (MS) 的作用机制，IFN-β 似乎有望成为一种抗动脉粥样硬化药物。初步研究表明，重组 IFN-β 可以减少动脉粥样硬化小鼠模型的主动脉病变大小和炎症。然而，与重组 IFN-β 蛋白疗法相关的高成本、频繁的副作用和不方便的给药方案可能会阻碍其在心血管疾病领域的广泛应用。为了实现 IFN-β 疗法在动脉粥样硬化中的潜在益处，该提案将评估基于电穿孔 (EP) 介导的编码 IFN-β 基因的质粒 DNA 肌肉内转移的替代递送方法。所提出的基于 DNA 的 IFN-β 产品作为动脉粥样硬化治疗的基本可行性取决于证明基于基因的 IFN-β 递送能够降低动脉粥样硬化的严重程度。因此，这些研究的首要目标是评估 EP 介导的基于基因的 IFN-β 疗法在特征明确的动脉粥样硬化小鼠模型中减轻斑块形成的能力。对于一个成功的产品，有必要证明基于基因的 IFN-β 和传统他汀类药物疗法的组合优于单独的他汀类药物疗法；这将在第二个目标中得到解决。此外，这些研究将描述与基于基因的 IFN-β 给药（单独或与他汀类药物联合治疗）相关的任何不良事件的特征。如果功效和初步安全性研究表明基于基因的 IFN-β 治疗动脉粥样硬化是可行的，则将完成进一步的非临床测试，并在 SBIR II 期中启动 I 期人体临床研究。 动脉粥样硬化是一种发生在心血管系统内的慢性炎症过程，会导致动脉壁增厚并形成限制血流的斑块。近 75% 的心血管疾病死亡与动脉粥样硬化有关，因此非常需要新的疗法来减缓其进展。拟议的研究将评估基于基因的干扰素β疗法治疗动脉粥样硬化的潜力，从而解决当前医疗保健中非常关键的需求。