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）：与动脉粥样硬化有关的心血管疾病对人类的生活造成了巨大损失，并且负责美国的主要医疗保健费用，尽管他汀类药物疗法的出现降低了冠心病死亡的风险，而胆固醇降低和免疫疾病均导致了这一乡村死亡。因此，对于能够改变促进动脉粥样硬化的基本生化和细胞事件的新干预措施的迫切需要。重组干扰素-BETA（IFN-BETA）是一种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患者（MS）。根据其所谓的多发性硬化症（MS）的作用机制，IFN-BETA似乎具有抗动脉粥样硬化剂的希望。在初步研究中，重组IFN-β被证明可降低动脉粥样硬化小鼠模型中主动脉病变的大小和炎症。但是，与重组IFN-β蛋白质疗法相关的高成本，频繁的副作用和不便的给药时间表可能排除其在心血管疾病环境中的广泛使用。为了实现IFN-β疗法在动脉粥样硬化中的潜在益处，该提案将根据电穿孔（EP）介导的质粒内传递的替代方法来评估编码IFN-BETA基因的质粒DNA的肌肉内转移。提出的基于DNA的IFN-β产物作为动脉粥样硬化的治疗方法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，这些研究的第一个目的将评估基于EP介导的基因IFN-β疗法在动脉粥样硬化的小鼠模型中减弱斑块形成的能力。对于成功的产品，有必要证明基于基因的IFN-β和常规他汀类药物疗法的组合仅优于他汀类药物疗法。这将在第二个目标中解决。此外，这些研究将表征与基于基因的IFN-β给药相关的任何不良事件，无论是单独还是与他汀类药物疗法结合使用。如果功效和初始安全性研究表明，基于基因的IFN-β疗法可用于动脉粥样硬化，则将完成进一步的非临床测试，并在SBIR II期中启动I期人类临床研究。 动脉粥样硬化是一种慢性炎症过程，发生在心血管系统内，导致动脉壁增厚，并形成限制血液流动的斑块。动脉粥样硬化与心血管疾病的所有死亡人数中的近75％有关，并且非常需要新的疗法会减缓其进展。拟议的研究将评估基于基因的干扰素β疗法对动脉粥样硬化的潜力，因此将解决当前医疗服务中非常关键的需求。