Electroporation-mediated Gene-based Interferon-beta

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的生命造成了巨大的损失，并且是美国医疗保健费用的主要部分。尽管他汀类药物的出现通过降低胆固醇和免疫调节作用降低了冠心病的死亡风险，但心脏病仍然是美国的主要死亡原因。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)是一种获得批准的免疫调节药物，具有良好的安全记录，已被用于安全治疗数千名多发性硬化症（MS）患者。基于其在多发性硬化症（MS）治疗中的作用机制，ifn - β似乎有望成为一种抗动脉粥样硬化药物。在初步研究中，重组ifn - β被证明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蛋白治疗相关的高成本、频繁的副作用和不方便的给药计划可能阻碍了其在心血管疾病中的广泛应用。为了实现ifn - β治疗动脉粥样硬化的潜在益处，本提案将评估一种基于电穿孔（EP）介导的编码ifn - β基因的质粒DNA肌内转移的替代递送方法。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，这些研究的第一个目的是评估ep介导的基于基因的ifn - β治疗在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和传统他汀类药物治疗的组合优于单独他汀类药物治疗；这将在第二个目标中讨论。此外，这些研究将描述与基于基因的ifn - β给药相关的任何不良事件，无论是单独使用还是与他汀类药物联合使用。如果有效性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，将完成进一步的非临床试验，并将在SBIR II期启动I期人体临床研究。

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.