Hyperlipidemia treatment by RNA interference

描述（由申请人提供）：尽管取得了很大进展，但心血管疾病（CVD），包括高血压、冠心病（CHD）、缺血性脑血管疾病（中风）和外周血管疾病，仍然是美国和其他发达国家成人死亡率和发病率的主要原因。高效降胆固醇药物（他汀类药物）的引入已经清楚地证明了高胆固醇血症和CHD之间的因果关系。尽管染色疗法在医学上取得了巨大的成功，但仍有相当数量的患者遭受毒性，需要停止给药。我们建议开发最近发现的RNA干扰技术来治疗高胆固醇血症。我们还将探讨在脂质代谢途径的其他交界处的干预。发现双链RNA以序列特异性方式强烈抑制基因表达。小（21-25 bp）干扰RNA（siRNA）的应用同样有效、特异，并且避免了非特异性效应（例如，干扰素诱导）。我们最近已经证明，siRNA可以有效地引入体内肝细胞，并用于调节基因表达。在SBIR第一阶段的资助提案中，我们将使用我们的血管内体内递送方法来表征siRNA的活性特征，并探索使用siRNA治疗高血压的可能性。这些实验应该证明使用siRNA用于治疗目的和其他应用如靶验证的可行性。在伴随的第二阶段申请中，我们建议基于Mirus DNA颗粒（人工病毒）技术开发有效的siRNA递送系统。

DESCRIPTION (provided by applicant): Despite much progress, cardiovascular diseases (CVD), which include hypertension, coronary heart disease (CHD), ischemic cerebrovascular disease (strokes) and peripheral vascular disease, remain among the leading causes of mortality and morbidity of adults in the USA and other developed countries. The introduction of highly-effective cholesterol-lowering drugs (statins) have clearly demonstrated a causative relationship between hypercholesterolemia and CHD. Despite the enormous medical success of stain therapy, a significant number of patients suffer toxicity, requiring cessation of drug administration. We propose to develop the recently discover RNA interference technology to treat hypercholesterolemia. We will also explore intervention at other junctures in the lipid metabolism pathway. Double stranded RNA was found to strongly inhibit gene expression in a sequence-specific manner. Application of small (21-25 bp) interfering RNA (siRNA) is equally effective, specific, and avoids the induction of non-specific effects (e.g., interferon induction). We have recently demonstrated that siRNA can be efficiently introduced in liver cells in vivo, and used to modulate gene expression. In this SBIR Phase I grant proposal, we will use our intravascular in vivo delivery methods to characterize the siRNA activity profile and explore the possibilities to use siRNA for the treatment of hyperlipidemias. These experiments should demonstrate the feasibility of using siRNA for therapeutic purposes and in other application such as target validation. In the accompanying Phase II application, we propose to develop efficient siRNA delivery systems, based on Mirus DNA particle (artificial virus) technologies.