Development of Vasoactive Therapeutic

描述（由申请人提供）： 美国每年约有30，000名患者患有蛛网膜下腔出血（SAH）。虽然SAH仅占卒中的5-10%，但其影响比例要高得多，因为SAH患者通常比其他卒中患者更年轻（平均年龄为50岁）。近一半的SAH患者死于初始出血或由SAH诱导的血管痉挛引起的继发性并发症。唯一批准用于治疗蛛网膜下腔出血引起的血管痉挛的药物是钙通道拮抗剂尼莫通（尼莫地平）。尽管尼莫通能显著改善存活患者的预后，但它不能改变血管痉挛的发生率或程度，也不能降低死亡率。因此，对于治疗SAH诱导的血管痉挛的药剂存在显著未满足的临床需求。药理学血管舒张药，激活环核苷酸依赖的信号通路，集中在磷酸化的小热休克相关蛋白HSP 20是在很大程度上无效的治疗SAH。我们最近发现，蛛网膜下腔出血诱导的血管痉挛与HSP 20的下调有关。这一发现可以解释为什么药理学血管舒张剂在治疗蛛网膜下腔出血诱导的血管痉挛中无效;下游蛋白效应分子不能被激活。更重要的是，我们已经确定，SAH后24小时单次鞘内注射HSP 20磷酸肽类似物可以完全抑制血管痉挛。该II期项目的目标是商业化开发一种基于蛋白质组学的治疗药物，通过将内源性松弛蛋白（HSP 20）的类似物直接注射到脑脊液中来预防SAH诱导的血管痉挛。基于蛋白质组学的方法通过将蛋白质转导结构域（PTD，“载体”）融合到生物活性分子（“货物”）来将蛋白质/肽递送到细胞中。I期项目证明了HSP 20类似物在体外有效地松弛来自多种物种的平滑肌。该提案的具体目的是在进入I期临床试验之前进行体内PTD-HSP 20类似物的安全性测试。由于目前没有有效的药物用于治疗蛛网膜下腔出血诱导的血管痉挛，这种蛋白质组学治疗将具有显着的治疗潜力。该产品利用“后基因组”平台来工程化生物活性蛋白质/肽分子，并有可能成为第一个基于蛋白质组学的药物。

DESCRIPTION (provided by applicant): Approximately 30,000 patients per year in the US suffer from subarachnoid hemorrhage (SAH). Although SAH represents only 5-10% of strokes, its impact is proportionally much higher because SAH patients are typically younger (mean age is 50 years) than other stroke patients. Nearly half of SAH patients die from either the initial hemorrhage or secondary complications that are caused by SAH-induced vasospasm. The only approved pharmaceutical for SAH-induced vasospasm is the calcium channel antagonist Nimotop (nimodipine). Although Nimotop significantly improves the outcome of surviving patients, it does not alter the incidence or magnitude of vasospasm and does not decrease mortality. Thus, there is a significant unmet clinical need for an agent to address SAH-induced vasospasm. Pharmacologic vasorelaxants, which activate cyclic nucleotide-dependent signaling pathways that converge at the phosphorylation of the small heat shock-related protein HSP20 are largely ineffective for treating SAH. We have recently determined that SAH-induced vasospasm is associated with down regulation of HSP20. This finding may explain why pharmacological vasorelaxants are ineffective in the treatment of SAH-induced vasospasm; the downstream protein effector molecule is not available to be activated. More importantly, we have determined that a single intrathecal injection of the HSP20 phosphopeptide analogue, 24 hours after the SAH, completely inhibits vasospasm. The goal of this Phase II project is to commercially develop a proteomic-based therapeutic to prevent SAH-induced vasospasm by directly injecting analogs of an endogenous relaxing protein (HSP20) in to the cerebrospinal fluid. Proteomic-based approaches deliver proteins/peptides into cells by fusing protein transduction domains (PTDs, "carriers") to biologically active molecules ("cargo"). The Phase I project demonstrated that HSP20 analogs are effective at relaxing smooth muscle from a variety of species in vitro. The specific aims of this proposal are to conduct safety testing of PTD-HSP20 analogs in vivo prior to advancement into phase I clinical trials. Since there is currently no effective agent for the treatment of SAH-induced vasospasm, this proteomic treatment would have significant therapeutic potential. This product utilizes a "post-genomic" platform for engineering biologically active protein/peptide molecules and has the potential to be the first proteomic-based pharmaceutical.