Development of Vasoactive Therapeutic

描述(由申请人提供)： 在美国，每年大约有30,000名患者患有蛛网膜下腔出血(SAH)。尽管SAH仅占中风的5%-10%，但其影响比例要高得多，因为SAH患者通常比其他中风患者年轻(平均年龄为50岁)。近一半的SAH患者死于SAH引起的血管痉挛引起的初始出血或继发性并发症。唯一被批准用于治疗SAH引起的血管痉挛的药物是钙通道拮抗剂尼莫通(尼莫地平)。尽管尼莫通显著改善了存活患者的预后，但它不会改变血管痉挛的发生率或程度，也不会降低死亡率。因此，有一个重大的临床需求尚未得到满足的药物来解决SAH诱导的血管痉挛。药物血管松弛药激活环核苷酸依赖的信号通路，这些信号通路在小的热休克相关蛋白HSP20的磷酸化处汇聚，在治疗SAH方面基本上无效。我们最近确定SAH诱导的血管痉挛与HSP20的下调有关。这一发现可能解释了为什么药物血管松弛药在治疗SAH诱导的血管痉挛方面无效；下游的蛋白效应分子不能被激活。更重要的是，我们已经确定，蛛网膜下腔出血后24小时鞘内注射一次HSP20磷酸肽类似物，完全抑制血管痉挛。这个二期项目的目标是开发一种基于蛋白质组的治疗药物，通过将内源性松弛蛋白(HSP20)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”)与生物活性分子(“Cargo”)融合，将蛋白质/多肽输送到细胞内。第一阶段项目证明HSP20类似物在体外可以有效地松弛各种物种的平滑肌。这项建议的具体目的是在进入I期临床试验之前在体内对PTD-HSP20类似物进行安全性测试。由于目前还没有有效的药物来治疗SAH诱导的血管痉挛，这种蛋白质组学治疗将具有巨大的治疗潜力。该产品利用“后基因组”平台设计具有生物活性的蛋白质/多肽分子，有可能成为第一个基于蛋白质组的药物。

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.