Selection & Optimization of a Therapeutic Protein for Acute Ischemic Stroke Functional Recovery

项目总结/摘要 中风是导致严重长期残疾的主要原因。年发病率约为80万， 美国，全球1700万。只有10%的中风幸存者恢复完全正常的功能和活动。 在美国，超过720万人在中风中幸存下来，但继续生活在其衰弱的影响中。 百分之八十七（87%）的中风是缺血性的（由于缺乏血液供应而造成的损害）。 大脑的特定区域）。据估计，大约百分之五十的缺血性中风的结果， 紧急大血管闭塞（ELVO），大脑主要动脉急性阻塞。 作为治疗性临床试验的初始靶点，该卒中亚组特别有吸引力，因为 患者人群和疾病表现更加同质，目前的治疗模式是 这是一个公认的，受益的潜力是最大的，因为ELVO会导致最严重和致残的 中风的类型 Stream Biomedical正在商业化一种治疗性蛋白质，重组人串珠素结构域V (rDV)，在小动物中已被证明具有显着的神经保护和神经修复作用 （血管生成性和神经源性），急性给药时可显著改善功能 在缺血性中风之后。最初的目标治疗适应症是治疗急性缺血性卒中 临床目的是改善卒中后的功能结局。 本翻译提案的发展目标是进行研究，以确定 优选rDV或其片段rLG 3作为治疗候选物，以开发和定义优选的 可扩展的重组微生物生产工艺，并对铅进行IND研究 蛋白质/工艺候选物，包括蛋白质表征、剂量范围确定、药效学， 安全药理学和毒理学。

Project Summary/Abstract Stroke is a leading cause of serious long term disability. Annual incidence is approximately 800,000 in the US, and 17,000,000 worldwide. Only 10% of stroke survivors return to full normal function and activity. Over 7.2 million people in the US have survived a stroke, but continue to live with its debilitating effects. Eighty-seven percent (87%) of strokes are ischemic (damage resulting from lack of blood supply to a particular region of the brain). It is estimated that approximately fifty percent of ischemic strokes results from Emergent Large Vessel Occlusions (ELVOs), with an acute blockage of a main artery in the brain. This subgroup of stroke is particularly attractive as an initial target for therapeutic clinical trials, as the patient population and disease presentation is more homogenous, the current therapeutic paradigm is well-established, and the potential for benefit is greatest as ELVO causes the most severe and disabling type of stroke. Stream Biomedical is commercializing a therapeutic protein, recombinant human perlecan domain V (rDV), which has been shown in small animals to be significantly neuroprotective and neuroreparative (angiogenic and neurogenic), resulting in dramatic functional improvement when administered acutely after ischemic stroke. The initial target therapeutic indication is for the treatment of acute ischemic stroke resulting from ELVO, and the clinical objective is to improve functional outcomes post-stroke. The development objectives of this translational proposal are to conduct studies to determine a preference for rDV or its fragment rLG3 as the therapeutic candidate, to develop and define a preferred scalable recombinant microbial production process and conduct IND-enabling studies of the lead protein/process candidate including protein characterization, dose-range finding, pharmacodynamics, safety pharmacology and toxicology.