Long-term therapeutic effects of synthetic bryostatin-1 in advanced AD without memantine

项目负责人/主要研究者（末、首、中）：孙妙昆 项目总结/摘要 记忆障碍和痴呆症，包括阿尔茨海默病（AD），作为全球优先事项的重要性 得到了很好的认可。许多靶向AD病理的化合物已经在临床前开发， 在临床试验中失败，主要是因为缺乏治疗效果。 Neurotrope生物科学公司正在开发苔藓抑素-1，一种相对选择性的蛋白激酶Cε激活剂， AD的治疗（IND 71，276）。苔藓抑素-1具有一些独特的药理学特性， 包括增强脑源性神经营养因子（BDNF）信号通路的激活， 重塑，促突触发生，促突触成熟，抗凋亡，抗A β寡聚体，抗 过度磷酸化的tau蛋白和抗炎。重要的是，在适当的剂量下， 在临床试验中耐受，并产生一段时间的治疗晚期AD的疗效 没有美金刚的病人然而，目前尚不清楚这种治疗效果是否会持续， 对于持续数年甚至数十年的AD来说，轮廓是非常理想的。该提案的目的是直接 测试慢性苔藓抑素-1（合成）治疗晚期AD的长期治疗益处 患者这项拟议的研究将确定12周的合成苔藓抑素-1治疗， 恢复突触功能并增强突触能力，以支持认知挑战， 抗AD病理学的作用，将有效地产生长期和有效的改善认知 晚期AD患者中。如果治疗效果是短暂的，第二次治疗将适用于 在第一个12周治疗结束后逆转认知能力下降。临床试验研究完全是 用于开发创新疗法，可促进预防和治疗AD的进展， 其他AD相关痴呆，这是商业开发的必要和重要的IIa期试验， AD治疗。我们预计，这项研究的完成将大大促进治疗AD的进展 和其他AD相关痴呆症，并加快有效治疗药物的商业化， 市场，从而为AD治疗的成功结果铺平了道路。 OMB编号0925-0001/0002（2018年1月批准至2020年3月31日修订版）页码续页格式页码

Program Director/Principal Investigator (Last, First, Middle): Miao-Kun Sun Project Summary/Abstract The importance of memory impairment and dementias, including Alzheimer’s disease (AD), as a global priority has been well recognized. Many compounds that target AD pathologies have been developed preclinically but have failed in clinical trials, mostly for the lack of therapeutic efficacies. Neurotrope Bioscience Inc. is developing bryostatin-1, a relatively selective protein kinase Cε activator, for the treatment of AD (IND 71,276). Bryostatin-1 has a combination of some unique pharmacological profiles, including enhancing activation of the brain-derived neurotrophic factor (BDNF) signaling pathways, pro-synaptic remodeling, pro-synaptogenesis, pro-synaptic maturation, anti-apoptosis, anti-Aβ oligomers, anti- hyperphosphorylated tau, and anti-inflammatory. Importantly, at appropriate doses, it has been found well tolerated in clinical trials and to produce a period of therapeutic efficacy for the treatment of the advanced AD patients in the absence of memantine. It is not clear, however, whether the therapeutic benefit would last, a profile highly desirable for AD, which lasts years and even decades. The objective of this proposal is to directly test the long-term therapeutic benefit of the chronic bryostatin-1 (synthetic) treatment for the advanced AD patients. The proposed study will establish whether a 12-week treatment with synthetic bryostatin-1, through restoring synaptic functions and enhancing synaptic capacity in supporting cognitive challenges in addition to actions of anti-AD pathologies, will effectively produce long-term and effective improvements in cognition of the advanced AD patients. If the therapeutic effect is short-lived, a second treatment will be applied to reverse the cognitive decline after the end of the first 12-week treatment. The clinical trial research is entirely for the development of innovative therapeutics that may advance progress in preventing and treating AD and other AD-related dementias, a necessary and important phase IIa trial for the commercial development of AD therapeutics. We anticipate that completion of this study would greatly facilitate progress in treating AD and other AD-related dementias and speed-up the commercialization of the effective therapeutics into market, thus paving the road toward successful outcomes in AD therapy. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page