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

项目主任/首席调查员(最后、第一、中间)：孙妙坤 项目摘要/摘要 记忆障碍和痴呆，包括阿尔茨海默病(AD)，作为全球优先事项的重要性 得到了广泛的认可。许多针对AD病理的化合物已经在临床前开发出来，但 在临床试验中都失败了，主要是因为缺乏治疗效果。 Neurotrope Bioscience Inc.正在开发Bryostatin-1，一种相对选择性的蛋白激酶Cε激活剂，用于 AD的治疗(IND 71,276)。Bryostatin-1结合了一些独特的药理特性， 包括增强脑源性神经营养因子(BDNF)信号通路的激活，突触前 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，和抗炎。重要的是，在适当的剂量下，它已经被发现很好 在临床试验中耐受，并为晚期AD的治疗产生一段时间的疗效 患者在没有美金刚的情况下。然而，目前还不清楚这种治疗益处是否会持续下去。 AD的个人资料非常令人向往，持续数年甚至数十年。这项提议的目的是直接 慢性Bryostatin-1(合成)治疗晚期AD的远期疗效观察 病人。拟议的研究将确定用合成的Bryostatin-1进行为期12周的治疗是否通过 恢复突触功能，增强突触能力以支持认知挑战 对抗AD病理的作用，将有效地产生长期有效的认知改善 晚期阿尔茨海默病患者中。如果治疗效果是短暂的，将进行第二次治疗 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，以促进预防和治疗AD的进展和 其他与AD有关的痴呆症，这是商业开发的必要和重要的IIa阶段试验 广告治疗学。我们预计，这项研究的完成将极大地促进AD治疗的进展 和其他与AD相关的痴呆症，并加快有效疗法的商业化 从而为AD治疗的成功铺平了道路。 OMB编号0925-0001/0002(01/18修订版批准至2020年3月31日)页面续格式页面

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