Alzheimer's Disease Therapeutic

阿尔茨海默病治疗

• 批准号: 8323257
• 负责人: TREVOR P. CASTOR
• 金额: $ 118.35万
• 依托单位: APHIOS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323257
• 关键词: Adverse effects; Affect; Agitation; Alzheimer' s Disease; American; Americas; Amyloid beta-Protein; Animal Model; Antineoplastic Agents; Behavioral; Bioavailable; Biological Assay; Biological Availability; Bladder Control; Brain; California; Cancer Patient; Capital; Cause of Death; Cells; Cerebral cortex; Cessation of life; Characteristics; Clinical Trials; Cognition Disorders; Cognitive; Complex; Cyclic GMP; Defecation; Demographic Aging; Development; Diagnosis; Disease; Disease Progression; Down-Regulation; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Emotional; Engineering; Europe; Face; Fibroblasts; Frequencies; Functional disorder; Generations; Hippocampus (Brain); Human; Humidity; Impaired cognition; In Vitro; Institutes; Japan; Judgment; Laboratories; Language; Lead; Learning; Legal patent; Macrolides; Marketing; Measures; Medical; Memory; Methodology; Methods; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mosses; Nanotechnology; Nausea; Neurons; Neurosciences; Oils; Oral; Outcome; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Phosphorylation; Plasma; Polymers; Population; Preventive; Product R; Protein Kinase C; Quality of life; Radioactive; Research Institute; Research Personnel; Running; Scientist; Sea; Senile Plaques; Series; Short-Term Memory; Staging; Symptoms; Temperature; Therapeutic; Time; Toxicology; Transgenic Mice; United States; Vomiting; Wild Type Mouse; base; behavior change; brain tissue; bryostatin; chemotherapy; commercialization; cost; demographics; design; dosage; good laboratory practice; improved; in vivo; manufacturing process; meetings; membrane activity; nanoparticle; nervous system disorder; neuroprotection; novel; novel therapeutics; pre-clinical; preclinical study; premature; product development; research and development; shogaol; stability testing

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is a significant neurological disorder that afflicts more than 4.5 million Americans and more than 10 million people worldwide. The lack of a cure for AD will result in a demand for better and safer AD drugs. All of the drugs on the market today have serious side effects. Recently, researchers at The Blanchette Rockefeller Neurosciences Institute, Rockville, MD have hypothesized and shown that protein kinase C (PKC) and its activation are important means of ameliorating AD pathophysiology and cognitive impairment. They have shown that sub-nanomolar concentrations of bryostatin 1, a potent PKC activator, dramatically enhance the generation of non-amyloidogenic soluble amyloid precursor protein (sAPP) in fibroblasts from AD patients. Bryostatin 1 was effective in reducing brain amyloid plaques (A240 and A242 in AD) in double-transgenic mice while improving behavioral outcomes and the rate of premature death. These researchers have also shown that bryostatin 1 not only produces a neuroprotective effect but also enhances cognitive memory in AD animal models. Bryostatin 1 is a complex cyclic macrolide molecule that occurs in very small concentrations (~ 5 to 25 ppm) in a bryozoan, sometimes referred to as a "sea moss" found off the coast in Southern California. Bryostatin 1 is also more hydrophobic than paclitaxel, the potent anticancer drug with well-known formulation difficulties. Aphios has developed and patented improved methodologies and manufacturing processes for cost-effectively isolating pharmaceutical-grade bryostatin 1 from Bugula neritina. Our scientists and engineers have also developed methods for formulating hydrophobic molecules such as bryostatin 1 in stable, readily bioavailable oil-based formulations, and novel nanotechnology formulations of bryostatin 1 that will further improve oral bioavailability. Aphios' Zindol(R) product, which contains oil soluble gingerols and shogaols, recently completed a successful Phase II/III clinical trial for nausea and emesis in cancer patients undergoing chemotherapy. Our Phase I Specific Aims are to: (1) Develop conventional and nanotechnology oral formulations of bryostatin 1; and (2) Test stability of selected formulations under accelerated conditions of temperature and humidity, and evaluate in vitro characteristics and in vivo efficacy. We have set three milestones to be achieved before moving on to Phase II. Our Phase I milestones are as follows: stable lyophilized and/or oil-based nanoparticles formulation of bryostatin-1 in the size range of 100 to 200 nm range containing 1 to 10 5g/mL bryostatin 1 with a drug:polymer ratios of 1:10 to 1:100; brief (5-15 minutes), low dosages (0.04-0.2 nM) and application frequencies 1-2 x /week will provide maximal PKC activation and minimal downregulation; and 30% to 50% enhancement of learning and memory in the wild type of mice and even greater enhancement in the transgenic mice due to neuroprotection. Our Phase II Specific Aims are as follows: (1) Specific Aim 1: For selected formulations, radioactive bryostatin 1 will be assayed to determine the pharmacokinetics and tissue distribution. Pharmacologic efficacy will also be measured, particularly in the brain and plasma compartments by total PKC activity, membrane/cytosolic PKC activity ratios, and phosphorylation of ERK 1/2 MAP Kinase; and (2) Specific Aim 2: Establish cGMP manufacturing of the bryostatin 1 API (active pharmaceutical ingredient) and FDP (final or formulated drug product) at the pilot-scale level. Establish a Drug Master File, design IND-enabling preclinical studies and Phase I/II clinical trials, and draft IND package: In a Phase III commercialization effort, we will conduct IND-enabling preclinical in vivo studies, including toxicology, efficacy, pharmacology and stability testing of selected formulation of bryostatin 1 drug product under Good Laboratory Practices (GLP) conditions. These studies will be conducted by a CRO such as Southern Research Institute or Covance Laboratories. As part of our commercialization effort, Aphios Corporation will also establish a wholly owned subsidiary Amylon Pharmaceuticals to focus on the discovery and development of novel therapeutics for Alzheimer's Disease and Cognitive Disorders with bryostatin-1 as its lead compound. Amylon Pharmaceuticals will raise a Series A round of $20 million USD in equity capital to accelerate the development of bryostatin 1 for Alzheimer's Disease and Cognitive Disorders. This capital will be utilized to: (i) establish a management and product development team; (ii) conduct Phase I human clinical trials; (iii) research and development of second- generation products; and (iv) manufacture cGMP products over a two-year period. Within 12 months of the Series A raise, Amylon plans to initiate the establishment of a $25 million USD Series B round to conduct Phase II clinical trials in year 3. Later, Amylon plans to do an IPO to raise $100 million to conduct Phase III clinical trials and commercialize bryostatin 1 for Alzheimer's Disease and Cognitive Disorders. Alternatively, at this stage, Amylon will merge with a mid-tier public company or be acquired by a multinational pharmaceutical company.

描述（由申请人提供）：阿尔茨海默氏病（AD）是一种严重的神经系统疾病，在全球范围内折磨超过450万美国人，超过1000万人。缺乏AD治疗将导致人们对更好，更安全的广告药物的需求。当今市场上的所有药物都有严重的副作用。最近，马里兰州罗克维尔的Blanchette洛克菲勒神经科学研究所的研究人员假设并表明蛋白激酶C（PKC）及其激活是改善AD AD病理生理学和认知障碍的重要手段。他们已经表明，在AD患者的成纤维细胞中，在有效的PKC激活剂中，亚纳摩尔浓度（一种有效的PKC激活剂）显着增强了非淀粉样蛋白生殖可溶性淀粉样蛋白前体蛋白（SAPP）的产生。 Bryostatin 1可在双重转基因小鼠中有效地减少脑淀粉样蛋白斑块（A240和A242），同时改善行为结果和过早死亡的速度。这些研究人员还表明，Bryostatin 1不仅产生神经保护作用，而且还可以增强AD动物模型的认知记忆。 Bryostatin 1是一种复杂的环状大环内酯分子，在一个浓浓度（〜5至25 ppm）中发生，有时被称为在南加州海岸发现的“海苔藓”。 Bryostatin 1也比Paclitaxel（具有众所周知的配方困难的有效抗癌药物）更疏水。 Aphios已开发并获得了改进的方法和制造过程，用于从Bugula Neritina将药物级的Bryostatin 1隔离。我们的科学家和工程师还开发了制定疏水分子的方法，例如在稳定的，易于生物利用的油基配方中，以及新颖的Bryostatin 1中的新型纳米技术配方，这些方法将进一步改善口服生物可利用性。 Aphios的Zindol（R）产品中包含油的生姜和Shogaols，最近完成了一项成功的II/III期临床试验，用于进行化学疗法的癌症患者中的恶心和发酵性。我们的I阶段特定目的是：（1）开发Bryostatin 1的常规和纳米技术口服配方； （2）在温度和湿度的加速条件下，选定制剂的测试稳定性，并评估体外特征和体内功效。在进行第二阶段之前，我们已经设定了三个里程碑。我们的I阶段里程碑如下：稳定的冻干和/或油性纳米颗粒在100至200 nm范围内的Bryostatin-1公式，含有1至10 5G/ml Bryostatin 1含药物：聚合物比率为1:10至1：100;简短（5-15分钟），低剂量（0.04-0.2 nm）和应用频率1-2 x /周将提供最大的PKC激活和最小的下调；在野生类型的小鼠中学习和记忆的增强30％至50％，由于神经保护作用，转基因小鼠的增强。我们的II期特异性目的如下：（1）特定目标1：对于选定的配方，将分析放射性乳头状胺1以确定药代动力学和组织分布。还将测量药理学疗效，尤其是在大脑和血浆室中，通过总PKC活性，膜/胞质PKC活性比以及ERK 1/2 MAP激酶的磷酸化； （2）具体目标2：在试验级级别上建立Bryostatin 1 API（活性药物成分）和FDP（最终或配方药物）的CGMP生产。建立一个药物主文件，设计成能源的临床前研究和I/II期临床试验，以及IND包装：在第三阶段的商业化工作中，我们将进行体内研究，包括毒理学，功效，药理学和稳定性测试Bryostatin 1药物在良好的实验室实践（GLP PP）条件（GLP PP）中。这些研究将由CRO（例如南方研究所或Covance实验室）进行。作为我们商业化工作的一部分，Aphios Corporation还将建立一个全资子公司Amylon Pharmaceuticals，专注于以Bryostatin-1作为其铅化合物的发现和开发阿尔茨海默氏病的新型治疗剂和认知障碍。 Amylon Pharmaceuticals将筹集一系列2000万美元的股本资本，以加速阿尔茨海默氏病和认知疾病的Bryostatin 1的发展。该资本将用于：（i）建立管理和产品开发团队； （ii）进行I期人类临床试验； （iii）第二代产品的研究和开发； （iv）在两年期间生产CGMP产品。在A系列加薪的12个月内，Amylon计划启动建立2500万美元的B系列B轮，在第3年进行II期临床试验。后来，Amylon计划进行IPO，以筹集1亿美元，以进行III III期临床试验并将其商业化Bryostatin 1 bryostatin 1 for Alzheimer的病和认知性分离。另外，在此阶段，Amylon将与中层上市公司合并，或者由跨国制药公司收购。

项目成果

Bryostatin-1 vs. TPPB: dose-dependent APP processing and PKC-α, -δ, and -ε isoform activation in SH-SY5Y neuronal cells.

• DOI: 10.1007/s12031-012-9816-3
• 发表时间: 2012-09
• 期刊: Journal of molecular neuroscience : MN
• 作者: Yi P;Schrott L;Castor TP;Alexander JS
• 通讯作者: Alexander JS

Acute oral Bryostatin-1 administration improves learning deficits in the APP/PS1 transgenic mouse model of Alzheimer's disease.

• DOI: 10.2174/1567205012666141218141904
• 发表时间: 2015
• 期刊: Current Alzheimer research
• 影响因子: 2.1
• 作者: L. Schrott;K. Jackson;P. Yi;F. Dietz;G. S. Johnson;T. Basting;G. Purdum;T. Tyler;J. Ríos;T. Castor;J. Alexander

Nanoparticle-Encapsulated Bryostatin-1 Activates α-Secretase and PKC Isoforms In vitro and Facilitates Acquisition and Retention of Spatial Learning in an Alzheimer's Disease Mouse Model.

纳米颗粒封装的 Bryostatin-1 在体外激活 α-分泌酶和 PKC 同工型，并促进阿尔茨海默病小鼠模型空间学习的获取和保留。

• DOI: 10.2174/1567205018666210218155835
• 发表时间: 2020
• 期刊: Current Alzheimer research
• 影响因子: 2.1
• 作者: Schrott,Lisa;Yi,Ping;Jackson,Kasey;Jackson,GabrielS;Webb,Christopher;Minagar,Alireza;Yun,JWinny;Purdum,Geoffrey;Rios,DavidJ;Tyler,TheodoreA;Vizcanio,MariaI;Castor,JudithL;Castor,Trevor;Alexander,JonathanS
• 通讯作者: Alexander,JonathanS