Small molecule therapy for Alzheimer's Disease

阿尔茨海默病的小分子疗法

• 批准号: 9504274
• 负责人: PAZHANI SUNDARAM
• 金额: $ 13.86万
• 依托单位: RECOMBINANT TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-10 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9504274
• 关键词: Adsorption; Adverse effects; Affect; Affinity; Age; Albumins; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Antibodies; Award; Behavioral; Belief; Binding; Biochemical; Biodistribution; Biological; Biological Assay; Bone Marrow; Brain; Brain Diseases; Businesses; Canis familiaris; Cardiac; Cardiovascular system; Categories; Characteristics; Chromosome abnormality; Clinical; Clinical Trials; Cognitive; Complex; Connecticut; Conscious; Cross-Over Studies; Data; Decision Making; Dementia; Deposition; Development; Disease; Disease Progression; Dose; Drug Kinetics; Drug Metabolic Detoxication; Early Intervention; Ensure; Enzyme-Linked Immunosorbent Assay; Equilibrium; Erythrocytes; Escherichia coli; Etiology; Evaluation; Excretory function; Formulation; Funding; Future; Gel; Generations; Goals; Grant; Histidine; Human; Image; In Vitro; Individual; Injectable; Investigation; Label; Lead; Link; Lymphocyte; Memory; Memory impairment; Metabolism; Mus; Mutation; Neuraxis; Onset of illness; Outcome; Pathogenesis; Pathway interactions; Peptides; Performance; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacology Study; Phase; Polyethylene Glycols; Positioning Attribute; Positron-Emission Tomography; Process; Property; Protein Isoforms; Quality Control; Rattus; Reaction; Research; Research Design; Research Personnel; Respiration; Retro-Inverso Peptide; Route; Safety; Salmonella typhimurium; Senile Plaques; Suggestion; Symptoms; System; Testing; Therapeutic; Therapeutic Index; Time; Toxic effect; Toxicogenetics; Toxicology; Translating; Tryptophan; Work; abeta accumulation; amyloid peptide; base; commercialization; drug candidate; experimental study; genotoxicity; immunoreaction; improved; in vivo; innovation; male; mouse model; novel therapeutics; peptide A; peptide B; phase 2 study; practical application; prevent; protein aminoacid sequence; public health relevance; research clinical testing; research study; respiratory; scaffold; small molecule; subcutaneous; success; treatment strategy

 DESCRIPTION (provided by applicant): Alzheimer's disease [AD] represents a progressive degenerative illness that affects the brain, resulting in memory impairment. The complex etiology of AD is not fully resolved, although toxic isoforms of amyloid-β (Aβ) plaques are strongly implicated. Current treatment options are considered to be symptomatic. They are only moderately effective in stabilizing or improving cognitive and functional symptoms. Majority of the research into treatment for Alzheimer's focused on the protein beta amyloid, which is the main component of deposits found in the brain of Alzheimer's sufferers. Unfortunately in the past, many anti-amyloid drugs failed in advanced stages due to safety or efficacy concerns. Thus, there is an unmet need for therapies that halt or substantially slow disease progression. Over the past decade, our continued research has yielded a system to treat AD. Our treatment strategy is based on the observation that Aβ peptides are in a dynamic equilibrium between the periphery and central nervous system (CNS). Our lead candidate, "Amytrap", is composed of a retro-inverso peptide (RIP) that can sequester toxic β-amyloid peptides Aβ -40 and Aβ-42 in the periphery, thereby drawing these toxic peptides out of the CNS. Our research studies have demonstrated the 'proof of principle' of this sequestration effect in vitro and in vivo. The research focused on evaluating the binding capacity of different RI peptides [Amytrap with different peptide sequences] to peptides A β -40 and A β -42 in vitro along with its effects on clearance of plaques from the brain in an AD mouse model. The results show that Amytrap is able to reduce Aβ levels in brain extracts from AD model mice. The reduction in Aβ levels was associated with improved memory parameters in these mice. Further we have observed suggestive evidence that administration of Amytrap to AD mice at younger age is more effective. This important piece of observation is consistent with the recent findings resulting fro failed/re-emerging human clinical trials. We have further improved the properties of this Amytrap system by linking the RIP to albumin. One of the advantages of the albuminized peptide is the absence of any untoward immune reactions. Recently, we have obtained additional evidence via imaging experiments that Amytrap does not cross the BBB thus reassuring our peripheral sink hypothesis. However, Amytrap warrants further investigation to test its potential as a disease modifying agent. In this phase 2 application, we attempt the next logical decision making point. We propose to conduct expanded studies on efficacy, genetic toxicology and safety pharmacology of the Amytrap molecule. Studies will focus on understanding the properties of Amytrap and translating them to practical applications which will enable us to commercialize Amytrap. Determining the minimum and maximum effective dose of the Amytrap molecule on performance in the "y" maze is one of our primary goals that will result in a therapeutic index. We plan to examine the genotoxic potential of Amytrap by standard experiments in vitro and in vivo. We will consequently conduct safety pharmacology studies and evaluate the effect of Amytrap on the CNS, respiratory and cardiac systems over long term. We believe Amytrap is ideally positioned in that it closely resembles its biological target. Further, Amytrap is safe and economical with no side effects. Therefore, we anticipate that Amytrap will be accepted in humans. The proposed commercialization plan includes a strong research team [including a CRO, well verse with IND enabling studies], a comprehensive business plan and commitments from potential strategic partners including Connecticut Innovations Inc [CII] and BioPharma Strategy Advisors, CA. To this effect, CII has already awarded a small grant to RT to fund efforts to bridge the phase 1 with the phase 2 research. The outcome of the proposed phase 2 studies is expected to satisfy mandatory requirements to position Amytrap for a future investigative new drug [IND] filing and subsequent human clinical testing.

 描述（由申请人提供）：阿尔茨海默病[AD]是一种影响大脑的进行性退行性疾病，导致记忆障碍。AD的复杂病因尚未完全解决，尽管淀粉样蛋白-β（Aβ）斑块的毒性同种型强烈参与。目前的治疗方案被认为是对症的。它们在稳定或改善认知和功能症状方面只有适度的效果。大多数关于阿尔茨海默氏症治疗的研究都集中在β淀粉样蛋白上，这是阿尔茨海默氏症患者大脑中发现的沉积物的主要成分。不幸的是，在过去，许多抗淀粉样蛋白药物由于安全性或有效性问题而在晚期阶段失败。因此，对于停止或基本上减缓疾病进展的疗法存在未满足的需求。 在过去的十年里，我们的持续研究已经产生了一个治疗AD的系统。我们的治疗策略是基于观察到Aβ肽在外周和中枢神经系统（CNS）之间处于动态平衡。我们的主要候选物“Amytrap”由一种反转录肽（RIP）组成，其可以在外周隔离毒性β-淀粉样肽Aβ -40和Aβ-42，从而将这些毒性肽从CNS中抽出。我们的研究已经在体外和体内证明了这种隔离效应的“原理证明”。研究重点是评价不同RI肽[具有不同肽序列的Amytrap]与肽A β -40和A β -42的体外结合能力，沿着其对AD小鼠模型脑斑块清除的影响。结果表明，Amytrap能够降低AD模型小鼠脑提取物中的Aβ水平。Aβ水平的降低与这些小鼠的记忆参数改善相关。此外，我们已经观察到提示性证据，即向年龄较小的AD小鼠施用Amytrap更有效。这一重要的观察结果与最近失败/重新出现的人类临床试验的结果一致。我们通过将RIP与白蛋白连接，进一步改善了该Amytrap系统的性质。白蛋白化肽的优点之一是不存在任何不利的免疫反应。最近，我们通过成像实验获得了额外的证据，表明Amytrap不会穿过BBB，从而再次证实了我们的外周汇假说。然而，Amytrap值得进一步研究，以测试其作为疾病修饰剂的潜力。在第二阶段的应用程序中，我们尝试下一个逻辑决策点。我们建议对Amytrap分子的有效性、遗传毒理学和安全药理学进行扩展研究。研究将侧重于了解Amytrap的特性，并将其转化为实际应用，使我们能够将Amytrap商业化。确定Amytrap分子对“y”迷宫中的表现的最小和最大有效剂量是我们的主要目标之一，这将产生治疗指数。我们计划通过体外和体内标准实验检查Amytrap的遗传毒性潜力。因此，我们将进行安全药理学研究，并评价Amytrap对CNS、呼吸系统和心脏系统的长期影响。我们认为Amytrap的理想定位是因为它与其生物靶标非常相似。此外，Amytrap是安全和经济的，没有副作用。因此，我们预计Amytrap将被人体接受。拟议的商业化计划包括一个强大的研究团队[包括一个CRO，以及IND使能研究]，一个全面的商业计划和潜在战略合作伙伴的承诺，包括康涅狄格州创新公司[CII]和BioPharma Strategy Advisors，CA。为此，CII已经向RT提供了一笔小额赠款，用于资助第一阶段与第二阶段研究的衔接。预计拟定II期研究的结果将满足强制性要求，以将Amytrap用于未来的研究性新药[IND]申报和后续的人体临床试验。