SMALL MOLECULE THERAPY FOR ALZHEIMER'S DISEASE

阿尔茨海默病的小分子疗法

• 批准号: 8905196
• 负责人: PAZHANI SUNDARAM
• 金额: $ 51.92万
• 依托单位: RECOMBINANT TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8905196
• 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; 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; Immune; In Vitro; Individual; 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; 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; Rodent; Route; Safety; Salmonella typhimurium; Senile Plaques; Staging; Symptoms; System; Testing; Therapeutic; Therapeutic Index; Time; Toxic effect; Toxicogenetics; Toxicology; Translating; Tryptophan; Work; abeta accumulation; amyloid peptide; base; commercialization; drug candidate; immunogenic; improved; in vivo; innovation; male; meetings; mouse model; novel therapeutics; peptide A; phase 2 study; practical application; prevent; protein aminoacid sequence; public health relevance; research clinical testing; research study; respiratory; scaffold; small molecule; 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（由适用提供）：阿尔茨海默氏病[AD]代表了一种影响大脑的进行性退行性疾病，导致记忆力障碍。尽管淀粉样蛋白β（Aβ）斑块的有毒同工型强烈暗示，AD的复杂病因并未完全解决。当前的治疗选择被认为是有症状的。它们仅在稳定或改善认知和功能性症状方面有效。大多数对阿尔茨海默氏症治疗的研究都集中在蛋白质β淀粉样蛋白上，这是阿尔茨海默氏症患者大脑中沉积物的主要组成部分。不幸的是，过去，由于安全或效率的问题，许多抗淀粉样药物在高级阶段失败。这是对停止或大大缓慢疾病进展的疗法的未满足需求。在过去的十年中，我们的持续研究产生了一个用于治疗广告的系统。我们的治疗策略是基于以下观察结果：AβPETIDE处于周围和中枢神经系统（CNS）之间的动态平衡。我们的主要候选者“ Amytrap”由外围有毒毒性的β-淀粉样蛋白PetidesAβ-40和Aβ-42组成的复古插入肽（RIP）组成，从而从CNS中抽出这些有毒的Petides。我们的研究表明，体外和体内这种隔离效应的“原理证明”。该研究的重点是评估不同ri pepperides [具有不同肽序列的杏仁体]的结合能力，以便在体外对pepperidesaβ -40和β-42的结合能力以及对AD小鼠模型中大脑清除斑块清除的影响。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的改善有关。此外，我们已经观察到暗示性的证据，表明在年龄较小的AD小鼠中给予Amytrap更有效。这一重要的观察结果与最近的发现一致，导致未能通过/重新出现人类临床试验。我们通过将RIP与专辑联系起来进一步提高了此Amytrap系统的属性。白蛋白肽的优点之一是没有任何不良的免疫反应。最近，我们通过成像实验获得了其他证据，表明Amytrap不会越过BBB，从而放弃了我们的外围水槽假设。但是，Amytrap需要进一步研究以检验其作为疾病修饰剂的潜力。在此阶段2应用程序中，我们尝试下一个逻辑决策点。我们建议对杏仁分子的有效性，遗传毒理学和安全药理学进行扩展研究。研究将着重于了解杏组的特性，并将其转化为实用应用，这将使我们能够商业化Amytrap。在“ Y”迷宫中，确定Amytrap分子的最小和最大有效剂量是我们的主要目标之一，它将导致治疗指数。我们计划通过标准实验在体外和体内检查杏组的遗传毒性潜力。因此，我们将进行安全药理学研究，并评估杏仁膜对CNS，呼吸系统和心脏系统的影响。我们认为，Amytrap的位置非常适合，因为它与其生物学靶标非常相似。此外，Amytrap是安全且经济的，没有副作用。因此，我们预计将在人类中接受Amytrap。拟议的商业化计划包括一个强大的研究团队（包括CRO，良好的经文，具有启示性研究]，一项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Innovations Inc [CII]和Biopharma Strategy Advisors，CA。为此，CII已经授予了RT的一笔少量赠款，以资助为第2阶段研究桥接第一阶段的努力。预计拟议的第二阶段研究的结果有望满足强制性要求，以定位未来的调查新药[IND]备案和随后的人类临床测试。