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（由申请人提供）：阿尔茨海默病[AD]代表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β淀粉样蛋白 (Aβ) 斑块的毒性异构体密切相关。目前的治疗方案被认为是针对症状的。它们在稳定或改善认知和功能症状方面仅​​具有中等效果。阿尔茨海默病治疗的大部分研究都集中在β淀粉样蛋白上，它是阿尔茨海默病患者大脑中沉积物的主要成分。不幸的是，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，对阻止或显着减缓疾病进展的治疗的需求尚未得到满足。 在过去的十年里，我们不断的研究已经产生了治疗 AD 的系统。我们的治疗策略基于对 Aβ 肽在外周神经系统和中枢神经系统 (CNS) 之间处于动态平衡的观察。我们的主要候选药物“Amytrap”由逆反肽 (RIP) 组成，可以将有毒的 β-淀粉样肽 Aβ -40 和 Aβ-42 隔离在外周，从而将这些有毒肽从 CNS 中抽出。我们的研究已经证明了这种体外和体内隔离效应的“原理证明”。该研究的重点是评估不同 RI 肽 [具有不同肽序列的 Amytrap] 在体外与肽 A β -40 和 A β -42 的结合能力，及其对 AD 小鼠模型中脑部斑块清除的影响。结果表明，Amytrap 能够降低 AD 模型小鼠大脑提取物中的 Aβ 水平。 Aβ 水平的降低与这些小鼠的记忆参数改善有关。此外，我们观察到提示性证据表明，对年轻的 AD 小鼠施用 Amytrap 更有效。这一重要的观察结果与失败/重新出现的人体临床试验的最新发现是一致的。通过将 RIP 与白蛋白连接，我们进一步改进了该 Amytrap 系统的特性。白蛋白化肽的优点之一是不存在任何不良的免疫反应。最近，我们通过成像实验获得了更多证据，表明 Amytrap 不会穿过血脑屏障，从而证实了我们的外周汇假设。然而，Amytrap 值得进一步研究，以测试其作为疾病调节剂的潜力。在此第二阶段应用程序中，我们尝试下一个逻辑决策点。我们建议对 Amytrap 分子的功效、遗传毒理学和安全药理学进行扩展研究。研究重点是了解 Amytrap 的特性并将其转化为实际应用，这将使我们能够将 Amytrap 商业化。确定 Amytrap 分子对“y”迷宫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来检查 Amytrap 的遗传毒性潜力。因此，我们将进行安全药理学研究，并评估 Amytrap 对中枢神经系统、呼吸系统和心脏系统的长期影响。我们相信 Amytrap 的定位非常理想，因为它与其生物靶标非常相似。此外，Amytrap 安全、经济，无副作用。因此，我们预计 Amytrap 将被人类接受。拟议的商业化计划包括强大的研究团队（包括精通 IND 赋能研究的 CRO）、全面的商业计划以及康涅狄格州创新公司 [CII] 和加利福尼亚州生物制药战略顾问公司等潜在战略合作伙伴的承诺。为此，CII 已经向 RT 提供了一笔小额赠款，以资助第一阶段与第二阶段研究的衔接工作。拟议的 2 期研究的结果预计将满足 Amytrap 未来研究性新药 [IND] 申请和随后的人体临床测试的强制性要求。