Small molecule therapy for Alzheimer's Disease

 描述(申请人提供)：阿尔茨海默病[AD]是一种进行性退行性疾病，影响大脑，导致记忆障碍。阿尔茨海默病的复杂病因尚未完全解决，尽管毒性亚型淀粉样蛋白(Aβ，Aβ)斑块与此密切相关。目前的治疗方案被认为是有症状的。它们在稳定或改善认知和功能症状方面只有适度的效果。治疗阿尔茨海默氏症的大部分研究集中在蛋白质β淀粉样蛋白上，这是阿尔茨海默氏症患者大脑中发现的沉积的主要成分。不幸的是，在过去，由于安全性或有效性的考虑，许多抗淀粉样蛋白药物在晚期失败。因此，对阻止或显著减缓疾病进展的疗法的需求尚未得到满足。在过去的十年里，我们的持续研究已经产生了一种治疗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之间处于动态平衡。我们的主要候选药物“AMYTRAP”由一种逆转录多肽组成，它可以将有毒的β-淀粉样多肽Aβ-40和Aβ-42隔离在外围，从而将这些有毒多肽从中枢神经系统中提取出来。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”。本研究旨在评价不同RI多肽[具有不同多肽序列的AMYTRAP]与多肽Aβ-40和Aβ-42的体外结合能力及其对AD模型小鼠脑内斑块清除的影响。结果表明，AMYTRAP能降低AD模型小鼠脑提取液中Aβ的水平。Aβ水平的降低与这些小鼠记忆参数的改善有关。此外，我们观察到有提示证据表明，在AD小鼠年龄较小时给予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是一致的。通过将RIP连接到白蛋白上，我们进一步改善了该AmyTrap系统的性能。白蛋白多肽的优点之一是没有任何不良免疫反应。最近，我们通过成像实验获得了更多的证据，证明Amytrap没有穿过血脑屏障，从而证实了我们的外周下沉假说。然而，AMYTRAP需要进一步研究，以测试其作为疾病改良剂的潜力。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AMYTRAP分子的有效性、遗传毒理学和安全药理学进行更广泛的研究。研究将集中在了解AMYTRAP的性质并将其转化为实际应用，这将使我们能够将AMTRAP商业化。确定AMYTRAP分子在“y”迷宫中的最小和最大有效剂量是我们的主要目标之一，这将导致一个治疗指数。我们计划通过标准的体外和体内实验来检测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。我们认为AmyTrap的定位非常理想，因为它与其生物目标非常相似。此外，AMYTRAP是安全和经济的，没有副作用。因此，我们预计AMYTRAP将在人类中被接受。拟议的商业化计划包括一支强大的研究团队[包括一名CRO，与IND使能研究完全相反]、一份全面的商业计划以及包括康涅狄格创新公司[CII]和加利福尼亚州BioPharma Strategy Advisors在内的潜在战略合作伙伴的承诺。为此，CII已经向RT提供了一小笔赠款，用于资助连接第一阶段和第二阶段研究的努力。拟议的第二阶段研究的结果预计将满足强制性要求，为未来的调查性新药[IND]申请和随后的人体临床测试定位AmyTrap。

 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.