Small molecule inhibitor of amyloid precursor protein synthesis

淀粉样前体蛋白合成的小分子抑制剂

基本信息

批准号：
7801346
负责人：
Maria Maccecchini
金额：
$ 21.35万
依托单位：
ANNOVIS BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7801346
关键词：
5&apos Untranslated Regions Abbreviations Accounting Acetylcholinesterase Acetylcholinesterase Inhibitors Acute Affect Aging Alzheimer&apos s Disease American Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Animals Behavior Bioavailable Biological Markers Brain Canis familiaris Cell Culture Techniques Cells Cessation of life Cholinesterase Inhibitors Cholinesterases Clinical Clinical Research Cognition Data Dementia Dependence Deterioration Development Disease Dose Drug Delivery Systems Drug Design Elderly Enzyme-Linked Immunosorbent Assay Event Excision Exposure to FDA approved Genetic Translation Glutamates Goals Half-Life Hour Human Immunohistochemistry Institutes Licensing Mediating Memantine Messenger RNA Molecular Mus Mutation Neuroblastoma Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Neurotransmitters Oral Oral Administration Parents Patient Care Pharmaceutical Preparations Pharmacotherapy Phase Phase I Clinical Trials Plasma Population Protein Biosynthesis Proteins Recovery Research Rodent Saline Sampling Senile Plaques Small Business Innovation Research Grant Tartrates Therapeutic Time Toxic effect Transgenic Mice Translating Western Blotting Work amyloid pathology base cholinergic clinically relevant cost design economic impact efficacy trial familial Alzheimer disease inhibitor/antagonist mouse model neurotoxic phenserine pre-clinical preclinical study presenilin prevent public health relevance receptor secretase small molecule social tau Proteins volunteer

项目摘要

DESCRIPTION (provided by applicant): The product that will result from this SBIR is a small molecule drug therapy for Alzheimer's Disease (AD) that works by inhibiting amyloid precursor protein synthesis. AD accounts for two-thirds of all dementia, afflicting more than 26 million people worldwide, and in excess of 4 million Americans. The amyloid hypothesis of AD proposes that increased levels of amyloid-beta (Ab) peptides in the brain, possibly in their aggregated form, mediate a cascade of events leading to neuronal dysfunction, degeneration and clinical dementia. At present, currently approved therapies are considered to be primarily symptomatic. Although a large number of potentially disease-modifying therapeutic strategies are in current development, primarily focused on Ab and tau, the primary constituents of amyloid plaques and NFTs, respectively, none has been approved for AD treatment. [+]-Phenserine-tartrate is an experimental drug that has been exclusively licensed by QR Pharma. In both cell cultures and in animals [+]-phenserine-tartrate has been found to lower the rate of amyloid precursor protein synthesis. APP mRNA is efficiently translated and can be regulated at the level of its 5'-untranslated region (5'-UTR). [+]-phenserine-tartrate acts to lower the rate of APP synthesis via this 5'-UTR, reducing APP protein as well as Ab (1-40 and 1-42) by up to 50% in neuronal cultures and mice following both i.p. and oral administration. [+]-Phenserine-tartrate has been successfully developed through FDA required preclinical studies, has been FDA-approved for human use, and has begun Phase 1 clinical trials (single and repeated dosing). [+]- Phenserine-tartrate was well tolerated in both rodents and dogs in preclinical toxicological studies following oral administration and, likewise, was well tolerated in healthy elderly volunteers after oral dosing. A comparison of plasma concentrations achieved in humans following a well-tolerated dose with Ab-lowering concentrations in rodents suggests that effective concentrations can be achieved in humans. Collectively, these data indicate that [+]-phenserine-tartrate is an orally bioavailable small drug that readily enters the brain and can effectively lower Ab without toxicity. In all species, plasma Posiphen disappeared with a half-life of 2 to 4 hours following oral dosing, generating the major metabolite, [+]-N1,N8-bisnorposiphen, via its [+]-N1- and [+]-N8-norposiphen intermediates. These intermediates have been found to possess anticholinesterase activity, and since they achieve substantially greater concentrations than the parent drug, require to be characterized and optimized to support continued assessment of activities in the next phase of clinical studies in AD subjects. PUBLIC HEALTH RELEVANCE: The product that will result from this SBIR is a small molecule drug therapy for Alzheimer's Disease that works by inhibiting a molecular cause of the disease. Alzheimer's Disease accounts for two-thirds of all dementia. Although a number of potentially disease-modifying therapeutic strategies are in current development, none has so far been approved.

描述（由申请人提供）：该 SBIR 产生的产品是一种治疗阿尔茨海默病 (AD) 的小分子药物疗法，通过抑制淀粉样前体蛋白合成发挥作用。 AD 占所有痴呆症的三分之二，全世界有超过 2600 万人，超过 400 万美国人受其困扰。 AD 的淀粉样蛋白假说提出，大脑中β-淀粉样蛋白 (Ab) 肽水平的增加（可能以聚集形式）介导了一系列导致神经元功能障碍、变性和临床痴呆的事件。目前，目前批准的疗法被认为主要是针对症状的。尽管目前正在开发大量潜在的缓解疾病的治疗策略，主要集中于Ab和tau蛋白（分别是淀粉样斑块和NFT的主要成分），但尚未批准用于AD治疗。 [+]-Phenserine-tartrate是QR Pharma独家授权的实验药物。在细胞培养物和动物中，已发现[+]-苯酚酒石酸盐可降低淀粉样蛋白前体蛋白的合成率。 APP mRNA 可以有效翻译，并且可以在其 5'-非翻译区 (5'-UTR) 水平上进行调节。 [+]-phenserine-tartrate 通过该 5'-UTR 降低 APP 合成率，在神经元培养物和小鼠中减少 APP 蛋白和抗体（1-40 和 1-42）高达 50% ip和口服给药。 [+]-Phenserine-tartrate 已通过 FDA 要求的临床前研究成功开发，已获得 FDA 批准用于人类，并已开始 1 期临床试验（单次和重复给药）。 [+]- 在口服给药后的临床前毒理学研究中，啮齿动物和狗对苯酚酒石酸盐具有良好的耐受性，同样，在健康的老年志愿者中口服给药后也具有良好的耐受性。将耐受良好的剂量后在人类中达到的血浆浓度与在啮齿动物中降低抗体的浓度进行比较表明，在人类中可以达到有效的浓度。总的来说，这些数据表明[+]-phenserine-tartrate是一种口服生物利用度小的药物，很容易进入大脑，可以有效降低Ab且无毒性。在所有物种中，口服给药后，血浆 Posiphen 消失，半衰期为 2 至 4 小时，通过其 [+]-N1- 和 [+]-N8 产生主要代谢物 [+]-N1,N8-bisnorposiphen -去甲昔芬中间体。这些中间体被发现具有抗胆碱酯酶活性，并且由于它们的浓度比母体药物高得多，因此需要对其进行表征和优化，以支持下一阶段 AD 受试者临床研究中活性的持续评估。公共健康相关性：该 SBIR 产生的产品是一种治疗阿尔茨海默病的小分子药物疗法，通过抑制该疾病的分子原因发挥作用。阿尔茨海默病占所有痴呆症的三分之二。尽管目前正在开发许多可能改善疾病的治疗策略，但迄今为止尚未获得批准。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse.

Posiphen 对 APP 的翻译抑制：在 APP/PS1 小鼠中的功效、药效学和药代动力学。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Teich, Andrew F;Sharma, Ekta;Barnwell, Eliza;Zhang, Hong;Staniszewski, Agnieszka;Utsuki, Tadanobu;Padmaraju, Vasudevaraju;Mazell, Cheryl;Tzekou, Apostolia;Sambamurti, Kumar;Arancio, Ottavio;Maccecchini, Maria L
通讯作者：
Maccecchini, Maria L