Pharmacokinetic and pharmacodynamic assessment of peptide-based therapy DA1 for the treatment of Alzheimer's disease

用于治疗阿尔茨海默病的肽疗法 DA1 的药代动力学和药效学评估

基本信息

批准号：
10546403
负责人：
Andrew Loring Schilb
金额：
$ 25.96万
依托单位：
JANUSQ, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546403
关键词：
Address Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient American Amyloid beta-Protein Behavioral Binding Bioenergetics Biological Assay Biotechnology Brain Caregivers Characteristics Clinic Cognition Cognitive Complex Data Dementia Dependence Deterioration Development Disease Dose Drug Kinetics Event Functional disorder Future Goals Grant Guanosine Triphosphate Phosphohydrolases Huntington Disease Impaired cognition In Vitro Knock-in Lead Link Measures Medical Medical Care Costs Membrane Memory Methods Mitochondria Mitochondrial Proteins Modeling Modification Mus Neurodegenerative Disorders Neurologic Deficit Neurons Outcome Pathogenesis Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Physiological Plasma Positioning Attribute Property Proteins Quality of life Rodent Rodent Model Role Safety Sampling Small Business Innovation Research Grant Stress Synapses Testing Therapeutic Time Toxic effect Universities Validation Work abeta accumulation abeta deposition absorption aged base brain tissue cholesterol trafficking clinical candidate cognitive ability cognitive function cognitive skill commercial application commercialization cost immunogenicity improved in vivo inhibitor liquid chromatography mass spectroscopy long term memory mitochondrial dysfunction mouse model nervous system disorder neuron loss neurotoxicity novel strategies novel therapeutics peptide drug pharmacokinetic characteristic pharmacokinetics and pharmacodynamics prevent response subcutaneous therapy development

项目摘要

PROJECT SUMMARY/ABSTRACT JanusQ, LLC is a startup biotech company, spun out of Case Western Reserve University, and developing a peptide-based therapy for treatment of mitochondrial dysfunction in Alzheimer’s Disease (AD), which is eroding the memory and cognitive abilities of ~6 million Americans. The role of amyloid-β (Aβ) in AD pathogenesis is poorly understood, and therapies addressing A have not been successful in the clinic. The observation that, like many other neurodegenerative diseases, AD is linked to mitochondrial dysfunction that leads to neurotoxicity suggests a novel strategy: ATAD3A is a mitochondrial protein that spans both inner and outer membranes and is critical in cholesterol trafficking and maintaining the mitochondrial nucleoid complex. However, during the stress of AD, ATAD3A oligomerizes and binds Drp1 (the mitochondrial-fission GTPase), causing mitochondrial fragmentation and nucleoid instability. DA1, a peptide newly discovered by a JanusQ cofounder, prevents ATAD3A oligomerization and association with Drp1, reduces mitochondrial fragmentation, improves nucleoid stability, and reduces behavioral and neurological deficits in rodent models of AD and Huntington’s disease. However, little is known about the disposition and dose-dependence of DA1 in vivo. Thus, it is difficult to know whether unmodified DA1 is already suitable as a clinical candidate for the treatment of AD, or whether future work will be required to optimize the peptide to improve its pharmacological characteristics (potency, absorption, distribution, elimination). The purpose of this SBIR grant is to make that determination. The project has three aims: (1) Assess the pharmacokinetics of DA1 in vivo to test exposure and stability by developing approaches to extract DA1 from plasma and brain tissue, collecting samples at various time points after administering the peptide subcutaneously (SQ), and quantitating the peptide using tandem liquid chromatography mass spectroscopy. (2) Perform preliminary in vitro safety/toxicity assessment of DA1, focusing on discovery-phase assays, with an assessment of potential off-target interactions and immunogenicity. (3) Assess DA1 dose-response characteristics using an in vivo AD mouse model, treating APP knock-in AD mice (aged 3–9 months) initially with three DA1 doses SQ. Validation assays will assess ATAD3A oligomerization, mitochondrial bioenergetics, measures of AD pathology(e.g., Aβ accumulation, synaptic integrity, neuronal loss), and cognitive function during AD development. These results will directly address our central hypothesis that DA1 has the pharmacological properties necessary for advancement to the clinic (vs. future peptide optimization). Thus, the proposed work is the next logical step toward the long-term goal of developing a peptide therapy to improve quality of life and survival of AD patients. Such a treatment would reduce reliance on medical caregivers and thus reduce overall medical costs. In the US, direct medical costs alone exceeded $305B in 2020. This SBIR grant is a crucial step for JanusQ to develop DA1 per se (or first to optimize DA1) as a breakthrough treatment for AD. Either approach would put JanusQ in a position to attract a commercialization partner.

项目摘要/摘要 Janusq，LLC是一家创业生物技术公司，从Case Western Reserve University脱离了一种基于肽的治疗阿尔茨海默氏病（AD）线粒体功能障碍的治疗削弱了约600万美国人的记忆和认知能力。淀粉样β（Aβ）在AD中的作用发病机理知之甚少，针对A的疗法在诊所没有成功。这观察到，与许多其他神经退行性疾病一样，AD与线粒体功能障碍有关导致神经毒性提出了一种新的策略：ATAD3A是一种跨越内部和的线粒体蛋白外膜，对于胆固醇运输和维持线粒体核苷络合物至关重要。但是，在AD的压力期间，ATAD3A的寡聚并结合DRP1（线粒体叶片GTPase），导致线粒体碎裂和核苷的不稳定性。 DA1，Janusq新发现的肽联合创始人，可防止ATAD3A的低聚和与DRP1的关联，可降低线粒体碎片化，提高核稳定性，并减少AD啮齿动物模型中的行为和神经系统缺陷亨廷顿氏病。然而，关于DA1在体内的性格和剂量依赖性知之甚少。那，很难知道未修改的DA1是否已经适合作为AD治疗的临床候选者或是否需要将来的工作来优化胡椒粉以改善其药物特征（效力，滥用，分布，消除）。 SBIR赠款的目的是做出决定。该项目具有三个目的：（1）评估体内DA1的药代动力学，以测试暴露和稳定性开发从血浆和脑组织提取DA1的方法，在不同时间点收集样品皮下施用肽后（平方英尺），并使用串联液体定量肽色谱质谱。（2）对DA1进行初步的体外安全/毒性评估关于发现相的评估，并评估了潜在的脱靶相互作用和免疫原性。（3）使用体内AD鼠标模型评估DA1剂量反应特征，治疗App敲入AD小鼠（年龄3-9个月）最初使用三个DA1剂量平方英尺。验证评估将评估ATAD3A低聚，线粒体生物能学，AD病理学测量（例如Aβ积累，突触完整性，神经元损失），和广告开发过程中的认知功能。这些结果将直接解决我们的中心假设 DA1具有前进到诊所所需的药物特性（与未来肽相比优化）。这是拟议的工作是朝着开发肽的长期目标的下一个逻辑步骤改善AD患者生活质量和生存的治疗。这种治疗将减少医疗保留护理人员，从而降低总体医疗费用。在美国，仅直接医疗费用在2020年就超过了305B美元。 SBIR赠款是Janusq开发DA1本身（或首先优化DA1）的关键步骤 AD的处理。两种方法都将使Janusq处于吸引商业化合作伙伴的位置。