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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' 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

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.

项目概要/摘要 JanusQ, LLC 是一家初创生物技术公司，从凯斯西储大学分离出来，致力于开发 一种基于肽的疗法，用于治疗阿尔茨海默病（AD）中的线粒体功能障碍， β 淀粉样蛋白 (Aβ) 在 AD 中的作用，损害了约 600 万美国人的记忆和认知能力。 对发病机制知之甚少，针对 A 的治疗方法在临床上尚未取得成功。 观察发现，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， 导致神经毒性的研究提出了一种新的策略：ATAD3A 是一种线粒体蛋白，跨越内部和外部 外膜，对于胆固醇运输和维持线粒体类核复合物至关重要。 然而，在 AD 应激期间，ATAD3A 寡聚化并结合 Drp1（线粒体裂变 GTP 酶）， DA1 是 JanusQ 新发现的一种肽，会导致线粒体断裂和类核不稳定。 联合创始人，防止 ATAD3A 寡聚化和与 Drp1 的关联，减少线粒体碎片， 改善 AD 和 AD 啮齿动物模型中的类核稳定性，并减少行为和神经功能缺陷 然而，对于 DA1 在体内的分布和剂量依赖性知之甚少。 很难知道未经修饰的 DA1 是否已经适合作为治疗 AD 的临床候选药物， 或者未来是否需要优化肽以改善其药理特性 （效力、吸收、分配、消除）。 SBIR 拨款的目的就是做出这一决定。 该项目有三个目标：(1) 评估 DA1 的体内药代动力学，通过以下方法测试暴露量和稳定性： 开发从血浆和脑组织中提取 DA1 的方法，在不同时间点收集样本 皮下注射肽 (SQ) 并使用串联液体定量肽后 (2) 进行 DA1 的初步体外安全性/毒性评估，重点关注 发现阶段分析，评估潜在的脱靶相互作用和免疫原性 (3)。 使用体内 AD 小鼠模型评估 DA1 剂量反应特征，治疗 APP 敲入 AD 小鼠 （3-9 个月大）最初使用 3 剂 DA1 SQ 验证测定将评估 ATAD3A 寡聚化， 线粒体生物能量学、AD 病理学测量（例如 Aβ 积累、突触完整性、神经元损失）、 这些结果将直接解决我们的中心假设： DA1 具有推进临床所需的药理学特性（与未来的肽相比） 因此，所提出的工作是实现开发肽的长期目标的下一个合乎逻辑的步骤。 改善 AD 患者的生活质量和生存率的治疗将减少对医疗的依赖。 在美国，2020 年仅直接医疗费用就超过 305B 美元。 此次 SBIR 资助是 JanusQ 开发 DA1 本身（或首先优化 DA1）作为突破的关键一步 这两种方法都可以让 JanusQ 吸引商业化合作伙伴。