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.

项目总结/摘要 JanusQ，LLC是一家初创生物技术公司，从凯斯西储大学分拆出来， 用于治疗阿尔茨海默病（AD）中线粒体功能障碍的基于肽的疗法， 侵蚀了大约600万美国人的记忆和认知能力。β淀粉样蛋白（Aβ）在AD中的作用 发病机制知之甚少，并且针对A β的治疗在临床上尚未成功。的 观察到，像许多其他神经退行性疾病一样，AD与线粒体功能障碍有关， 导致神经毒性提示了一种新的策略：ATAD 3A是一种线粒体蛋白， 外膜，并在胆固醇运输和维持线粒体类核复合物中起关键作用。 然而，在AD的应激过程中，ATAD 3A寡聚化并结合Drp 1（胞内分裂GT3）， 导致线粒体碎裂和类核不稳定。DA 1，JanusQ新发现的肽 共同创始人，防止ATAD 3A寡聚化和与Drp 1的结合，减少线粒体片段化， 改善类核稳定性，并减少AD啮齿动物模型中的行为和神经缺陷， 亨廷顿氏病。然而，很少有人知道的处置和剂量依赖性的DA 1在体内。因此，在本发明中， 很难知道未修饰的DA 1是否已经适合作为治疗AD的临床候选物， 或者是否需要未来的工作来优化肽以改善其药理学特征 （效力、吸收、分布、消除）。此SBIR补助金的目的是作出这一决定。 该项目有三个目的：（1）评估DA 1在体内的药代动力学，以测试暴露和稳定性， 开发从血浆和脑组织中提取DA 1的方法，在不同时间点收集样本 在皮下施用肽（SQ）并使用串联液体定量肽后， 色谱质谱法。(2)进行DA 1的初步体外安全性/毒性评估，重点是 在发现阶段试验中，评估潜在的脱靶相互作用和免疫原性。（三） 使用体内AD小鼠模型评估DA 1剂量反应特征，治疗APP敲入AD小鼠 (aged 3-9个月），最初给予三次DA 1剂量SQ。验证试验将评估ATAD 3A寡聚化， 线粒体生物能量学，AD病理学的测量（例如，Aβ蓄积、突触完整性、神经元损失）， 和认知功能的影响。这些结果将直接解决我们的中心假设， DA 1具有推进临床所必需的药理学性质（与未来的肽相比 优化）。因此，所提出的工作是朝着开发肽的长期目标迈出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。这样的治疗将减少对医疗的依赖。 护理人员，从而降低整体医疗成本。在美国，2020年仅直接医疗费用就超过3050亿美元。 对于JanusQ来说，SBIR资助是开发DA 1本身（或首先优化DA 1）作为突破的关键一步 治疗AD。无论哪种方式，JanusQ都能吸引商业化合作伙伴。