Macrophage-targeted dendrimer 2-PMPA for the treatment of age-related sarcopenia

巨噬细胞靶向树枝状大分子 2-PMPA 用于治疗年龄相关性肌少症

• 批准号: 10683227
• 负责人: Ahmet Hoke
• 金额: $ 51.81万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683227
• 关键词: Acids; Address; Adult; Affect; Aging; Animal Model; Animals; Autopsy; Behavioral; Biodistribution; Biological Assay; Biological Availability; Body Weight; Cells; Charge; Chronic; Circulation; Clinical; Clinical Chemistry; Clinical Research; Clinical Trials; Dendrimers; Denervation; Development; Diameter; Disease; Dose; Drug Kinetics; Economic Burden; Electromyography; Electrophysiology (science); Enzymes; FOLH1 gene; Fiber; Fracture; Future; Generations; Glutamates; Half-Life; Hand Strength; Health Care Costs; Histologic; Hospitalization; Human; Hydrolysis; Hydroxyl Radical; Immune; Infiltration; Inflammation; Inflammatory; Injury; Kinetics; Label; Link; Liquid substance; Locomotion; Macrophage; Magnetic Resonance Imaging; Maintenance; Measures; Microglia; Mus; Muscle; Muscle function; N-acetylaspartylglutamate; Neuromuscular Diseases; Neuromuscular Junction; Neuropeptides; Neurotransmitters; Oral; Pathologic; Patients; Penetration; Phagocytes; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Physical Function; Physiological; Plasma; Population; Prevention; Process; Risk; Source; Stains; Stomach; Surface; System; Testing; Tissues; Weight; age related; age-related muscle loss; aged; clinical translation; combat; cyanine dye 5; effective therapy; efficacy evaluation; experience; falls; fracture risk; glutamatergic signaling; in vivo; inhibitor; mortality; muscle aging; muscle form; nanoparticle; nerve supply; sarcopenia; severe COVID-19; small molecule; targeted delivery; translational approach; transmission process

PROJECT SUMMARY Age-related loss of muscle mass, or sarcopenia, is a hallmark of aging that affects up to 20% of those over 65 and up to 50% of those over 80, for which there are no pharmacological treatments. We recently discovered that the enzyme Glutamate Carboxypeptidase II (GCPII), which catalyzes the hydrolysis of N-acetylaspartylglutamate (NAAG) to glutamate, is highly upregulated in activated macrophages infiltrating muscle during aging, and that inhibiting the elevated GCPII activity with the inhibitor 2-PMPA (IC50 = 0.3nM) dramatically delays neuromuscular junction (NMJ) denervation, and muscle function and volume loss. Unfortunately, 2-PMPA is not clinically developable. It is highly polar, with negligible oral bioavailability (F<2%), a short half-life (<30m), and is active only with high systemic (IP) doses. Given its significant clinical potential, we propose to address these limitations by utilizing hydroxyl-dendrimers to facilitate its sustained and targeted delivery. Hydroxyl-dendrimers have shown promise as targeted delivery systems due to their size (~4-10 nm) and surface attributes. They are rapidly cleared from circulation under normal conditions but are selectively engulfed and retained by activated and phagocytic immune cells under injury or inflammatory conditions. This is a very translational approach, as targeted dendrimer delivery has been demonstrated to be efficacious in multiple animal models and recently shown to reduce inflammation and mortality in a Ph2 clinical trial in hospitalized patients with severe Covid-19 (NCT04458298). We have assembled a highly experienced team with extensive expertise in neuromuscular disorders and aging (Hoke), dendrimer nanoparticles (Kannan), and animal pharmacology, pharmacokinetics, and clinical translation (Slusher). Together we plan to develop dendrimer-2PMPA (D-2PMPA) for age-related sarcopenia by implementing the following aims: AIM 1. Synthesize and characterize generation 4 (G4) and generation 6 (G6) D-2PMPA conjugates. AIM 2. Assess D-2PMPA (G4 and G6) pharmacokinetics, target engagement, and biodistribution in aged mice. AIM 3. Evaluate the efficacy (behavioral, electrophysiological, and histological) and tolerability of the selected D-2PMPA conjugate in aged mice. Successful execution of these aims will result in a D-2PMPA conjugate ready for IND-enabling studies to support future clinical studies to combat age-related sarcopenia.

项目概要 与年龄相关的肌肉质量损失或肌肉减少症是衰老的一个标志，影响到 65 岁以上人群中高达 20% 的人 80 岁以上的人中有高达 50% 的人没有药物治疗。我们最近发现 谷氨酸羧肽酶 II (GCPII)，催化 N-乙酰天冬氨酰谷氨酸的水解 (NAAG) 转化为谷氨酸，在衰老过程中浸润肌肉的活化巨噬细胞中高度上调，并且 使用抑制剂 2-PMPA (IC50 = 0.3nM) 抑制升高的 GCPII 活性可显着延迟神经肌肉 交界处（NMJ）去神经支配，以及肌肉功能和体积损失。不幸的是，2-PMPA 并没有在临床上使用。 可开发的。它具有高极性，口服生物利用度可忽略不计 (F<2%)，半衰期短 (<30m)，且具有活性 仅适用于高全身（IP）剂量。鉴于其巨大的临床潜力，我们建议解决这些限制 通过利用羟基树枝状聚合物来促进其持续和有针对性的递送。羟基树枝状聚合物已表明 由于其尺寸（~4-10 nm）和表面属性，有望成为靶向递送系统。他们很快就被清除了 在正常条件下不进入循环，但被激活和吞噬细胞选择性地吞噬和保留 免疫细胞处于损伤或炎症状态。这是一种非常具有转化性的方法，有针对性 树枝状聚合物递送已被证明在多种动物模型中有效，并且最近被证明 在一项针对重症 Covid-19 住院患者的 2 期临床试验中减少炎症和死亡率 （NCT04458298）。我们组建了一支经验丰富的团队，在神经肌肉领域拥有丰富的专业知识 疾病和衰老（Hoke）、树枝状聚合物纳米颗粒（Kannan）以及动物药理学、药代动力学、 和临床翻译（Slusher）。我们计划共同开发 dendrimer-2PMPA (D-2PMPA)，用于与年龄相关的疾病 肌肉减少症通过实现以下目标： AIM 1. 合成和表征第 4 代 (G4) 和 第 6 代 (G6) D-2PMPA 缀合物。目标 2. 评估 D-2PMPA（G4 和 G6）药代动力学、目标 老年小鼠的参与度和生物分布。目标 3. 评估疗效（行为、电生理、 所选 D-2PMPA 缀合物在老年小鼠中的组织学和耐受性。成功执行这些 目标将产生 D-2PMPA 缀合物，为 IND 启用研究做好准备，以支持未来的临床研究 对抗与年龄相关的肌肉减少症。