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

项目摘要 与肥胖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岁以上人群的20 80岁以上的人中有50%没有药物治疗。我们最近发现 谷氨酸羧肽酶II（GCPII），催化N-乙酰基谷氨酸的水解 在衰老过程中，在浸润肌肉的活化巨噬细胞中，NAAG与谷氨酸的转化率高度上调， 用抑制剂2-PMPA（IC 50 = 0.3nM）抑制升高的GCPII活性显著延迟神经肌肉 连接（NMJ）去神经支配，以及肌肉功能和体积损失。不幸的是，2-PMPA在临床上 可开发的它是高度极性的，具有可忽略的口服生物利用度（F<2%），半衰期短（<30 m），并且具有活性 仅使用高全身性（IP）剂量。鉴于其显著的临床潜力，我们建议解决这些局限性 通过利用羟基树枝状聚合物来促进其持续和靶向递送。羟基树枝状聚合物显示 由于其尺寸（~4-10 nm）和表面属性，有望作为靶向递送系统。它们很快就被清除了 在正常情况下，它们从循环中排出，但被活化和吞噬细胞选择性地吞噬和保留。 免疫细胞损伤或炎症条件下。这是一种非常有针对性的翻译方法， 树枝状聚合物递送已经在多种动物模型中被证明是有效的， 在严重Covid-19住院患者的II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，在神经肌肉方面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），和动物药理学，药代动力学， 临床翻译（Slusher）我们计划共同开发树枝状聚合物-2PMPA（D-2PMPA），用于与年龄相关的 通过实施以下目标来治疗肌肉减少症：AIM 1.合成和表征第4代（G4）， 第6代（G6）D-2 PMPA缀合物。AIM 2.评估D-2PMPA（G4和G6）的药代动力学，目标 接合和老年小鼠中的生物分布。AIM 3.评价疗效（行为、电生理、 和组织学）和所选D-2PMPA缀合物在老年小鼠中的耐受性。成功执行这些 目的是使D-2PMPA结合物准备好用于IND使能研究，以支持未来的临床研究， 与年龄相关的肌肉减少症作斗争

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.