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

项目总结 在65岁以上的人群中，高达20%的人会受到与年龄相关的肌肉萎缩或骨质疏松症的影响 在80岁以上的人群中，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-乙酰天冬氨酸谷氨酸水解酶 (NAAG)到谷氨酸，在衰老过程中活化的巨噬细胞渗透的肌肉中高度上调，并且 用抑制剂2-PMPA(IC50=0.3 nM)抑制升高的GCPII活性显著延迟神经肌肉 交界处(NMJ)失神经，肌肉功能和容量丧失。不幸的是，2-PMPA不能用于临床 可开发的。它是高度极性的，口服生物利用度可以忽略不计(F&lt；2%)，半衰期很短(&lt；30m)，并且是有效的 仅在全身(IP)剂量较高的情况下。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大分子来促进其持续和靶向递送。羟基树枝状大分子已经显示出 由于其尺寸(~4-10 nm)和表面属性，有望成为靶向递送系统。它们很快就会被清除 在正常情况下从循环中脱离，但被活化和吞噬的细胞选择性地吞噬和保留 损伤或炎症条件下的免疫细胞。这是一种非常具有翻译性的方法，因为 树枝状大分子给药已被证明在多种动物模型中有效，最近显示 在PH2临床试验中降低重症新冠肺炎住院患者的炎症和死亡率 (NCT04458298)。我们组建了一支经验丰富的团队，在神经肌肉方面拥有广泛的专业知识 疾病与衰老(HOKE)、树枝状大分子纳米粒(KANAN)、动物药理学、药代动力学、 和临床翻译(Slusher)。我们计划共同开发用于年龄相关的树状大分子-2PMPA(D-2PMPA) 目的1.合成和鉴定第4代(G4)和 第6代(G6)D-2PMPA偶联物。目的2.评估D-2PMPA(G4和G6)的药代动力学，靶点 在老龄小鼠体内的参与和生物分布。目的3.评估疗效(行为、电生理、 和组织学)和选择的D-2PMPA结合物在老年小鼠中的耐受性。成功地执行了这些 AIMS将产生D-2PMPA结合物，准备用于IND-Enabling研究，以支持未来的临床研究 与年龄相关的石棺减少症作斗争。

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.