NINDS CREATE DISCOVERY: Development of dendrimer-N-acetylcysteine for the treatment of neonatal brain injury

项目摘要 脑性瘫痪是儿童常见的慢性神经系统疾病之一，目前尚无有效的治疗方法。半个月 美国有100万18岁以下儿童患有脑瘫，每6名儿童中就有1名患有某种形式的发育不良 残疾。围产期缺氧缺血性脑病与母婴炎症/免疫 调节失调是脑性瘫痪和相关残疾的主要原因。尽管集体证据来自于 至少6项大型临床试验证实，治疗性低温可改善结局，40%-50%的婴儿 接受低温治疗的人仍然会死亡或遭受严重的神经残疾。仍然迫切需要 为没有资格接受低温治疗的患者开发治疗方法，并为符合以下条件的患者提供辅助治疗 低温可改善神经保护，并解决低温和复温的负面影响。 这是这个为期三年半的NINDS Create Discovery项目的目标。 最近的研究表明，在早期，通过激活的胶质细胞介导的减轻神经炎症 分期不仅可以延缓发病，还可以为治疗提供更长的治疗窗口。然而， 通过血脑屏障输送药物以靶向和治疗弥漫性神经炎是一个主要的 挑战。我们的团队发现，系统地给药的端羟基聚酰胺胺 (PAMAM)树枝状大分子(~4 nm)靶向激活损伤脑组织中的神经胶质细胞，而不需要靶向配体。 有趣的是，静脉注射抗炎药N-乙酰半胱氨酸(NAC)与 树状大分子(D-NAC)，在临床相关的CP临床前模型中，导致了显著的神经保护作用 效果。基于我们使用先导化合物D-NAC的强大概念验证数据，我们建议优化 在CREATE的发现阶段，该化合物进一步用于围产期/新生儿脑损伤 应用，以向最终的开发阶段和临床试验进展。三个目标是 确定，以及适当的里程碑：(1)优化D-NAC的合成以扩大生产，以及 证明重现性、纯度和储存稳定性。(2)测定药代动力学、PK-PD关系， D-NAC在兔脑性瘫痪模型中的最小有效剂量、最佳剂量及消除。(三)确定 目标2中确定的最佳剂量D-NAC在兔母体炎症模型中的长期疗效 采用低温诱导慢性阻塞性肺疾病和足月小鼠缺氧缺血模型。

Project Summary Cerebral palsy is one of the common chronic childhood neurological disorders and has no effective cure. Half a million children under the age of 18 in the US have CP, and 1 in 6 children have some form of developmental disability. Perinatal hypoxic-ischemic encephalopathy (HIE) and maternal-fetal inflammation/immune dysregulation are major causes of cerebral palsy and related disabilities. Although the collective evidence from at least 6-large clinical trials confirms that therapeutic hypothermia improves outcome, 40%-50% of infants treated with hypothermia still die or suffer significant neurologic disability. There remains a critical need for development of therapies for patients who do not qualify for hypothermia, and for adjunct therapies with hypothermia that improve neuroprotection and address the negative effects of hypothermia and rewarming. This is the goal of this 3½ year NINDS CREATE DISCOVERY project. Recent studies suggest that attenuating neuroinflammation, mediated by activated glia, in the early stages can not only delay the onset, but may also provide a longer therapeutic window for treatment. However, delivering drugs across the blood-brain-barrier to target and treat diffuse neuroinflammation is a major challenge. Our team discovered that systemically-administered hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers (~4 nm) target activated glia in the injured brain, without the need for targeting ligands. Interestingly, intravenous administration of the anti-inflammatory drug N-acetyl cysteine (NAC) conjugated to the dendrimer (D-NAC), in clinically-relevant preclinical models of CP, resulted in striking neuroprotective effects. Building on our strong proof-of concept data using our lead compound D-NAC, we propose to optimize this compound further for use in perinatal/neonatal brain injury, during the discovery phase of the CREATE application, for progressing towards an eventual developmental phase and clinical trials. Three aims are identified, along with appropriate milestones: (1) Optimize the synthesis of D-NAC for scale up production, and demonstrate reproducibility, purity and storage stability. (2) Determine pharmacokinetics, PK-PD relationship, minimal effective dose, optimal dose and elimination of D-NAC in rabbit model of cerebral palsy. (3) Determine long term efficacy of D-NAC at the optimal dose identified in Aim 2, in rabbit model of maternal inflammation induced CP and in term mouse hypoxic-ischemia model with hypothermia.