Direct CNS Delivery System for BDNF AntagoNATs using Heterotopic Mucosal Grafting for the Treatment of Parkinson's Disease

项目总结 治疗神经疾病最大的障碍是血脑屏障 阻止98%的潜在神经药物进入中枢神经系统(CNS)。脑区 派生神经营养因子(BDNF)是帕金森病(PD)AS中研究最多的靶点之一。 它可以逆转疾病的发展。脑源性神经营养因子是一种人工合成的类寡核苷酸化合物，能够 上调内源性BDNF的表达。ANTAGO NAT解决重组BDNF的问题 治疗包括非靶标毒性、免疫原性和不适当的翻译后修饰 增加靶点特异性，改善神经元摄取，并提供适当的亚细胞 表达蛋白的区隔化。化学上类似于安塔戈-纳曲酮的化合物 被证明是安全的，最近已经得到FDA的批准。尽管BDNF AntagoNAT有很大的前景 对于帕金森病的治疗，他们不能越过血脑屏障。目前绕过血脑屏障的方法成本高昂，有 显著的复杂性，并且不能轻易地扩展。经鼻途径绕过血脑屏障 然而，目前的技术依赖于通过嗅黏膜的扩散，并具有主要的 缺点包括表面积受限、药物接触可变、药代动力学不可预测、有限 粘膜滞留时间长，药物稳定性差。这一创新的提议汇集了独特的、多方面的 纪律专家团队，以克服每一个挑战。我们团队开发了一种创新的 可广泛输送高分子量的鼻腔内异位粘膜移植技术 治疗药物直接进入中枢神经系统。这种方法是基于已有的内窥镜颅底手术 已经在全球安全运行了十多年。我们之前已经证明了BDNF AntagoNAT 治疗策略是非免疫原性的，减少了偏离目标的毒性，克服了重组 神经营养蛋白传递，并能够成功上调BDNF在临界端的表达 经粘膜给药后的器官靶点。我们进一步证明了粘膜移植 技术安全、经济高效且高度可扩展。最后，我们的数据显示我们的双人车厢 脂质体-凝胶(Lig)递送系统在保护寡核苷酸货物的同时改善中枢神经系统 通过在粘膜表面提供一个缓释库来进行分布。我们的总体目标是优化 Lig公式，建立BDNF反义核酸经粘膜给药的定量药代动力学模型 Lig，并在两种互补的帕金森病啮齿动物模型上用组织学方法验证其治疗效果。 行为和实时成像终端。这种创新的BDNF AnagoNAs递送系统代表着一种 平台技术，可以消除BBB作为交付的固定障碍，并允许使用 安非他明治疗目前无法用药的多种中枢神经系统疾病。我们的建议是明确的 旨在收集关键的临床前数据，为首次人体试验提供快速途径。

PROJECT SUMMARY The most significant obstacle in the treatment of neurological disorders is the blood-brain barrier (BBB) which prevents 98% of all potential neuropharmaceuticals from reaching the central nervous system (CNS). Brain derived neurotrophic factor (BDNF) is one of the most intensely studied targets in Parkinson’s disease (PD) as it can reverse disease progression. BDNF AntagoNATs are synthetic oligonucleotide-like compounds capable of upregulating endogenous BDNF expression. AntagoNATs solve the problems of recombinant BDNF therapies including off-target toxicity, immunogenicity, and improper post-translational modification while increasing target specificity, improving neuronal uptake, and providing appropriate subcellular compartmentalization of the expressed protein. Compounds chemically similar to AntagoNATs have been shown to be safe and have been recently FDA approved. Despite the significant promise of BDNF AntagoNAT therapies for PD, they cannot cross the BBB. Current methods to bypass the BBB are expensive, have significant complications, and cannot be easily scaled. The trans-nasal pathway to bypass the BBB holds significant promise however current techniques rely on diffusion through the olfactory mucosa and have major drawbacks including a restricted surface area, variable drug contact, unpredictable pharmacokinetics, limited mucosal residence time, and poor drug stability. This innovative proposal brings together a unique, multi- disciplinary team of experts to overcome each of these challenges. Our group has developed an innovative intranasal heterotopic mucosal grafting technique capable of delivering a wide range of high molecular weight therapeutics directly into the CNS. This method is based on established endoscopic skull base procedures that have been safely performed globally for over a decade. We have previously shown that the BDNF AntagoNAT therapeutic strategy is non-immunogenic, reduces off target toxicity, overcomes the limitations of recombinant neurotrophic protein delivery, and is capable of successfully upregulating BDNF expression in critical end organ targets following transmucosal delivery. We have further demonstrated that the mucosal grafting technique is safe, cost effective, and highly scalable. Finally, our data indicate that our dual-compartment Liposome-in-Gel (LiG) delivery system is capable of protecting oligonucleotide cargo while improving CNS distribution by providing a sustained release depot at the mucosal surface. Our overall goal is to optimize the LiG formulation, create a quantitative pharmacokinetic model of transmucosal BDNF AntagoNAT delivery using LiG, and validate the therapeutic efficacy in two complementary rodent models of PD using histologic, behavioral, and live imaging endpoints. This innovative delivery system for BDNF AntagoNATs represents a platform technology which can eliminate the BBB as a fixed barrier to delivery and enable the use of AntagoNATs in the treatment of multiple currently undruggable CNS disorders. Our proposal is specifically designed to gather the critical pre-clinical data needed to provide a rapid pathway to first-in-human trials.