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

使用异位粘膜移植治疗帕金森病的 BDNF AntagoNAT 直接中枢神经系统递送系统

• 批准号: 10534663
• 负责人: Benjamin Bleier
• 金额: $ 50.44万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534663
• 关键词: Animals; Anisotropy; Area; Behavioral; Biological Assay; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Bypass; Central Nervous System; Central Nervous System Diseases; Chemicals; Clinical Trials; Complement; Data; Diffusion; Diffusion Magnetic Resonance Imaging; Disease Progression; Drug Delivery Systems; Drug Kinetics; Drug Stability; Encapsulated; Engineering; FDA approved; Formulation; Functional Magnetic Resonance Imaging; Gel; Genetic; Goals; Histologic; Image; Liposomes; Methodology; Methods; Mitochondria; Modeling; Molecular Weight; Monitor; Mucous Membrane; Nerve Growth Factors; Neurodegenerative Disorders; Neurons; Nose; Olfactory Mucosa; Oligonucleotides; Organ; PINK1 gene; Parkinson Disease; Pathologic; Pathway interactions; Pharmaceutical Preparations; Post-Translational Protein Processing; Procedures; Proteins; Rattus; Recombinants; Rodent Model; Rotenone; Specificity; Surface; System; Techniques; Therapeutic; Time; Toxic effect; Toxin; Transcript; Treatment Efficacy; Treatment-related toxicity; Up-Regulation; behavioral phenotyping; blood-brain barrier crossing; burden of illness; cost; cost effective; design; first-in-human; immunogenicity; improved; innovation; multidisciplinary; nervous system disorder; neurotoxicity; novel; pharmacokinetic model; pre-clinical; prevent; residence; skull base; technology platform; uptake

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.

项目摘要 治疗神经障碍中最重要的障碍是血脑屏障（BBB）， 阻止98%的潜在神经药物到达中枢神经系统（CNS）。大脑 衍生神经营养因子（BDNF）是帕金森病（PD）中研究最深入的靶点之一， 它可以逆转疾病进展。BDNF AntagoNAT是合成的类BDNF化合物， 内源性脑源性神经营养因子的表达。AntagoNAT解决了重组BDNF的问题 治疗包括脱靶毒性、免疫原性和不适当的翻译后修饰， 增加靶特异性，改善神经元摄取，并提供适当的亚细胞 表达的蛋白质的区室化。化学上类似于AntagoNAT的化合物已经被 它是安全的，最近已经被FDA批准。尽管BDNF AntagoNAT的重要前景 在PD的治疗中，它们不能穿过BBB。目前绕过BBB的方法是昂贵的， 严重的并发症，并且不能容易地缩放。绕过血脑屏障的经鼻通道 然而，目前的技术依赖于通过嗅觉粘膜的扩散， 缺点包括受限的表面积、可变的药物接触、不可预测的药代动力学、有限的 粘膜滞留时间和药物稳定性差。这一创新的提案汇集了一个独特的，多- 专家团队的专业知识，以克服这些挑战。我们的团队开发了一种创新的 能够递送宽范围高分子量的鼻内异位粘膜移植技术 将药物直接注入中枢神经系统。该方法基于已建立的内窥镜颅底手术， 已经在全球范围内安全运行了十多年。我们之前已经证明，BDNF AntagoNAT 治疗策略是非免疫原性的，减少脱靶毒性，克服重组的局限性， 神经营养蛋白的传递，并能够成功地上调BDNF的表达，在关键的末端 经粘膜递送后的器官靶点。我们进一步证明了粘膜移植 该技术安全、成本有效且高度可扩展。最后，我们的数据表明，我们的双室 凝胶脂质体（LiG）递送系统能够保护寡核苷酸货物，同时改善CNS 通过在粘膜表面提供持续释放的储库来分配。我们的总体目标是优化 LiG制剂，建立了一个定量的药物动力学模型的经粘膜BDNF AntagoNAT的交付，使用 LiG，并使用组织学， 行为和实时成像端点。这种创新的BDNF AntagoNATs递送系统代表了 平台技术，可以消除BBB作为交付的固定障碍， AntagoNAT在治疗多种目前不可用的CNS疾病中的应用。我们的建议是， 旨在收集为首次人体试验提供快速途径所需的关键临床前数据。

项目成果

Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis.

• DOI: 10.1016/j.jaci.2022.04.034
• 发表时间: 2022-10
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Nocera, Angela L.;Mueller, Sarina K.;Workman, Alan D.;Wu, Dawei;McDonnell, Kristen;Sadow, Peter M.;Amiji, Mansoor M.;Bleier, Benjamin S.
• 通讯作者: Bleier, Benjamin S.

Traumatic brain injury and the development of parkinsonism: Understanding pathophysiology, animal models, and therapeutic targets.

• DOI: 10.1016/j.biopha.2022.112812
• 发表时间: 2022-05
• 期刊: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

Osmotic core-shell polymeric implant for sustained BDNF AntagoNAT delivery in CNS using minimally invasive nasal depot (MIND) approach.

使用最小侵入性鼻仓库（思维）方法，用于在中枢神经系统中持续BDNF拮抗递送的渗透核壳聚合物植入物。

• DOI: 10.1016/j.biomaterials.2021.120989
• 发表时间: 2021-09
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Padmakumar S;Jones G;Khorkova O;Hsiao J;Kim J;Bleier BS;Amiji MM
• 通讯作者: Amiji MM

Radioanatomic Characteristics of the Posteromedial Intraconal Space: Implications for Endoscopic Resection of Orbital Lesions.

后内侧锥内空间的放射解剖学特征：对眼眶病变内窥镜切除术的影响。

• DOI: 10.3174/ajnr.a6822
• 发表时间: 2020
• 期刊: AJNR. American journal of neuroradiology
• 作者: Jafari,A;Lehmann,AE;Wolkow,N;Juliano,AF;Bleier,BS;Reinshagen,KL
• 通讯作者: Reinshagen,KL

Endonasal CNS Delivery System for Blood-Brain Barrier Impermeant Therapeutic Oligonucleotides Using Heterotopic Mucosal Engrafting.

使用异位粘膜上的鼻鼻中枢神经系统输送系统无形治疗性寡核苷酸的递送系统。

• DOI: 10.3389/fphar.2021.660841
• 发表时间: 2021
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Pawar G;Parayath NN;Sharma AA;Coito C;Khorkova O;Hsiao J;Curry WT;Amiji MM;Bleier BS
• 通讯作者: Bleier BS