MSCs engineered to produce Brain-Derived Neurotrophic Factor for the Treatment of Huntington's disease

间充质干细胞经过改造可产生脑源性神经营养因子，用于治疗亨廷顿病

• 批准号: 9362838
• 负责人: Kyle Fink
• 金额: $ 63.02万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9362838
• 关键词: Adult; Alpha Cell; Anxiety; Area; Atrophic; Biological Assay; Blood - brain barrier anatomy; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cell Therapy; Cells; Clinical Trials; Collaborations; Corpus striatum structure; DNA; Devices; Disease; Dose; Double-Blind Method; Drug or chemical Tissue Distribution; Evaluation; Family suidae; Formulation; Future; Growth; Growth Factor; Harvest; Human; Huntington Disease; Immune; Implant; In Vitro; Injection of therapeutic agent; Investigational Drugs; Label; Laboratories; Magnetic Resonance Imaging; Mesenchymal; Mesenchymal Stem Cells; Methods; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neurons; Operative Surgical Procedures; Outcome; Positioning Attribute; Procedures; Production; Proteins; Publishing; RNA; Recovery; Reporting; Reproducibility; Rodent Model; Site; Spinal Cord; Stromal Cells; Surface; Techniques; Testing; Therapeutic; Transgenic Organisms; Transportation; Treatment Factor; Up-Regulation; Veterinary Medicine; Veterinary Schools; animal data; animal facility; assay development; brain tissue; cellular engineering; disease phenotype; dosage; efficacy study; falls; gene therapy; good laboratory practice; implantation; in vivo; meetings; nerve stem cell; neurogenesis; neuropathology; neurorestoration; neurotrophic factor; novel; novel therapeutics; preconditioning; stem; time use; vector

Huntington's disease (HD) is a brutal neurodegenerative disorder with no cure, and there is a critical unmet need for disease-modifying treatments. We are developing a novel therapy for HD: intrastriatal implantation of human Mesenchymal Stem/Stromal Cells (MSCs) engineered to secrete Brain-Derived Neurotrophic Factor (MSC/BDNF), a growth factor needed in the degenerating striatal regions of the brain. BDNF is low in humans and mice with HD, and up- regulation of BDNF in the brains of transgenic rodent models of HD has ameliorated the disease phenotype. Due to pro-survival effects in striatal neuropathology, BDNF is a strong candidate for neuroprotective therapies. The challenge is delivery into the brain, since BDNF does not cross the blood-brain barrier. MSC/BDNF combines the beneficial effects of MSC administration to the striata with the benefits of BDNF production. Unlike BDNF delivery via direct vector injection or protein administration into the brain, MSCs migrate into the areas of damage and have numerous beneficial effects. Although optimized MSCs will not persist longer than several months, we hypothesize that the neurorestorative effects of BDNF will outlast the survival of MSCs. This is supported by animal data from our laboratory and others. In our double-blinded efficacy studies, intrastriatal delivery of human MSC/BDNF significantly reduced anxiety and significantly increased neurogenesis in immune suppressed HD mice, with increased survival, in comparison to vehicle treated HD mice. Treatment with MSC/BDNF decreased striatal atrophy as compared to vehicle treated HD mice (PMID:26765769). This recovery may be due to the stimulation of endogenous neurogenesis promoted by BDNF, and enhanced by the secretion of various complementary therapeutic factors by the MSCs. In the planned studies, we will perform the following studies in support of an investigational new drug filing to the FDA (RAC and Pre- IND meetings already completed): in Aim 1 we will determine effective in vitro potency assays for MSC/BDNF and will define in vivo outcomes for each assay, in Aim 2 we will complete dose- finding efficacy and biosafety studies, and in Aim 3 we will perform MSC/BDNF striatal implantation studies in a porcine model. Our studies will define reproducible techniques and methods, at the level of Good Laboratory Practice, for evaluation of cell and gene therapy candidates to be used in neurodegenerative disorders. We will be positioned to move the MSC/BDNF candidate into clinical trials for HD initially, and to assist others in using the product for additional disorders in the future. We will better define mechanism of action of MSC/BDNF and will define potency assays, using promotion of in vivo neurogenesis as a readout.

亨廷顿氏病（HD）是一种残酷的神经退行性疾病，无法治愈，有一个 对改良疾病的治疗的关键需求。我们正在开发一种新颖的疗法 高清：植牙的人间充质茎/基质细胞（MSC） 分泌脑衍生的神经营养因子（MSC/BDNF），这是一个生长因子 大脑的退化纹状体区域。 BDNF在人类和HD的小鼠中很低，并且 在HD的转基因啮齿动物模型的大脑中BDNF的调节已改善该疾病 表型。由于在纹状体神经病理学中的促生物效应，BDNF是有力的候选者 神经保护疗法。挑战是将BDNF交付到大脑 血脑屏障。 MSC/BDNF结合了MSC给药的有益影响 纹状体具有BDNF生产的好处。与通过直接向量注入或 蛋白质给大脑施用，MSC迁移到损害区域，并具有 许多有益的影响。尽管优化的MSC不会持续时间比几个 几个月，我们假设BDNF的神经养生作用将超过 MSC。这得到了我们实验室和其他人的动物数据的支持。在我们的双盲中 功效研究，人类MSC/BDNF的近视递送显着降低焦虑和 免疫抑制的HD小鼠的神经发生显着增加，生存率增加， 与车辆处理过的高清小鼠进行比较。 MSC/BDNF治疗减少纹状体萎缩 与已处理的HD小鼠相比（PMID：26765769）。这种恢复可能是由于 BDNF促进的内源性神经发生的刺激，并通过分泌增强 MSC的各种互补治疗因素。在计划的研究中，我们将执行 以下研究支持向FDA提交的调查新药（RAC和PRE- IND会议已经完成）：在AIM 1中，我们将确定有效的体外效力分析 对于MSC/BDNF，将定义每个测定的体内结果，在AIM 2中，我们将完成剂量 - 找到功效和生物安全研究，在AIM 3中，我们将执行MSC/BDNF纹状体 猪模型中的植入研究。我们的研究将定义可再现技术和 在良好的实验室实践层面上，方法用于评估细胞和基因治疗 用于神经退行性疾病的候选者。我们将定位移动 MSC/BDNF候选人最初是临床试验的临床试验，并协助其他人使用该产品 将来其他疾病。我们将更好地定义MSC/BDNF的作用机制 并将使用体内神经发生作为读数来定义效力测定。