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.

亨廷顿舞蹈症（HD）是一种严重的神经退行性疾病，无法治愈，并且有一种 对疾病缓解治疗的严重未满足的需求。我们正在开发一种新疗法 HD：纹状体内植入人间充质干细胞/基质细胞（MSC） 分泌脑源性神经营养因子（MSC/BDNF），这是大脑发育所需的生长因子 大脑纹状体区域退化。患有 HD 的人类和小鼠体内 BDNF 水平较低，并且 调节 HD 转基因啮齿动物模型大脑中的 BDNF 可以改善这种疾病 表型。由于纹状体神经病理学中的促生存作用，BDNF 是一个强有力的候选者。 神经保护疗法。挑战在于将 BDNF 传递到大脑中，因为 BDNF 不会交叉 血脑屏障。 MSC/BDNF 结合了 MSC 给药的有益效果 纹状体具有 BDNF 产生的好处。与通过直接载体注射或 将蛋白质注射到大脑中，间充质干细胞迁移到受损区域并具有 许多有益的影响。尽管优化后的 MSC 的持续时间不会超过几个 几个月后，我们假设 BDNF 的神经恢复作用将比患者的生存期更持久。 间充质干细胞。我们实验室和其他实验室的动物数据支持了这一点。在我们的双盲实验中 功效研究表明，纹状体内输送人 MSC/BDNF 显着降低焦虑和 免疫抑制 HD 小鼠的神经发生显着增加，存活率增加 与媒介物处理的HD小鼠进行比较。 MSC/BDNF 治疗减少纹状体萎缩 与媒介物处理的 HD 小鼠相比 (PMID:26765769)。这种复苏可能是由于 BDNF 促进内源性神经发生的刺激，并通过 BDNF 的分泌而增强 间充质干细胞的各种补充治疗因子。在计划的研究中，我们将执行 以下研究支持向 FDA 提交研究性新药申请（RAC 和 Pre- IND 会议已完成）：在目标 1 中，我们将确定有效的体外效力测定 对于 MSC/BDNF 并将定义每次测定的体内结果，在目标 2 中，我们将完成剂量- 寻找功效和生物安全性研究，在目标 3 中，我们将进行 MSC/BDNF 纹状体 猪模型的植入研究。我们的研究将定义可重复的技术和 良好实验室规范水平的方法，用于评估细胞和基因治疗 用于神经退行性疾病的候选药物。我们将致力于推动 MSC/BDNF候选者初步进入HD临床试验，并协助其他人使用该产品 以防将来出现其他疾病。我们将更好地定义MSC/BDNF的作用机制 并将使用促进体内神经发生作为读数来定义效力测定。