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

亨廷顿病(HD)是一种无法治愈的残酷的神经退行性疾病，有一种 对疾病修正治疗的严重需求未得到满足。我们正在开发一种新的治疗方法 HD：人骨髓间充质干细胞(MSCs)纹状体内移植 分泌脑源性神经营养因子(MSC/BDNF)，一种生长因子，在 大脑中退化的纹状体区域。在患有HD的人和小鼠中，BDNF水平较低，而BDNF- 脑源性神经营养因子在转基因HD模型鼠脑中的调节作用 表型。由于在纹状体神经病理学中的促存活作用，BDNF是一种强有力的候选 神经保护性疗法。挑战在于将神经营养因子送入大脑，因为脑源性神经营养因子不能通过 血脑屏障。MSC/BDNF结合了MSC管理对 Striata具有生产BDNF的好处。不同于通过直接载体注射或 蛋白质进入大脑，骨髓间充质干细胞迁移到损伤区域，并 有许多有益的影响。尽管经过优化的MSCs不会持续超过几个 几个月后，我们假设BDNF的神经修复作用将持续时间超过 MSCs。这得到了我们实验室和其他实验室的动物数据的支持。在我们的双重盲目中 有效性研究表明，纹状体内注射人骨髓间充质干细胞/脑源性神经营养因子显著降低焦虑和 显著增加免疫抑制的HD小鼠的神经再生，并提高存活率 与赋形剂处理的HD小鼠进行比较。骨髓间充质干细胞/脑源性神经营养因子治疗减轻纹状体萎缩 与车辆处理的HD小鼠(PMID：26765769)进行比较。这一复苏可能是由于 脑源性神经营养因子促进内源性神经发生，并通过分泌 骨髓间充质干细胞的多种互补治疗因子。在计划的研究中，我们将进行 支持向FDA提交研究用新药的以下研究(RAC和PRE- IND会议已经完成)：在目标1中，我们将确定有效的体外效力分析 对于MSC/BDNF，并将定义每项检测的体内结果，在目标2中，我们将完成剂量- 寻找有效性和生物安全性研究，在目标3中，我们将进行MSC/BDNF纹状体 在猪模型上的植入研究。我们的研究将定义可重复使用的技术和 用于评价细胞和基因治疗的良好实验室操作规范的方法 用于神经退行性疾病的候选药物。我们将做好准备将 MSC/BDNF候选人初步进入HD的临床试验，并帮助其他人使用该产品 以备将来出现更多的障碍。我们将更好地明确MSC/BDNF的作用机制 并将定义效力分析，使用促进体内神经发生作为读数。

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.