Phase 1 Study of Autologous Mesenchymal Stem Cell in Multiple System Atrophy

描述(由申请人提供)： 多系统萎缩(MSA)是一种罕见的散发性多系统进行性疾病，以自主神经衰竭、直立性低血压、神经原性膀胱/勃起功能障碍、小脑性共济失调和帕金森氏症为特征。MSA的特征是异常聚集的�-突触核蛋白的胶质细胞质包涵体，以及 导致纹状体、小脑、脑干、皮质和脊髓的神经元丢失。虽然�-突触核蛋白聚集导致神经元丢失的确切机制尚未得到证实，但最近的证据表明，导致生长因子，特别是脑源性神经营养因子和胶质源性神经营养因子的缺乏。 间充质干细胞(MSCs)是多能干细胞，能够 在适当的条件下分化为各种类型的细胞。此外，MSCs 分泌各种细胞营养因子，进而发挥神经保护作用。动物 研究表明，人骨髓间充质干细胞对进展性疾病具有保护作用 多巴胺能和纹状体神经元的丢失，以及最近的神经保护作用 骨髓间充质干细胞在MSA转基因小鼠模型中得到证实。此外，积极的一面 应用颈动脉和椎动脉内MSC给患者的开放标记研究 MSA最近在韩国进行了一项双盲安慰剂对照试验， 报告说，在接受MSC治疗的患者队列中，疾病进展显著放缓。 由于到目前为止，还没有已知的干预措施可以改变疾病的进程，而且 MSA的对症治疗选择并不令人满意，这些最近报道的韩国研究引起了人们的兴趣，但研究人员指出，对动脉内给药导致脑缺血损害的安全性担忧抑制了人们的兴奋情绪。因此，研究人员开发了一种平台，允许通过鞘内途径将MSC直接输送到脊髓液中。 一项关于鞘内脂肪衍生的自体MSC利用剂量递增方案治疗MSA的安全性研究被提议，次要目标是使用经过选择和验证的神经和自主神经缺陷的测量来评估这种方法的有效性。假设这种方法是安全和可耐受的，增加MSCs的剂量将导致进展的逐步减缓、稳定或神经和自主神经缺陷的改善。该试验将在三个患者组中使用递增剂量的MSCs，每个患者组8人(单次剂量为1×107个细胞，两次剂量为5×107个细胞，两次剂量为1×108个细胞)。在干细胞注射期间，患者将住院3天，然后在最后一次注射MSC后每周随访4周(早期随访)，然后在6个月和12个月(后期随访)时使用标准化的神经学和自主仪器进行评估，并在3个月和9个月时进行额外的电话随访。 将使用严格的纳入和排除标准招募患者，以确保患者 有良好的MSA，但仍处于疾病阶段，允许检测到 疾病阶段的变化(仍在发展，而不是末期)。

DESCRIPTION (provided by applicant): Multiple system atrophy (MSA) is a rare, sporadic multi-system progressive and uniformly fatal disorder characterized by autonomic failure, orthostatic hypotension, neurogenic bladder/erectile dysfunction, cerebellar ataxia, and Parkinsonism. MSA is characterized by glial cytoplasmic inclusions of abnormally aggregated �-synuclein, and resulting neuronal loss in the striatum, cerebellum, brainstem, cortex, and spinal cord. Although the precise mechanism by which �-synuclein aggregation leads to neuronal loss is unproven, recent evidence suggests resulting deficiency of growth factors, especially Brain Derived Neurotrophic Factor and Glial-Derived Neurotrophic Factor. Mesenchymal stem cells (MSCs) are multipotent stem cells and are capable of differentiating into various cell types under appropriate conditions. Additionally, MSCs secrete various cytotrophic factors that, in turn, exert neuroprotective effects. Animal studies demonstrate that human MSCs have a protective effect against progressive dopaminergic and striatal neuronal loss, and recently, the neuroprotective effects of MSCs were confirmed in a transgenic mouse model of MSA. Furthermore, a positive open-label study using intracarotid and intravertebral arterial MSC delivery to patients with MSA was recently followed up with a double-blind placebo controlled trial in Korea, reporting significantly slower disease progression in the MSC treated patient cohort. Since to this point, there is no known intervention that can alter the disease course, and symptomatic treatment options for MSA are less than satisfactory, these recently reported Korean studies have been received with interest, but the investigators note that safety concerns regarding the intraarterial administration resulting in cerebral ischemic lesions have dampened the excitement. Therefore, the investigators have developed a platform to allow for MSC delivery directly into the spinal fluid by an intrathecal approach. A safety study is proposed on intrathecal adipose-derived autologous MSC treatment of MSA utilizing a dose-escalation protocol, with a secondary goal of assessing the efficacy of this approach using selected and validated measures of neurologic and autonomic deficits. The hypothesis is that this approach is safe and tolerable, and that increasing doses of MSCs will result in graded slowing of progression, stabilization, or improvement of neurologic and autonomic deficits. The trial will use escalating doses of MSCs over three patient groups of 8 patients each (single dose of 1 x 107 cells, two doses of 5 x 107 cells each, and two doses of 1 x 108 cells each). During stem cell administrations, patients will be hospitalized for 3 days, then will be followed weekly for 4 weeks following the last MSC administration (early follow-up), and then will be evaluated at 6 and 12 months (late follow-up) with standardized neurologic and autonomic instruments, and additional phone follow-up at 3 and 9 months. Patients will be recruited using strict inclusion and exclusion criteria that ensure patients have well-established MSA, but are still at a disease stage that allows for detection of a change in the disease stage (still evolving, not end-stage).