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

自体间充质干细胞治疗多系统萎缩的一期研究

• 批准号: 8925780
• 负责人: PHILLIP A LOW
• 金额: $ 20万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925780
• 关键词: Phase; Study; Autologous; Mesenchymal; Stem

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).

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和一致致死性疾病，其特征为自主神经功能衰竭、直立性低血压、神经源性膀胱/勃起功能障碍、小脑共济失调和帕金森综合征。MSA的特征是异常聚集的β-突触核蛋白的胶质细胞质内含物， 导致纹状体、小脑、脑干、皮质和脊髓中的神经元损失。虽然β-突触核蛋白聚集导致神经元损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缺乏，特别是脑源性神经营养因子和胶质源性神经营养因子。 间充质干细胞（MSC）是多能干细胞，并且能够 在适当的条件下分化成各种细胞类型。此外，MSC 分泌各种细胞营养因子，反过来发挥神经保护作用。动物 研究表明，人MSC具有对抗进行性炎症的保护作用， 多巴胺能和纹状体神经元的损失，最近，神经保护作用的 MSC在MSA转基因小鼠模型中得到证实。此外，积极的 使用颈动脉内和椎动脉内MSC递送至患者的开放标签研究 最近在韩国进行了一项双盲安慰剂对照试验， 报告了MSC治疗的患者组中疾病进展显著减慢。 因为到目前为止，还没有已知的干预措施可以改变疾病进程， 虽然MSA的对症治疗方案不太令人满意，但最近报道的韩国研究引起了人们的兴趣，但研究人员注意到，动脉内给药导致脑缺血性病变的安全性问题抑制了人们的兴奋。因此，研究人员开发了一个平台，允许MSC通过鞘内方法直接递送到脊髓液中。 建议使用剂量递增方案对MSA的鞘内脂肪来源的自体MSC治疗进行安全性研究，次要目标是使用选定和验证的神经和自主神经功能缺损指标评估该方法的疗效。假设这种方法是安全和可耐受的，并且增加MSC的剂量将导致神经和自主神经缺陷的进展、稳定或改善的分级减缓。该试验将在三个患者组中使用递增剂量的MSC，每组8名患者（单剂量1 x 107个细胞，两剂量5 x 107个细胞，两剂量1 x 108个细胞）。在干细胞给药期间，患者将住院3天，然后在最后一次MSC给药后每周随访4周（早期随访），然后在6个月和12个月（晚期随访）时使用标准化神经和自主神经仪器进行评估，并在3个月和9个月时进行额外的电话随访。 将使用严格的入选和排除标准招募患者，以确保患者 已经建立了良好的MSA，但仍处于疾病阶段，可以检测到 疾病阶段的变化（仍在发展，而不是终末期）。