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

描述（由申请人提供）：

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).