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 BDNF and GDNF. 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 great interest, but unfortunately, safety concerns regarding the intraarterial administration resulting in cerebral ischemic lesions have dampened the excitement. We and others have recently developed platforms that allow for safe MSC delivery directly into the spinal fluid;this intrathecal approach overcomes the safety concerns associated with intraarterial administration, and additionally should deliver stem cells into the CNS more effectively. In response to the rare disease RFA, we now propose a safety study 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 carefully selected and validated measures of neurologic and autonomic deficits. We hypothesize 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).

Public Health Relevance

Multiple system atrophy is a rare degenerative neurologic disease that affects various important functions, including motor control, balance, blood pressure regulation, and bladder function. Progression is relentless and the average survival after diagnosis is between 8 and 10 years. To this date, there is no intervention that can alter the disease course. Based on studies that suggest that nerve growth factors may increase neuronal survival in this disorder and encouraging recent clinical trials, we propose to study the safety and tolerability of administering autologous mesenchymal stem cells into the spinal fluid of patients with multiple system atrophy in a dose-escalation study of 24 patients. Careful study design and incorporation of selected measures of the disease course will allow for assessment of efficacy of this approach as a secondary aim. Patients will be followed for one year with careful monitoring and standardized assessment of neurologic and autonomic function at predetermined time points.

National Institute of Health (NIH)
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Special Emphasis Panel (ZFD1-OPD-N (S1))
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Mayo Clinic, Rochester
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