PHASE 1 STUDY OF AUTOLOGOUS MESENCHYMAL STEM CELL IN MULTIPLE SYSTEM ATROPHY

PROJECT SUMMARY/ABSTRACT Multiple system atrophy (MSA) is a rare, sporadic multi-system progressive anduniformly fatal disorder characterized by autonomic failure, orthostatic hypotension,neurogenic bladder/erectile dysfunction, cerebellar ataxia, and parkinsonism. MSA ischaracterized by glial cytoplasmic inclusions of abnormally aggregated ¿-synuclein, andresulting neuronal loss in the striatum, cerebellum, brainstem, cortex, and spinal cord.Although the precise mechanism by which ¿-synuclein aggregation leads to neuronalloss 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 ofdifferentiating into various cell types under appropriate conditions. Additionally, MSCssecrete various cytotrophic factors that, in turn, exert neuroprotective effects. Animalstudies demonstrate that human MSCs have a protective effect against progressivedopaminergic and striatal neuronal loss, and recently, the neuroprotective effects ofMSCs were confirmed in a transgenic mouse model of MSA. Furthermore, a positiveopen-label study using intracarotid and intravertebral arterial MSC delivery to patientswith 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, andsymptomatic treatment options for MSA are less than satisfactory, these recentlyreported Korean studies have been received with great interest, but unfortunately, safetyconcerns regarding the intraarterial administration resulting in cerebral ischemic lesionshave dampened the excitement. We and others have recently developed platforms thatallow for safe MSC delivery directly into the spinal fluid; this intrathecal approachovercomes the safety concerns associated with intraarterial administration, andadditionally should deliver stem cells into the CNS more effectively.In response to the rare disease RFA, we now propose a safety study on intrathecaladipose-derived autologous MSC treatment of MSA utilizing a dose-escalation protocol,with a secondary goal of assessing the efficacy of this approach using carefully selectedand validated measures of neurologic and autonomic deficits. We hypothesize that thisapproach is safe and tolerable, and that increasing doses of MSCs will result in gradedslowing of progression, stabilization, or improvement of neurologic and autonomicdeficits. The trial will use escalating doses of MSCs over three patient groups of 8patients each (single dose of 1 x 107 cells, two doses of 5 x 107 cells each, and twodoses of 1 x 108 cells each). During stem cell administrations, patients will behospitalized for 3 days, then will be followed weekly for 4 weeks following the last MSCadministration (early follow-up), and then will be evaluated at 6 and 12 months (late-follow-up) with standardized neurologic and autonomic instruments, and additionalphone follow-up at 3 and 9 months.Patients will be recruited using strict inclusion and exclusion criteria that ensure patientshave well-established MSA, but are still at a disease stage that allows for detection of achange in the disease stage (still evolving, not end-stage).