Project Details
Description
Project Summary/Abstract
Multiple system atrophy (MSA) is a rare, rapidly progressive, and invariably fatal neurodegenerative disease
for which there is no disease-modifying treatment. Recent insights into pathophysiologic mechanisms suggest
a crucial role of deprivation of neurotrophic factors which have been shown to be secreted by mesenchymal
stem cells (MSCs). In a recent phase I/II study adipose-derived autologous MSCs were delivered intrathecally
to patients with early MSA utilizing a dose-escalation design. At a dose of 50x106 MSCs, injections were
generally well tolerated, but thickening of cauda equina nerve roots was observed which was either
asymptomatic or associated with low back pain. The rate of disease progression assessed using the Unified
MSA Rating Scale (UMSARS) was markedly slower compared to a matched control group. An even more
favorable side effect profile and virtually lack of disease progression was seen in an add-on cohort receiving
25x106 MSCs per injection. Neurofilament light chain, an index of central axonal degeneration, decreased in all
patients receiving that dose. MSC administrations resulted in a marked, dose-dependent increase of
neurotrophic factors in CSF. 2-year survival was significantly higher than observed in natural history cohorts.
Based on these findings we propose a double-blind, placebo-controlled, adaptive design phase II trial of
adipose-derived intrathecal autologous MSCs in MSA with the goal to establish optimal treatment frequency
and simultaneously derive placebo-controlled efficacy and safety data in preparation for a multicenter phase III
trial. Up to 76 adult subjects with MSA will be enrolled. To ensure a homogenous patient population with
comparable rates of disease progression, we will restrict the study to early cases but still fulfilling strictest
diagnostic consensus criteria. Participants will undergo a subcutaneous fat biopsy to derive autologous MSCs,
which are cultured, expanded, and prepared for delivery in Mayo's Cell Therapeutics Lab. In a first phase,
subjects will be randomized 1:1:1 to receive 25x106 MSCs at two different injection intervals (every 6 months
or every 3 months) as the two active arms or lactated Ringer's solution as the placebo arm. A recruitment hold
after half the subjects have been enrolled will allow for an interim futility and efficacy analysis to select the
“winner” active treatment assuming futility criteria are not met. The study will then restart recruiting the second
half of subjects utilizing 2:1 randomization (“winner” active: placebo). Patients undergo clinical assessments at
baseline, 3, 6, 9, and 12 months to derive the primary endpoint, the rate of disease progression assessed
using UMSARS total and a mixed effects regression model. MRI of the head and lumbar spine will be
completed at baseline and 12 months to expand safety data and to assess the rate of atrophy of selected brain
regions using morphometric measures as surrogate markers of disease progression. Spinal fluid before and
after administrations, as well as stem cell product media will be collected to further explore biological properties
and effects of MSCs and to explore selected spinal fluid markers as biomarkers of disease progression.
Status | Active |
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Effective start/end date | 6/1/22 → 5/31/24 |
Funding
- U.S. Food and Drug Administration: $792,634.00
- U.S. Food and Drug Administration: $792,634.00
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