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Abstract
Objective This phase I/II study sought to explore intrathecal administration of mesenchymal stem cells (MSCs) as therapeutic approach to multiple system atrophy (MSA).
Methods Utilizing a dose-escalation design, we delivered between 10 and 200 million adipose-derived autologous MSCs intrathecally to patients with early MSA. Patients were closely followed with clinical, laboratory, and imaging surveillance. Primary endpoints were frequency and type of adverse events; key secondary endpoint was the rate of disease progression assessed by the Unified MSA Rating Scale (UMSARS).
Results Twenty-four patients received treatment. There were no attributable serious adverse events, and injections were generally well-tolerated. At the highest dose tier, 3 of 4 patients developed low back/posterior leg pain, associated with thickening/enhancement of lumbar nerve roots. Although there were no associated neurologic deficits, we decided that dose-limiting toxicity was reached. A total of 6 of 12 patients in the medium dose tier developed similar, but milder and transient discomfort. Rate of progression (UMSARS total) was markedly lower compared to a matched historical control group (0.40 ± 0.59 vs 1.44 ± 1.42 points/month, p = 0.004) with an apparent dose-dependent effect.
Conclusions Intrathecal MSC administration in MSA is safe and well-tolerated but can be associated with a painful implantation response at high doses. Compelling dose-dependent efficacy signals are the basis for a planned placebo-controlled trial.
Classification of evidence This phase I/II study provides Class IV evidence that for patients with early MSA, intrathecal MSC administration is safe, may result in a painful implantation response at high doses, and is associated with dose-dependent efficacy signals.
Glossary
- AE=
- adverse event;
- BDNF=
- brain-derived neurotrophic factor;
- CASS=
- Composite Autonomic Severity Score;
- COMPASS=
- Composite Autonomic Severity Scale;
- CRTU=
- Clinical Research and Trials Unit;
- GDNF=
- glial-derived neurotrophic factor;
- MSA=
- multiple system atrophy;
- MSA-C=
- multiple system atrophy predominantly involving cerebellar impairment;
- MSA-P=
- multiple system atrophy predominantly involving parkinsonism;
- MSC=
- mesenchymal stem cell;
- NGF=
- nerve growth factor;
- UMSARS=
- Unified MSA Rating Scale
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Comment, page 25
Class of Evidence: NPub.org/coe
- Received July 11, 2018.
- Accepted in final form February 14, 2019.
- © 2019 American Academy of Neurology
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