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July 02, 2019; 93 (1) Article

Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy

Wolfgang Singer, View ORCID ProfileAllan B. Dietz, Anita D. Zeller, Tonette L. Gehrking, James D. Schmelzer, Ann M. Schmeichel, Jade A. Gehrking, Mariana D. Suarez, David M. Sletten, Karla V. Minota Pacheco, Elizabeth A. Coon, Paola Sandroni, Eduardo E. Benarroch, Robert D. Fealey, Joseph Y. Matsumoto, James H. Bower, Anhar Hassan, Andrew McKeon, Anthony J. Windebank, Jay N. Mandrekar, Phillip A. Low
First published May 31, 2019, DOI: https://doi.org/10.1212/WNL.0000000000007720
Wolfgang Singer
From the Departments of Neurology (W.S., A.D.Z., T.L.G., J.D.S., A.M.S., J.A.G., M.D.S., D.M.S., K.V.M.P., E.A.C., P.S., E.E.B., R.D.F., J.Y.M., J.H.B., A.H., A.M., A.J.W., P.A.L.), Laboratory Medicine and Pathology (A.B.D.), and Biomedical Statistics and Informatics (J.N.M.), Mayo Clinic, Rochester, MN.
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Allan B. Dietz
From the Departments of Neurology (W.S., A.D.Z., T.L.G., J.D.S., A.M.S., J.A.G., M.D.S., D.M.S., K.V.M.P., E.A.C., P.S., E.E.B., R.D.F., J.Y.M., J.H.B., A.H., A.M., A.J.W., P.A.L.), Laboratory Medicine and Pathology (A.B.D.), and Biomedical Statistics and Informatics (J.N.M.), Mayo Clinic, Rochester, MN.
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Anita D. Zeller
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Tonette L. Gehrking
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James D. Schmelzer
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Ann M. Schmeichel
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Jade A. Gehrking
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Mariana D. Suarez
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David M. Sletten
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Karla V. Minota Pacheco
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Elizabeth A. Coon
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Paola Sandroni
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Eduardo E. Benarroch
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Robert D. Fealey
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Joseph Y. Matsumoto
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James H. Bower
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Anhar Hassan
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Andrew McKeon
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Anthony J. Windebank
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Phillip A. Low
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Citation
Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy
Wolfgang Singer, Allan B. Dietz, Anita D. Zeller, Tonette L. Gehrking, James D. Schmelzer, Ann M. Schmeichel, Jade A. Gehrking, Mariana D. Suarez, David M. Sletten, Karla V. Minota Pacheco, Elizabeth A. Coon, Paola Sandroni, Eduardo E. Benarroch, Robert D. Fealey, Joseph Y. Matsumoto, James H. Bower, Anhar Hassan, Andrew McKeon, Anthony J. Windebank, Jay N. Mandrekar, Phillip A. Low
Neurology Jul 2019, 93 (1) e77-e87; DOI: 10.1212/WNL.0000000000007720

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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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