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. MandrekarPhillip A. Low

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)e77-e87
JournalNeurology
Volume93
Issue number1
DOIs
StatePublished - Jul 2 2019

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Multiple System Atrophy
Mesenchymal Stromal Cells
Neurologic Manifestations
Disease Progression
Leg
Placebos
Pain
Control Groups
Injections
Therapeutics

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy. / Singer, Wolfgang; Dietz, Allan B.; Zeller, Anita D.; Gehrking, Tonette L.; Schmelzer, James D.; Schmeichel, Ann M.; Gehrking, Jade A.; Suarez, Mariana D.; Sletten, David M.; Minota Pacheco, Karla V.; Coon, Elizabeth A.; Sandroni, Paola; Benarroch, Eduardo E.; Fealey, Robert D.; Matsumoto, Joseph Y.; Bower, James H.; Hassan, Anhar; McKeon, Andrew; Windebank, Anthony J.; Mandrekar, Jay N.; Low, Phillip A.

In: Neurology, Vol. 93, No. 1, 02.07.2019, p. e77-e87.

Research output: Contribution to journalArticle

Singer, W, Dietz, AB, Zeller, AD, Gehrking, TL, Schmelzer, JD, Schmeichel, AM, Gehrking, JA, Suarez, MD, Sletten, DM, Minota Pacheco, KV, Coon, EA, Sandroni, P, Benarroch, EE, Fealey, RD, Matsumoto, JY, Bower, JH, Hassan, A, McKeon, A, Windebank, AJ, Mandrekar, JN & Low, PA 2019, 'Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy', Neurology, vol. 93, no. 1, pp. e77-e87. https://doi.org/10.1212/WNL.0000000000007720
Singer, Wolfgang ; Dietz, Allan B. ; Zeller, Anita D. ; Gehrking, Tonette L. ; Schmelzer, James D. ; Schmeichel, Ann M. ; Gehrking, Jade A. ; Suarez, Mariana D. ; Sletten, David M. ; Minota Pacheco, Karla V. ; Coon, Elizabeth A. ; Sandroni, Paola ; Benarroch, Eduardo E. ; Fealey, Robert D. ; Matsumoto, Joseph Y. ; Bower, James H. ; Hassan, Anhar ; McKeon, Andrew ; Windebank, Anthony J. ; Mandrekar, Jay N. ; Low, Phillip A. / Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy. In: Neurology. 2019 ; Vol. 93, No. 1. pp. e77-e87.
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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.",
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T1 - Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy

AU - Singer, Wolfgang

AU - Dietz, Allan B.

AU - Zeller, Anita D.

AU - Gehrking, Tonette L.

AU - Schmelzer, James D.

AU - Schmeichel, Ann M.

AU - Gehrking, Jade A.

AU - Suarez, Mariana D.

AU - Sletten, David M.

AU - Minota Pacheco, Karla V.

AU - Coon, Elizabeth A.

AU - Sandroni, Paola

AU - Benarroch, Eduardo E.

AU - Fealey, Robert D.

AU - Matsumoto, Joseph Y.

AU - Bower, James H.

AU - Hassan, Anhar

AU - McKeon, Andrew

AU - Windebank, Anthony J.

AU - Mandrekar, Jay N.

AU - Low, Phillip A.

PY - 2019/7/2

Y1 - 2019/7/2

N2 - 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.

AB - 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.

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