TY - JOUR
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.
N1 - Publisher Copyright:
© American Academy of Neurology.
PY - 2019/7/2
Y1 - 2019/7/2
N2 - ObjectiveThis phase I/II study sought to explore intrathecal administration of mesenchymal stem cells (MSCs) as therapeutic approach to multiple system atrophy (MSA).MethodsUtilizing 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).ResultsTwenty-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.ConclusionsIntrathecal 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 evidenceThis 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 - ObjectiveThis phase I/II study sought to explore intrathecal administration of mesenchymal stem cells (MSCs) as therapeutic approach to multiple system atrophy (MSA).MethodsUtilizing 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).ResultsTwenty-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.ConclusionsIntrathecal 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 evidenceThis 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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U2 - 10.1212/WNL.0000000000007720
DO - 10.1212/WNL.0000000000007720
M3 - Article
C2 - 31152011
AN - SCOPUS:85069264809
SN - 0028-3878
VL - 93
SP - E77-E87
JO - Neurology
JF - Neurology
IS - 1
ER -