Long-Term Safety, Immunologic Response, and Imaging Outcomes following Neural Stem Cell Transplantation for Pelizaeus-Merzbacher Disease

Nalin Gupta; Roland G Henry; Sang-Mo Kang; Jonathan Strober; Daniel A Lim; Tamara Ryan; Rachel Perry; Jody Farrell; Mary Ulman; Raja Rajalingam; Allyson Gage; Stephen L Huhn; A James Barkovich; David H Rowitch

doi:10.1016/j.stemcr.2019.07.002

Long-Term Safety, Immunologic Response, and Imaging Outcomes following Neural Stem Cell Transplantation for Pelizaeus-Merzbacher Disease

Stem Cell Reports. 2019 Aug 13;13(2):254-261. doi: 10.1016/j.stemcr.2019.07.002. Epub 2019 Aug 1.

Authors

Nalin Gupta¹, Roland G Henry², Sang-Mo Kang³, Jonathan Strober⁴, Daniel A Lim⁵, Tamara Ryan⁶, Rachel Perry⁶, Jody Farrell⁶, Mary Ulman⁷, Raja Rajalingam⁸, Allyson Gage⁹, Stephen L Huhn⁹, A James Barkovich¹⁰, David H Rowitch¹¹

Affiliations

¹ Department of Neurological Surgery, University of California San Francisco, 550 16(th) Street, 4(th) Floor, San Francisco, CA 94143-0137, USA; Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: nalin.gupta@ucsf.edu.
² Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA; Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA; Bioengineering Graduate Group, University of California San Francisco & Berkeley, San Francisco, CA 94143, USA.
³ Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Neurological Surgery, University of California San Francisco, 550 16(th) Street, 4(th) Floor, San Francisco, CA 94143-0137, USA.
⁶ Fetal Treatment Center, University of California San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA.
⁸ Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA.
⁹ StemCells Inc., Newark, CA 94560, USA.
¹⁰ Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA; Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA.
¹¹ Department of Neurological Surgery, University of California San Francisco, 550 16(th) Street, 4(th) Floor, San Francisco, CA 94143-0137, USA; Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Department of Paediatrics, University of Cambridge, Cambridge CB2 1TN, UK.

Abstract

Four boys with Pelizaeus-Merzbacher disease, an X-linked leukodystrophy, underwent transplantation with human allogeneic central nervous system stem cells (HuCNS-SC). Subsequently, all subjects were followed for an additional 4 years in this separate follow-up study to evaluate safety, neurologic function, magnetic resonance imaging (MRI) data, and immunologic response. The neurosurgical procedure, immunosuppression, and HuCNS-SC transplantation were well tolerated and all four subjects were alive at the conclusion of the study period. At year 2, all subjects exhibited diffusion MRI changes at the implantation sites as well as in more distant brain regions. There were persistent, increased signal changes in the three patients who were studied up to year 5. Two of four subjects developed donor-specific HLA alloantibodies, demonstrating that neural stem cells can elicit an immune response when injected into the CNS, and suggesting the importance of monitoring immunologic parameters and identifying markers of engraftment in future studies.

Keywords: Pelizaeus-Merzbacher disease; leukodystrophy; myelin; neural stem cells; neurodegenerative disease; oligodendrocyte; pediatric; transplantation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain / diagnostic imaging*
Brain / physiology
Child, Preschool
Follow-Up Studies
HLA Antigens / immunology
Humans
Infant
Isoantibodies / blood
Magnetic Resonance Imaging
Male
Neural Stem Cells / cytology
Neural Stem Cells / metabolism
Neural Stem Cells / transplantation*
Pelizaeus-Merzbacher Disease / immunology
Pelizaeus-Merzbacher Disease / pathology
Pelizaeus-Merzbacher Disease / therapy*
Severity of Illness Index
Stem Cell Transplantation / adverse effects
Transplantation, Homologous
Treatment Outcome

Substances

HLA Antigens
Isoantibodies

Grants and funding

MC_PC_12009/MRC_/Medical Research Council/United Kingdom