Document Detail

Neural stem cell engraftment and myelination in the human brain.
MedLine Citation:
PMID:  23052294     Owner:  NLM     Status:  MEDLINE    
Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy caused by mutation of the proteolipid protein 1 gene. Defective oligodendrocytes in PMD fail to myelinate axons, causing global neurological dysfunction. Human central nervous system stem cells (HuCNS-SCs) can develop into oligodendrocytes and confer structurally normal myelin when transplanted into a hypomyelinating mouse model. A 1-year, open-label phase-1 study was undertaken to evaluate safety and to detect evidence of myelin formation after HuCNS-SC transplantation. Allogeneic HuCNS-SCs were surgically implanted into the frontal lobe white matter in four male subjects with an early-onset severe form of PMD. Immunosuppression was administered for 9 months. Serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, including high-angular resolution diffusion tensor imaging (DTI), were performed at baseline and after transplantation. The neurosurgical procedure, immunosuppression regimen, and HuCNS-SC transplantation were well tolerated. Modest gains in neurological function were observed in three of the four subjects. No clinical or radiological adverse effects were directly attributed to the donor cells. Reduced T1 and T2 relaxation times were observed in the regions of transplantation 9 months after the procedure in the three subjects. Normalized DTI showed increasing fractional anisotropy and reduced radial diffusivity, consistent with myelination, in the region of transplantation compared to control white matter regions remote to the transplant sites. These phase 1 findings indicate a favorable safety profile for HuCNS-SCs in subjects with PMD. The MRI results suggest durable cell engraftment and donor-derived myelin in the transplanted host white matter.
Nalin Gupta; Roland G Henry; Jonathan Strober; Sang-Mo Kang; Daniel A Lim; Monica Bucci; Eduardo Caverzasi; Laura Gaetano; Maria Luisa Mandelli; Tamara Ryan; Rachel Perry; Jody Farrell; Rita J Jeremy; Mary Ulman; Stephen L Huhn; A James Barkovich; David H Rowitch
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Publication Detail:
Type:  Clinical Trial, Phase I; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Science translational medicine     Volume:  4     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-11     Completed Date:  2013-03-12     Revised Date:  2014-01-24    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  155ra137     Citation Subset:  IM    
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MeSH Terms
Brain / metabolism*,  pathology*
Middle Aged
Myelin Sheath / metabolism*
Neural Stem Cells / cytology*,  physiology*
Pelizaeus-Merzbacher Disease / genetics,  metabolism,  pathology,  therapy*
Stem Cell Transplantation / adverse effects,  methods
Grant Support
UL1 RR024131/RR/NCRR NIH HHS; UL1 RR024131/RR/NCRR NIH HHS; //Howard Hughes Medical Institute
Comment In:
Nat Rev Neurol. 2012 Dec;8(12):659   [PMID:  23147855 ]
Erratum In:
Sci Transl Med. 2012 Dec 19;4(165):165er8

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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