title: Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis.
abstract: OBJECTIVE
  Infantile and late-infantile neuronal ceroid lipofuscinoses (NCLs) are invariably fatal lysosomal storage diseases associated with defects in lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT-1) or tripeptidyl peptidase 1 (TPP1) activity. Previous preclinical studies have demonstrated that human CNS stem cells (HuCNS-SCs) produce both PPT-1 and TPP1 and result in donor cell engraftment and reduced accumulation of storage material in the brain when tested in an NCL mouse model.
  
  
  METHODS
  HuCNS-SC transplantation was tested in an open-label dose-escalation Phase I clinical trial as a potential treatment for infantile and late-infantile NCL. Study design included direct neurosurgical transplantation of allogeneic HuCNS-SCs into the cerebral hemispheres and lateral ventricles accompanied by 12 months of immunosuppression.
  
  
  RESULTS
  Six children with either the infantile or late-infantile forms of NCL underwent low- (3 patients) and high- (3 patients) dose transplantation of HuCNS-SCs followed by immunosuppression. The surgery, immunosuppression, and cell transplantation were well tolerated. Adverse events following transplantation were consistent with the underlying disease, and none were directly attributed to the donor cells. Observations regarding efficacy of the intervention were limited by the enrollment criteria requiring that patients be in advanced stages of disease.
  
  
  CONCLUSIONS
  This study represents the first-in-human clinical trial involving transplantation of a purified population of human neural stem cells for a neurodegenerative disorder. The feasibility of this approach and absence of transplantation-related serious adverse events support further exploration of HuCNS-SC transplantation as a potential treatment for select subtypes of NCL, and possibly for other neurodegenerative disorders.
authors.affiliation: Department of Neurological Surgery, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA. seldenn@ohsu.edu
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Selden
authors.forename: Amira
authors.initials: A
authors.lastname: Al-Uzri
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Huhn
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Koch
authors.forename: Darryn M
authors.initials: DM
authors.lastname: Sikora
authors.forename: Mina D
authors.initials: MD
authors.lastname: Nguyen-Driver
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Guillaume
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Koh
authors.forename: Sakir H
authors.initials: SH
authors.lastname: Gultekin
authors.forename: James C
authors.initials: JC
authors.lastname: Anderson
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Trenna L
authors.initials: TL
authors.lastname: Sutcliffe
authors.forename: Yakop
authors.initials: Y
authors.lastname: Jacobs
authors.forename: Robert D
authors.initials: RD
authors.lastname: Steiner
mesh_terms: D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D058953:Neural Stem Cells / Q000637:transplantation*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000175:diagnosis* / Q000601:surgery*; D019635:Neurosurgical Procedures / Q000379:methods*; D033581:Stem Cell Transplantation / Q000379:methods*; D013238:Stereotaxic Techniques; D016559:Tacrolimus / Q000008:administration & dosage; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D007166:Immunosuppressive Agents; C000717268:Tpp1 protein, mouse; D000091346:Tripeptidyl-Peptidase 1; D003907:Dexamethasone; C000717267:TPP1 protein, human; D009173:Mycophenolic Acid; D016559:Tacrolimus