Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis

Clinical article

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Object

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. Clinical trial registration no.: NCT00337636 (ClinicalTrials.gov).

Abbreviations used in this paper:BSID-II = Bayley Scales of Infant Development II; CAS = Callier-Azusa G-Scale; DMC = Data Monitoring Committee; EEG = electroencephalography; HuCNS-SC = human CNS stem cell; INCL = infantile NCL; LINCL = late-infantile NCL; MMF = mycophenolate mofetil; NCL = neuronal ceroid lipofuscinosis; OHSU = Oregon Health & Science University; PCR = polymerase chain reaction.
Article Information

Contributor Notes

Address correspondence to: Nathan R. Selden, M.D., Ph.D., Department of Neurological Surgery and Doernbecher Children's Hospital, Oregon Health & Science University, Mail Code CH8N, 3303 SW Bond Avenue, Portland, Oregon 97239. email: seldenn@ohsu.edu.Please include this information when citing this paper: published online April 12, 2013; DOI: 10.3171/2013.3.PEDS12397.
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