Neuroprotection of Host Cells by Human Central Nervous System Stem Cells in a Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis

StemCells, Inc., Palo Alto, CA 94304, USA.
Cell stem cell (Impact Factor: 22.27). 10/2009; 5(3):310-9. DOI: 10.1016/j.stem.2009.05.022
Source: PubMed


Infantile neuronal ceroid lipofuscinosis (INCL) is a fatal neurodegenerative disease caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). Ppt1 knockout mice display hallmarks of INCL and mimic the human pathology: accumulation of lipofuscin, degeneration of CNS neurons, and a shortened life span. Purified non-genetically modified human CNS stem cells, grown as neurospheres (hCNS-SCns), were transplanted into the brains of immunodeficient Ppt1(-/)(-) mice where they engrafted robustly, migrated extensively, and produced sufficient levels of PPT1 to alter host neuropathology. Grafted mice displayed reduced autofluorescent lipofuscin, significant neuroprotection of host hippocampal and cortical neurons, and delayed loss of motor coordination. Early intervention with cellular transplants of hCNS-SCns into the brains of INCL patients may supply a continuous and long-lasting source of the missing PPT1 and provide some therapeutic benefit through protection of endogenous neurons. These data provide the experimental basis for human clinical trials with these banked hCNS-SCns.

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Available from: Ahmad Salehi
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    • "Knockout mouse models for the infantile (PPT1-/-) [42] and late-infantile (TPP-I) [43] forms develop progressive and severe neurodegeneration and recapitulate the pathology of the human diseases. As predicted, in vitro preclinical studies show HuCNS-SC-based cross-correction of enzyme deficiency through PPT-1 uptake via the mannose 6-phosphate receptor in cultured PPT-1-deficient mouse and human fibroblasts [38]. In order to create a suitable xenotransplantation model for testing the long-term effects of HuCNS-SC, the PPT-1 knockout mouse was backcrossed to the immune deficient NOD-SCID mouse. "
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