Article

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: 22.15). 10/2009; 5(3):310-9. DOI: 10.1016/j.stem.2009.05.022
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Ahmad Salehi, Aug 23, 2015
0 Followers
 · 
187 Views
  • Source
    • "Among the NCLs, a preclinical trial using hCNS-SCns was developed in the mice model of CLN1 disease, Ppt1 [165]. Purified non-genetically modified 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 . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 265 mutations and 38 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances.
    Current pharmaceutical biotechnology 06/2011; 12(6):867-83. DOI:10.2174/138920111795542633 · 2.51 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The use of stem cells will likely have a critical role to play in the coming years in regenerative medicine. The retina has been one of the earliest targets for stem cell derived replacement therapy due to easy access and the potential for direct monitoring of replacement cells. In this review, we will cover recent advances in differentiating human embryonic stem cells (hESC) into retinal cells, transplantation of hESC-derived retinal cells into animal models of retinal degeneration, and current human clinical trials involving subretinal transplantation these cells.
    09/2013; 1(3). DOI:10.1007/s40135-013-0016-2
  • [Show abstract] [Hide abstract]
    ABSTRACT: The authors present the design and implementation of a multiprocessor with a hypercube interconnection network. The hardware configuration of the hypercube multiprocessor is realized by using 16 processing elements (PEs) with a single CPU and five parallel interfaces per PE. Four programmable parallel interfaces (PPI) are interconnected with four adjacent PEs in a hypercube manner, and the other PPI is directly connected to the control computer. The software structure is also presented, focusing on the communication mechanism between adjacent PEs of the hypercube multiprocessor and communication between the PE and the control computer. Furthermore, the implemented graphic display control and its interface are briefly described from the viewpoint of hardware. The designed system has wide applicability in parallel computation with load balancing among PEs of the hypercube multiprocessor
    Industrial Electronics Society, 1989. IECON '89., 15th Annual Conference of IEEE; 12/1989
Show more