Stem Cell Therapy for Motor Neuron Disease
Principal Investigator: Jeffrey Rothstein
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal adult onset neurological disorder that characteristically involve the degeneration of motor neurons. No effective treatment exists to substantially retard the progression of this disease, or to reverse the devastating and fatal disability. The use of stem cells in general and astroglial in particular, appears to represent a new approach to the treatment of neurodegenerative disease: rather than directly combating a pathological process, stem cell-based strategies could reinvoke developmental processes to insert new cells seamlessly into the degenerated environment. Recent studies document the potential of certain stem cells in promoting neuroprotection/recovery in a variety of nervous system injuries. The overall goal of this proposal will be to study the potential of murine astroglial stem cell transplantation as a therapeutic modality for the treatment of animal models ALS. In ALS patients and in animal models, defects in astroglial glutamate transporter GLT-1/EAAT2 lead to excitotoxic neural degeneration. Preliminary studies document that replacement of glutamate transport can effectively and dramatically slow down the disease; while use of selected trophic factors can enhance motor axon growth and also protect motor neurons. Glial-restricted progenitor cells appear to be able to engraft into spinal cord explants (in vitro), express the potentially neuroprotective astroglial GLT-1/EAAT2 glutamate transporter, and potently protect against glutamate-mediated neuronal death. The overall goal of this proposal will be to: 1) Characterize the normal regulation of glutamate transporter subtypes in glial progenitor cells in vitro and after engraftment; 2) Establish the neuroprotection by glial progenitor stem cells using in vitro models. To critically evaluate the role of glutamate transporter versus other properties of GRP (e.g. trophic factor release) we will perform comparisons with GRPs prepared from transporter null mice (GLT-1, GLAST, GLT-1/GLAST); 3) Determine if glial progenitor cells can protect against chronic neuronal injury by examining stem cell differentiation and neuroprotection in vivo in a transgenic animal model of ALS - G93A SOD 1 mutant mice and rats. Over all, these studies will provide data on the utility of astroglial stem cells to alter neurodegeneration in acute and chronic injury models relevant to ALS and hopefully provide important critical pre-clinical information.
Funding Period: 2002-12-01 - 2007-11-30
more information: NIH RePORT
- Stem cell transplantation for spinal cord neurodegenerationAngelo C Lepore
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Methods Mol Biol 793:479-93. 2011..The SOD1G93A rats and mice are currently the most well-studied animal model of the disease...
- Loss of the astrocyte glutamate transporter GLT1 modifies disease in SOD1(G93A) miceAndrea C Pardo
Department of Neurology, Johns Hopkins University, 600 N Wolfe St, Meyer 6 119, Baltimore, MD 21287, USA
Exp Neurol 201:120-30. 2006..This study suggests that astrocytes, and the astrocyte glutamate transporter GLT1, play a role in modifying disease progression and motor neuron loss in this model...
- Impaired SDF1/CXCR4 signaling in glial progenitors derived from SOD1(G93A) miceYongquan Luo
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA
J Neurosci Res 85:2422-32. 2007..These data indicate that the abnormalities in SOD1(G93A) glial progenitor expression of CXCR4 and its mediated signaling and function occur during spinal cord development and highlight nonneuronal (glial) abnormalities in this ALS model...
- Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALSAngelo C Lepore
Department of Neurology, The Johns Hopkins University School of Medicine, 600 N Wolfe St, Meyer 6 109, Baltimore, MD 21287, USA
Brain Res 1185:256-65. 2007....
- Selective ablation of proliferating astrocytes does not affect disease outcome in either acute or chronic models of motor neuron degenerationAngelo C Lepore
Department of Neurology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Meyer 6 119, Baltimore, MD 21287, USA
Exp Neurol 211:423-32. 2008..These findings demonstrate that while normal astrocyte function is an important factor in the etiology of motor neuron diseases such as ALS, astrocyte proliferation itself does not play a significant role...
- Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron diseaseAngelo C Lepore
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
Nat Neurosci 11:1294-301. 2008....