Genomes and Genes
Role of Potent Trophic Factors on Glia and Motor Neurons in ALS
Principal Investigator: Brian K Kaspar
Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease, which results in muscle paralysis and ultimate respiratory failure and death. The underlying cause for ALS remains unknown with no cure. Numerous reports, including work from our laboratory have demonstrated the potential for neurotrophic factors to be highly therapeutic in rodent models of familial ALS (fALS). Indeed, Insulin-like growth factor-1 (IGF-1), glial derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) delivered at disease onset in ALS rodent models have demonstrated profound effects in delaying disease progression. Recent studies have surprisingly demonstrated that astrocytes and microglia expressing a mutation in the enzyme superoxide dismutase can exacerbate motor neuron death, supporting earlier studies that ALS is a non-cell autonomous disease. Specifically, glial cells have been shown to develop aberrant activity, secreting toxic signals that lead to motor neuron demise. Based on these results, therapies designed to neutralize glial cell toxicity would be highly beneficial to ALS patients. Until genetic screening identifies new ALS inducing genes, therapies that could potentially prolong the lives of ALS patients should be developed. The mechanism by which neurotrophic factors prolong survival and motor function has remained elusive. Recent preliminary work by our laboratory has demonstrated that both IGF-1 and VEGF can act to suppress the mutant glial cell mediated toxicity. In this proposal, we will investigate the relative efficiency of IGF-1, VEGF and GDNF to suppress aberrant glial activity and delay motor neuron death. Specifically, these factors will be tested utilizing an invaluable in vitro model for ALS that was recently developed in our laboratory. We will also test these factors in an in vivo AAV (Adeno-Associated Virus) gene delivery paradigm that efficiently targets all regions of the spinal cord. We will analyze the mechanism by which these trophic factors mediate their effects on astrocytes and finally, we will test an optimal combination of these factors in familial fALS mice using our expertise in AAV vector gene delivery to the CNS. The specific aims of this proposal are: Specific Aim 1.) To determine the efficiency of neuroprotection and reduction of glial cell toxicity using potent neurotrophins in an in vitro based model of fALS. Specific Aim 2.) To determine whether IGF-1, VEGF, and GDNF act in combination to alter aberrant ALS glial activity and provide additive neuroprotection in an in vitro based model of fALS. Specific Aim 3.) To determine whether a combinatorial neurotrophic factor therapy is beneficial in a mouse model of fALS. PUBLIC HEALTH RELEVANCE Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease, which results in muscle paralysis and ultimate respiratory failure and death. The underlying cause for ALS remains unknown with no cure. We have shown the potential for neurotrophic factors to be highly therapeutic in rodent models of familial ALS including IGF-1, VEGF, and GDNF. Our proposal focuses on evaluating optimal trophic factors individually or in combination to delay motor neuron degeneration. We have developed an in vitro based model of ALS that utilizes stem cells directed to motor neurons and ALS containing astrocytes, which recapitulates the disease. We will subsequently test the optimal combination of these factors using gene delivery in a rodent model of this devastating disease in order to define an optimal therapy for this debilitating disorder.
Funding Period: 2009-08-01 - 2014-07-31
more information: NIH RePORT
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Center for Gene Therapy, The Research Institute at Nationwide Children s Hospital, 700 Children s Drive, Columbus, Ohio 43205, USA
Nat Biotechnol 27:59-65. 2009..It may also be useful for rapid postnatal genetic manipulations in basic neuroscience studies...
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Brain Sciences Sunnybrook Research Institute, Toronto, ON, Canada
Hum Gene Ther 23:1144-55. 2012..Transcranial focused ultrasound applications could fulfill a long-term goal of gene therapy: delivering vectors to diseased brain areas directly from the circulation, in a noninvasive manner...
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Center for Gene Therapy, Nationwide Children s Hospital Research Institute, Columbus, OH 43205, USA
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Genzyme Corporation, 49 New York Ave, Framingham, MA 01701 9322, USA
FASEB J 25:4369-77. 2011..680; females: r(2)=0.552) in ALS mice. These results suggest that stress is capable of accelerating disease progression and that strategies that modulate glucocorticoid metabolism might be a viable treatment approach for ALS...
- Astrocytes from familial and sporadic ALS patients are toxic to motor neuronsAmanda M Haidet-Phillips
The Research Institute at Nationwide Children s Hospital, Columbus, Ohio, USA
Nat Biotechnol 29:824-8. 2011..Our data highlight astrocytes as a non-cell autonomous component in SALS and provide an in vitro model system to investigate common disease mechanisms and evaluate potential therapies for SALS and FALS...
- Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codesMark E Hester
Center for Gene Therapy, The Research Institute at Nationwide Children s Research Institute, Columbus, Ohio, USA
Mol Ther 19:1905-12. 2011..Our results further exemplify the potential to use transcriptional coding for rapid and efficient production of defined cell types from hESCs and hiPSCs...
- AAV4-mediated expression of IGF-1 and VEGF within cellular components of the ventricular system improves survival outcome in familial ALS miceJames C Dodge
Genzyme Corporation, Framingham, Massachusetts 01701 9322, USA
Mol Ther 18:2075-84. 2010..These findings support the continued investigation of trophic factor-based therapies that target the CNS as a potential treatment of ALS...
- Two factor reprogramming of human neural stem cells into pluripotencyMark E Hester
The Research Institute at Nationwide Children s Research Institute, Columbus, Ohio, USA
PLoS ONE 4:e7044. 2009....
- Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosisAshley E Frakes
Center for Gene Therapy, The Research Institute at Nationwide Children s Hospital, Columbus, OH 43205, USA Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
Neuron 81:1009-23. 2014....
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- Role of MMP-9 in selective motor neuron degeneration in ALSChristopher Henderson; Fiscal Year: 2013..Overall, the results should provide novel insights into the mechanisms of motor neuron degeneration in ALS and important preclinical indications as to the potential of MMP-9 as a therapeutic target for future development. ..
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- Impairment of the glial glutamate transporter GLT1 in ALSDavide Trotti; Fiscal Year: 2013..The scope of this last aim could then be key, in particular if results of aim 1-2 establisha role of the astroglial CTE-SUMO1 fragment in motor neuron toxicity and ALS pathogenesis. ..
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- Targeted investigation of tissue specific oxidative stress in the etiology of ALSHolly Van Remmen; Fiscal Year: 2013....
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