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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064492-05
Application #
8536963
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Gubitz, Amelie
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$297,896
Indirect Cost
$91,024
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
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Fidler, Jonathan A; Treleaven, Christopher M; Frakes, Ashley et al. (2011) Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone. FASEB J 25:4369-77
Dodge, James C; Treleaven, Christopher M; Fidler, Jonathan A et al. (2010) AAV4-mediated expression of IGF-1 and VEGF within cellular components of the ventricular system improves survival outcome in familial ALS mice. Mol Ther 18:2075-84
Foust, Kevin D; Kaspar, Brian K (2009) Over the barrier and through the blood: to CNS delivery we go. Cell Cycle 8:4017-8
Hester, Mark E; Song, Sungwon; Miranda, Carlos J et al. (2009) Two factor reprogramming of human neural stem cells into pluripotency. PLoS One 4:e7044