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.
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.
|Rinaldi, Federica; Motti, Dario; Ferraiuolo, Laura et al. (2017) High content analysis in amyotrophic lateral sclerosis. Mol Cell Neurosci 80:180-191|
|Meyer, Kathrin; Kaspar, Brian K (2017) Glia-neuron interactions in neurological diseases: Testing non-cell autonomy in a dish. Brain Res 1656:27-39|
|Song, SungWon; Miranda, Carlos J; Braun, Lyndsey et al. (2016) Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis. Nat Med 22:397-403|
|Israelson, Adrian; Ditsworth, Dara; Sun, Shuying et al. (2015) Macrophage migration inhibitory factor as a chaperone inhibiting accumulation of misfolded SOD1. Neuron 86:218-32|
|Frakes, Ashley E; Ferraiuolo, Laura; Haidet-Phillips, Amanda M et al. (2014) Microglia induce motor neuron death via the classical NF-?B pathway in amyotrophic lateral sclerosis. Neuron 81:1009-1023|
|Miranda, Carlos J; Braun, Lyndsey; Jiang, Yuying et al. (2012) Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling. Aging Cell 11:542-52|
|Thevenot, Emmanuel; Jordao, Jessica F; O'Reilly, Meaghan A et al. (2012) Targeted delivery of self-complementary adeno-associated virus serotype 9 to the brain, using magnetic resonance imaging-guided focused ultrasound. Hum Gene Ther 23:1144-55|
|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|
|Haidet-Phillips, Amanda M; Hester, Mark E; Miranda, Carlos J et al. (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29:824-8|
|Hester, Mark E; Murtha, Matthew J; Song, SungWon et al. (2011) Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes. Mol Ther 19:1905-12|
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