Role of Potent Trophic Factors on Glia and Motor Neurons in ALS

Summary

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

Top Publications

  1. pmc Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes
    Kevin D Foust
    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
  2. pmc Targeted delivery of self-complementary adeno-associated virus serotype 9 to the brain, using magnetic resonance imaging-guided focused ultrasound
    Emmanuel Thévenot
    Brain Sciences Sunnybrook Research Institute, Toronto, ON, Canada
    Hum Gene Ther 23:1144-55. 2012
  3. pmc Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling
    Carlos J Miranda
    Center for Gene Therapy, Nationwide Children s Hospital Research Institute, Columbus, OH 43205, USA
    Aging Cell 11:542-52. 2012
  4. pmc Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone
    Jonathan A Fidler
    Genzyme Corporation, 49 New York Ave, Framingham, MA 01701 9322, USA
    FASEB J 25:4369-77. 2011
  5. pmc Astrocytes from familial and sporadic ALS patients are toxic to motor neurons
    Amanda M Haidet-Phillips
    The Research Institute at Nationwide Children s Hospital, Columbus, Ohio, USA
    Nat Biotechnol 29:824-8. 2011
  6. pmc Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes
    Mark E Hester
    Center for Gene Therapy, The Research Institute at Nationwide Children s Research Institute, Columbus, Ohio, USA
    Mol Ther 19:1905-12. 2011
  7. pmc AAV4-mediated expression of IGF-1 and VEGF within cellular components of the ventricular system improves survival outcome in familial ALS mice
    James C Dodge
    Genzyme Corporation, Framingham, Massachusetts 01701 9322, USA
    Mol Ther 18:2075-84. 2010
  8. pmc Two factor reprogramming of human neural stem cells into pluripotency
    Mark E Hester
    The Research Institute at Nationwide Children s Research Institute, Columbus, Ohio, USA
    PLoS ONE 4:e7044. 2009
  9. pmc Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis
    Ashley 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

Detail Information

Publications10

  1. pmc Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes
    Kevin D Foust
    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...
  2. pmc Targeted delivery of self-complementary adeno-associated virus serotype 9 to the brain, using magnetic resonance imaging-guided focused ultrasound
    Emmanuel Thévenot
    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...
  3. pmc Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling
    Carlos J Miranda
    Center for Gene Therapy, Nationwide Children s Hospital Research Institute, Columbus, OH 43205, USA
    Aging Cell 11:542-52. 2012
    ....
  4. pmc Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone
    Jonathan A Fidler
    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...
  5. pmc Astrocytes from familial and sporadic ALS patients are toxic to motor neurons
    Amanda 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...
  6. pmc Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes
    Mark 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...
  7. pmc AAV4-mediated expression of IGF-1 and VEGF within cellular components of the ventricular system improves survival outcome in familial ALS mice
    James 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...
  8. pmc Two factor reprogramming of human neural stem cells into pluripotency
    Mark E Hester
    The Research Institute at Nationwide Children s Research Institute, Columbus, Ohio, USA
    PLoS ONE 4:e7044. 2009
    ....
  9. pmc Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis
    Ashley 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
    ....

Research Grants62

  1. Evaluating HMG-CoA reductase as a therapeutic target in ALS
    Christopher Henderson; Fiscal Year: 2013
    ..Lastly, our data should stimulate further research into the specific processes modulated by statins in motor neurons, and thereby help identify more selective targets - such as protein prenylation - for future drug development. ..
  2. Role of MMP-9 in selective motor neuron degeneration in ALS
    Christopher 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. ..
  3. Immune Regulation of Neuronal Injury and Repair
    KATHRYN JANE JONES; Fiscal Year: 2013
    ..Identification of defects in neural:immune interactions will have an important positive impact because they can then be the target of therapeutic intervention in ALS treatment. ..
  4. Gene delivery to muscle and nerve for laminin-alpha2-deficient MD (MDC1A)
    Xiao Xiao; Fiscal Year: 2013
    ..The success of this research plan could be potentially translatable to MDC1A patients and to other neuromuscular diseases as well. ..
  5. The Nrf2-ARE Pathway in Amyotrophic Lateral Sclerosis
    Jeffrey A Johnson; Fiscal Year: 2013
    ..Test the efficacy of clinically relevant approaches for the treatment o ALS using viral-mediated delivery of Nrf2 or non- viral delivery of Keap1 siRNA. ..
  6. High Throughput Screening for Compounds to Mitigate Toxicity of FUS/TLS &SOD1
    Robert H Brown; Fiscal Year: 2013
    ..Moreover, it is conceivable that the compounds discovered in these studies will prove beneficial in neurodegenerative conditions other than ALS alone. ..
  7. DEFINING THE MECHANISM OF TDP-43 RELATED NEURODEGENERATION
    Robert Baloh; Fiscal Year: 2013
    ..These studies will examine previously unexplored pathways of ALS pathogenesis, and identify new avenues for therapeutics development. ..
  8. Neural Mechanisms of Itch
    ROBERT H LA MOTTE; Fiscal Year: 2013
    ..abstract_text> ..
  9. Blocking TLR-Activation of Regulatory T cells Slows Disease in ALS
    Stanley H Appel; Fiscal Year: 2013
    ..These experiments will lead to the identification of the most effective human TLR2 siRNAs and treatment protocols which can be directly translated to ALS patients. ..
  10. Modeling Mutant Profilin 1 Toxicity and ALS in vivo
    Zuoshang Xu; Fiscal Year: 2013
    ....
  11. STUDYING THE ROLE OF INFLAMMATORY MEDIATOR MIR-155 IN A MOUSE MODEL OF ALS
    ERICA DANIELLE KOVAL; Fiscal Year: 2013
    ..If successful, the proposed experiments will expand our understanding of the role of microRNAs in neuroinflammation and may also help inform the development of a novel ALS therapeutic. ..
  12. Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity
    Timothy C Cope; Fiscal Year: 2013
    ..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
  13. Neuronal RNA processing defects in ALS4 caused by SETX mutations
    Craig L Bennett; Fiscal Year: 2013
    ..This underscores the importance of senataxin function in the survival of various neuronal populations. Our studies seek to determine the molecular mechanisms leading to motor neuron loss in ALS4 and further characterize the ..
  14. CENTER FOR BIOMEDICAL RESEARCH
    Timothy Turner; Fiscal Year: 2013
    ..abstract_text> ..
  15. Novel gene therapy strategies for Canavan disease
    Guang Ping Gao; Fiscal Year: 2013
    ..These proposed studies will significantly advance our current understanding of CD, and serve as the basis for the development of safe and effective rAAV gene therapeutics for CD patients. ..
  16. Impairment of the glial glutamate transporter GLT1 in ALS
    Davide 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. ..
  17. The Morris K Udall Parkinson's Disease Research Center of Excellence
    Ted M Dawson; Fiscal Year: 2013
    ..abstract_text> ..
  18. Mechanisms underlying selective motor pool vulnerability in mouse and human SMA
    Justin C Lee; Fiscal Year: 2013
    ..Future studies that focus on underlying mechanisms of neuroprotection may provide insight into principles of neurodegeneration broadly. ..
  19. PPG - Gene Therapy for Cystic Fibrosis Lung Disease
    Paul B McCray; Fiscal Year: 2013
    ..The discoveries from this PPG will accelerate the development of gene-based medicine for patients who suffer from this devastating disease...
  20. Glutathione in mitochondrial dysfunction and disease progression in ALS-models
    Marcelo R Vargas; Fiscal Year: 2013
    ..abstract_text> ..
  21. Defining a clinically relevant time point for astrocyte targeted therapy in ALS
    Brian K Kaspar; Fiscal Year: 2013
    ..This work will generate important insights to unravel the optimal therapeutic time window for attenuating aberrant glial cell toxicity in ALS providing the basis for a translational approach to remove mtSOD1 in patients. ..
  22. Injury and Recovery in Developing Brain
    Flora M Vaccarino; Fiscal Year: 2013
    ..The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth. ..
  23. The Pathogenesis of Facioscapulohumeral Muscular Dystrophy
    Stephen J Tapscott; Fiscal Year: 2013
    ..Together, these studies combine genetic, epigenetic, transcriptional and developmental approaches to defining the molecular deficits that cause FSHD and will provide a new basis for developing therapies. ..
  24. Expanding the National Health Accounts
    David M Cutler; Fiscal Year: 2013
    ..Establishment of a set of national health accounts will allow us as a society to understand which medical interventions improve the health of the U.S. population most efficiently. ..
  25. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  26. RNA-Targeted Dysregulation of Survival Factors in ALS: HuR to the Rescue
    Peter H King; Fiscal Year: 2013
    ..2. To determine the molecular impact of transgenic HuR expression in motor neurons and astrocytes with regard to posttranscriptional regulation and production of cytoprotective factors. ..
  27. SOD1/Bcl-2 induced mitochondrial dysfunction in FALS and SALS.
    Piera Pasinelli; Fiscal Year: 2013
    ..Using ALS mouse models (with a genetic mutation) and cells derived from patients without a genetic link, we will study a potentially common mechanism of disease pathogenesis that targets the powerhouse of cells (mitochondria). ..
  28. Role of ABC efflux transporters in ALS
    Davide Trotti; Fiscal Year: 2013
    ..In this application we propose to study the regulation and role of these ABC transporters in ALS. Our ultimate goal is to understand the pathogenic mechanisms of ALS to improve the chances of success of pharmacotherapy for this disease. ..
  29. Skeletal Muscle Mechanisms of Disease in ALS
    Lee J Martin; Fiscal Year: 2013
    ..This work will determine if abnormalities in skeletal muscle have causal roles in the disease mechanisms. Skeletal muscle could provide new tissue- and molecular targets for drug discovery in ALS. ..
  30. Targeted investigation of tissue specific oxidative stress in the etiology of ALS
    Holly Van Remmen; Fiscal Year: 2013
    ....
  31. Study on Neurodegeneration Using TDP-43 Transgenic Rats
    Hongxia Zhou; Fiscal Year: 2013
    ..Proposed studies will not only develop desirable animal models for ALS research, but also would establish a foundation for developing ALS therapies targeting astrocytes or mutant TDP-43. ..
  32. Defects of mitochondrial dynamics in ALS
    Giovanni Manfredi; Fiscal Year: 2013
    ..abstract_text> ..
  33. Studies of Motoneuron Death - Insight Into the SMAs and ALS
    Carol Milligan; Fiscal Year: 2013
    ..The results of this work will contribute to our understanding of why motoneurons may be susceptible to injury and death in neurodegenerative diseases such as the SMAs and ALS. ..
  34. Novel neurotrophic therapy in a mouse model of ALS
    Alpaslan Dedeoglu; Fiscal Year: 2013
    ..The novel studies we propose will produce data to improve our understanding of disease mechanisms and test the beneficial effects of 7,8-DHF in ALS. ..
  35. XIAP Gene Therapy in Huntington's Disease
    Michael G Kaplitt; Fiscal Year: 2013
    ..Given our promising preliminary data and recent use of gene therapy in human Parkinson's disease, this application may also facilitate development of XIAP gene therapy for human HD. ..
  36. Mechanisms of Central Synaptic Dysfunction in SMA
    GEORGE ZACHARIAS MENTIS; Fiscal Year: 2013
    ..Collectively, these experiments have the potential to elucidate the importance of synaptic defects in the progression of the disease in SMA mice. ..
  37. Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
    CHRISTOPHER MARK NORRIS; Fiscal Year: 2013
    ..These studies provide a highly novel approach to the study of activated astrocytes and could have a major impact on the development of treatment strategies for AD and other neurodegenerative conditions. ..
  38. GENE THERAPY FOR METABOLIC DISORDERS
    Chester B Whitley; Fiscal Year: 2013
    ..abstract_text> ..
  39. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  40. Neurofilaments, SOD1 and Motor Neuron Diseases
    Don W Cleveland; Fiscal Year: 2013
    ..This question is of especially high interest for astrocytes, which are known to generate one or more toxicities from their synthesis of ALS causing mutants in SOD1. ..
  41. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  42. National Gene Vector Biorepository and Coordinating Center at Indiana University
    Kenneth Cornetta; Fiscal Year: 2013
    ..We will also develop a standardize assay designed specifically to meet the FDA requirements and improve the clinical relevance of assay output. ..
  43. FUS/TLS GAIN AND LOSS OF FUNCTION IN ALS: ANIMAL AND CELLULAR MODELS OF DISEASE
    NEIL ALAN SHNEIDER; Fiscal Year: 2013
    ....
  44. Motor Neuron Disease in Mouse Models of ALS: Where Does The End Begin
    Carol Milligan; Fiscal Year: 2013
    ..We anticipate that after identifying the location of early nervous system changes in ALS we will use this information to propel further studies into disease biomarkers and the development of therapeutic interventions. ..
  45. TBI-Induced Cerebral Metabolic Depression and Recovery
    David A Hovda; Fiscal Year: 2013
    ..This program project will be housed within the UCLA Brain Injury Research Center (Dr. David A. Hovda, Director) so as to assure appropriate imaging, administrative and laboratory support. ..
  46. UNDERSTANDING THE ROLE OF MITOCHONDRIAL IMPORT IN AMYOTROPHIC LATERAL SCLEROSIS
    Matthew Crisp; Fiscal Year: 2013
    ..Finally, we will apply this model applies to additional forms of ALS by examining TOM protein levels in sporadic and familial TDP-43 human spinal cords. ..
  47. The Aging Pituitary-Gonadal Axis
    George R Bousfield; Fiscal Year: 2013
    ..While currently available preparations work well in young women, they become increasingly ineffective in older women, requiring higher doses and prolonged administration yet producing fewer oocytes. ..
  48. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  49. Peroxynitrite, nitrotyrosine and HSP90 in neuronal death
    ALVARO G ESTEVEZ; Fiscal Year: 2013
    ..Completion of the specific aims will provide a mechanistic basis for explaining how motor neurons are particularly vulnerable to SOD mutations and establish a link between sporadic and familial SODs. ..
  50. Mechanism of FUS Mutations in the Pathogenesis of ALS
    Eric J Huang; Fiscal Year: 2013
    ....