Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) are fatal motor neuron disorders for which no significant treatments currently exist. Delivery of a therapeutic agent across the blood brain barrier (BBB) to the central nervous system is a significant problem that prevents the effective development of therapies to treat neurodegenerative diseases such as SMA and ALS. Here we propose to develop a simple vascular delivery to transduce genes across the BBB and have an impact on treatment of neurological disorders. We have discovered the unique capacity for the adeno-associated virus (serotype 9) to traverse the BBB and to efficiently target motor neurons and astrocytes within the brain and spinal cord. Here we wish to expand on these studies in mice and to translate them into the non-human primate in order to develop promising therapies for motor neuron disease. Here we propose (1) to optimize the correction of SMA and treatment of ALS in mouse models, (2) to develop a vascular delivery route for motor neuron and astrocytes targeting in the non-human primate and (3) to determine if ALS targets identified in mutant SOD1 mouse models function in human sporadic and familial SOD1 ALS models. We have assembled a team of investigators with all the critical expertise for the study of both SMA and ALS. This proposal includes studies that will not only further the understanding of the biological mechanism of motor neuron disease, but will also lead to the development of a technique for vascular delivery of therapeutics that will have widespread impact for many neurological disorders.

Public Health Relevance

This delivery system will revolutionize therapies for all neurological disorders. We will specifically focus on the two major motor neuron disorders, Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS). The delivery of SMN in SMA will have a major benefit.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
High Impact Research and Research Infrastructure Programs (RC2)
Project #
1RC2NS069476-01
Application #
7856455
Study Section
Special Emphasis Panel (ZNS1-SRB-E (32))
Program Officer
Porter, John D
Project Start
2009-09-30
Project End
2011-08-31
Budget Start
2009-09-30
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$1,679,896
Indirect Cost
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Ferraiuolo, Laura; Meyer, Kathrin; Sherwood, Thomas W et al. (2016) Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism. Proc Natl Acad Sci U S A 113:E6496-E6505
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Meyer, Kathrin; Ferraiuolo, Laura; Miranda, Carlos J et al. (2014) Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A 111:829-32
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Mitrpant, Chalermchai; Porensky, Paul; Zhou, Haiyan et al. (2013) Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy. PLoS One 8:e62114
Foust, Kevin D; Salazar, Desirée L; Likhite, Shibi et al. (2013) Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Mol Ther 21:2148-59
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

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