Leukodystrophies disrupt the growth/maintenance of the myelin sheath, leading to progressive degeneration of white matter and early death. Krabbe disease, a genetically based leukodystrophy detected chiefly in infants, is due to a deficiency of ?-galactosylceramidase (GALC), resulting in the accumulation of the toxic metabolite galactosyl-sphingosine, known as psychosine. Our previous findings using in vitro cell systems mimicking psychosine toxicity in neurons and oligodendrocytes, as well as in the twitcher mouse, the naturally occurring mouse model of Krabbe disease, identified downstream effects of psychosine such as lipid raft alterations, deficits in axonal transport, and deregulation of the IGF-1-Akt pathway. These observations add to the current view of Krabbe disease as a demyelinating condition with strong neuroinflammation. The intimate interaction between myelin and axons prompted us to propose that a more efficacious treatment of this disease will require a global approach, where gene correction of GALC deficiency needs to be complemented with approaches to reduce neuroinflammation and to increase the protection of neurons, and axons. Therefore, our goal for this cycle is to optimize a new combination of therapies using state-of-the-art adeno-associated viruses for global expression of therapeutic GALC in the nervous system of the twitcher mouse, in combination with hematopoietic replacement, and small molecule-based neuropharmacology to reduce neuroinflammation, cell death, and neurodegeneration. This project delivers an unparalleled opportunity to advance our understanding of Krabbe disease, and to pre-clinically test new combined therapies, with the goal of formulating safer and more powerful treatments for affected Krabbe children.

Public Health Relevance

Leukodystrophies such as Krabbe disease often affect infants and young children worldwide and are currently largely untreatable. Our proposed research is relevant to public health and NIH's mission because it will determine the therapeutic impact of new combined treatments using gene therapy, hematopoietic replacement, and small molecule neuroprotection.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Morris, Jill A
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University of Illinois at Chicago
Anatomy/Cell Biology
Schools of Medicine
United States
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Abdelkarim, Hazem; Marshall, Michael S; Scesa, Giuseppe et al. (2018) ?-Synuclein interacts directly but reversibly with psychosine: implications for ?-synucleinopathies. Sci Rep 8:12462
Marshall, Michael S; Issa, Yazan; Jakubauskas, Benas et al. (2018) Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy. Mol Ther 26:874-889
Wang, Haibo; Moyano, Ana Lis; Ma, Zhangyan et al. (2017) miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS. Dev Cell 40:566-582.e5
D'Auria, Ludovic; Reiter, Cory; Ward, Emma et al. (2017) Psychosine enhances the shedding of membrane microvesicles: Implications in demyelination in Krabbe's disease. PLoS One 12:e0178103
Nicaise, Alexandra M; Bongarzone, Ernesto R; Crocker, Stephen J (2016) A microglial hypothesis of globoid cell leukodystrophy pathology. J Neurosci Res 94:1049-61
D'Auria, Ludovic; Bongarzone, Ernesto R (2016) Fluid levity of the cell: Role of membrane lipid architecture in genetic sphingolipidoses. J Neurosci Res 94:1019-24
Zhu, Hongling; Ornaghi, Francesca; Belin, Sophie et al. (2016) Generation of a LacZ reporter transgenic mouse line for the stereological analysis of oligodendrocyte loss in galactosylceramidase deficiency. J Neurosci Res 94:1520-1530
Karumuthil-Melethil, Subha; Marshall, Michael S; Heindel, Clifford et al. (2016) Intrathecal administration of AAV/GALC vectors in 10-11-day-old twitcher mice improves survival and is enhanced by bone marrow transplant. J Neurosci Res 94:1138-51
Bongarzone, Ernesto R (2016) A tribute to the work and life of Dr. Knud H. Krabbe: Advances in genetics, neuropathogenesis, therapies, and clinical management of Krabbe's disease. J Neurosci Res 94:963-4
Scesa, Giuseppe; Moyano, Ana Lis; Bongarzone, Ernesto R et al. (2016) Port-to-port delivery: Mobilization of toxic sphingolipids via extracellular vesicles. J Neurosci Res 94:1333-40

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