Krabbe disease, also known as globoid cell leukodystrophy (GLD), is a neurological disorder caused by an autosomal recessive mutation in the galactocerebrosidase (GALC) enzyme. Currently, the only available treatment for those affected with this disease is bone marrow transplantation, which can be complicated by graft versus host disease (GVHD) if an immune response is mounted by the donor cells. Bone marrow transplantation is also only effective if a clinical diagnosis is made in the first few months of life. This disease is a result of a deficiency of the functional GALC enzyme and the consequent death of myelin-producing oligodendrocytes as a result of psychosine accumulation, a substrate of GALC. The hypothesis of this proposal is that the intra-cranial transplantation of GALC-transduced mesenchymal stem cells (MSCs) can prevent the onset of and improve the pathology associated with GLD in the twitcher mouse model. If the transplanted GALC-transduced MSCs engraft into the host brain and distribute throughout the brain and spinal cord, they may increase the amount of functional GALC in the CNS to supra-normal levels. In addition, MSCs secrete a variety of cytokines and growth factors that have both paracrine and autocrine activities which may suppress the local inflammation, the immune system, inhibit fibrosis and apoptosis, stimulate angiogenesis, and promote mitosis and differentiation of the host stem cells. The MSCs used in this study will be derived from the adipose tissue of C57BI/6 GFP+ transgenice mice (GFPTgASCs) in order to simulate a clinical allogeneic transplantation scenario.
In Specific Aim 1, the ability of lentiviral vectors pseudotyped with various envelope glycoproteins to transduce GFPTgASCs with functional GALC enzyme will be evaluated. Next, the ability of GALC-transduced GFPTgASCs to rescue twitcher mouse oligodendrocytes from the toxic effects of psychosine by cross-corrective and/or paracrine mechanisms will be assessed in Specific Aim 2. Finally, the therapeutic potential of intracerebroventricular transplantation of GALC-transduced GFPTgASCs in the twitcher mouse model of GLD will be evaluated. In a clinical transplantation scenario, MSCs could be isolated from the fat tissue of a healthy donor. These MSCs could then be manipulated into over-expressing the functional GALC enzyme that is missing in the cells of a patient with GLD using a viral vector. Finally, these cells could be transplanted into the brain of a patient with GLD in an effort to reduce and/or reverse the effects of GLD in the central nervous system. The approach outlined in this study using a mouse model may be applicable to humans suffering from GLD, and would circumvent the problem of GVHD present in current therapies employed to treat this disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F03A-F (20))
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Tagle, Danilo A
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Tulane University
Schools of Medicine
New Orleans
United States
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Ripoll, Cynthia B; Flaat, Mette; Klopf-Eiermann, Jessica et al. (2011) Mesenchymal lineage stem cells have pronounced anti-inflammatory effects in the twitcher mouse model of Krabbe's disease. Stem Cells 29:67-77
Bunnell, Bruce A; Betancourt, Aline M; Sullivan, Deborah E (2010) New concepts on the immune modulation mediated by mesenchymal stem cells. Stem Cell Res Ther 1:34