Krabbe disease or globoid cell leukodystrophy is a severe disorder of CNS and PNS myelin caused by mutations in the gene coding for galactocerebrosidase (GALC). The accumulation of one substrate, psychosine, is cytotoxic and induces the apoptotic death of oligodendrocytes (OLG) in the CNS and Schwann cells in the PNS. This is a project to treat murine and canine models using several approaches, including gene therapy and stem cell transplantation. A new transgenic mouse model (trs5O2) with low GALC activity was generated and will be utilized in some treatment studies. These mice live longer than twitcher (twi) mice and have large litters resulting in more affected pups for study. Recent studies show that the human GALC is not efficiently processed in rodent tissues so mouse GALC (mGALC) cDNA will be cloned into several viral vectors, including MFG, AAV and avian C-type retrovirus (SNV) for in vivo and ex vivo gene therapy trials. Insulin-like growth factor-I (IGF-1) has been shown to induce the proliferation of OLG progenitors, to increase remyelination after chemical or viral insults, and to prevent apoptotic death of OLG. Therefore, successful treatment of this disease may require delivery of GALC activity to prevent psychosine accumulation plus IGF-I to prevent apoptotic cell death and to induce remyelination. Initially IGF-1 will be injected subcutaneously in trsSO2 and twi mice to evaluate its effect clinically, biochemically and pathologically. A bi-cistronic viral vector containing mGALC cDNA plus IGF-I cDNA will be constructed in order to supply GALC activity plus IGF-1 to induce remyelination. A transgenic mouse that expresses IGF-1 under control of the myelin basic promoter will be generated and mated with GALC deficient mice to investigate its role in inducing remyelination when GALC activity is supplied via gene therapy or stem cell transplantation. Transduced and untransduced hematopoietic stem cells will be transplanted in the mouse and canine models with IGF-l supplementation. The effect of L-cycloserine to prolong life of the munne and canine models will be investigated. Treated dogs will be followed clinically and monitored by MRI and biochemical and pathological studies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Medical Biochemistry Study Section (MEDB)
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Mckeon, Catherine T
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Thomas Jefferson University
Internal Medicine/Medicine
Schools of Medicine
United States
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Chuang, Wei-Lien; Pacheco, Josh; Zhang, X Kate et al. (2013) Determination of psychosine concentration in dried blood spots from newborns that were identified via newborn screening to be at risk for Krabbe disease. Clin Chim Acta 419:73-6
Luzi, Paola; Abraham, Ronnie M; Rafi, Mohammad A et al. (2009) Effects of treatments on inflammatory and apoptotic markers in the CNS of mice with globoid cell leukodystrophy. Brain Res 1300:146-58
Duffner, Patricia K; Caggana, Michele; Orsini, Joseph J et al. (2009) Newborn screening for Krabbe disease: the New York State model. Pediatr Neurol 40:245-52; discussion 253-5
Rafi, Mohammad A; Coppola, Stephanie; Liu, Shu Ling et al. (2003) Disease-causing mutations in cis with the common arylsulfatase A pseudodeficiency allele compound the difficulties in accurately identifying patients and carriers of metachromatic leukodystrophy. Mol Genet Metab 79:83-90