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Krabbe disease (KD) is an autosomal recessive lysosomal disorder caused by the deficiency of galactocerebrosidase (GALC) activity. This results in a severe, fatal disorder primarily affecting young children. While most patients die by 3 years of age, later onset forms, including adults are also diagnosed with KD. This laboratory has diagnosed nearly 400 patients of all ages with KD. We were the first laboratory to purify GALC and clone the GALC cDNA and gene. In addition to human patients with KD, there are three naturally occurring animal models with low GALC activity. Their GALC genes have also been cloned in this laboratory and the mutations causing the low GALC activity have been determined. We have identified nearly 60 mutations causing KD in the human patients available to us. At present we are developing methods to treat KD, starting initially with the animal models. We have placed human and mouse cDNAs into several viral vectors including retroviral, adeno-associated viruses, lentivirus and SV40. We have successfully transduced oligodendrocytes from the twitcher mice model with viral vectorrs containing human GALC cDNA and corrected them to a normal phenotype. We are now starting in vivo studies in mice. We have given the canine model bone marrow transplants and seen an amelioration of clinical features. At present we are investigating the role of growth factors and substrate inhibitors on the onset of symptoms in the mouse models. This studies will lead to a better understanding of the role of GALC in producing healthy myelin and provide information that will lead to effective treatment for this severe genetic disease.
Krabbe disease (KD) is an autosomal recessive lysosomal disorder caused by the deficiency of galactocerebrosidase (GALC) activity. This results in a severe, fatal disorder primarily affecting young children. While most patients die by 3 years of age, later onset forms, including adults are also diagnosed with KD. This laboratory has diagnosed nearly 400 patients of all ages with KD. We were the first laboratory to purify GALC and clone the GALC cDNA and gene. In addition to human patients with KD, there are three naturally occurring animal models with low GALC activity. Their GALC genes have also been cloned in this laboratory and the mutations causing the low GALC activity have been determined. We have identified nearly 60 mutations causing KD in the human patients available to us. At present we are developing methods to treat KD, starting initially with the animal models. We have placed human and mouse cDNAs into several viral vectors including retroviral, adeno-associated viruses, lentivirus and SV40. We have successfully transduced oligodendrocytes from the twitcher mice model with viral vectorrs containing human GALC cDNA and corrected them to a normal phenotype. We are now starting in vivo studies in mice. We have given the canine model bone marrow transplants and seen an amelioration of clinical features. At present we are investigating the role of growth factors and substrate inhibitors on the onset of symptoms in the mouse models. This studies will lead to a better understanding of the role of GALC in producing healthy myelin and provide information that will lead to effective treatment for this severe genetic disease.
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Nada Kojak, Daisuke Kajimura,Junko Kuno, Kristina Solarino, Ambereen Khan,David Wenger, Roberto Donnianni, Michael Glasser,Yajun Tang, Terrence Turner,Roxanne Ally, Jose Rojas,
TRANSGENIC RESEARCH (2023): S10-S11
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Lysosomal Storage Disorderspp.114-125, (2022)
Allison M. Bradbury,Jessica H. Bagel, Paul Szabolocs,Xiao H. Wang, Ian J. Hendricks,Michael H. Gelb,Neil Hackett,David A. Wenger,Charles H. Vite,Maria L. Escolar
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JIMD reportsno. 1 (2020): 61-67
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