title: Hematopoietic Stem cell transplantation and lentiviral vector-based gene therapy for Krabbe's disease: Present convictions and future prospects.
abstract: Currently, presymtomatic hematopoietic stem and progenitor cell transplantation (HSPCT) is the only therapeutic modality that alleviates Krabbe's disease (KD)-induced central nervous system damage. However, all HSPCT-treated patients exhibit severe deterioration in peripheral nervous system function characterized by major motor and expressive language pathologies. We hypothesize that a combination of several mechanisms contribute to this phenomenon, including 1) nonoptimal conditioning protocols with consequent inefficient engraftment and biodistribution of donor-derived cells and 2) insufficient uptake of donor cell-secreted galactocerebrosidease (GALC) secondary to a naturally low expression level of the cation-independent mannose 6-phosphate-receptor (CI-MPR). We have characterized the effects of a busulfan (Bu) based conditioning regimen on the efficacy of HSPCT in prolonging twi mouse average life span. There was no correlation between the efficiency of bone marrow engraftment of donor cells and twi mouse average life span. HSPCT prolonged the average life span of twi mice, which directly correlated with the aggressiveness of the Bu-mediated conditioning protocols. HSPC transduced with lentiviral vectors carrying the GALC cDNA under control of cell-specific promoters were efficiently engrafted in twi mouse bone marrow. To facilitate HSPCT-mediated correction of GALC deficiency in target cells expressing low levels of CI-MPR, a novel GALC fusion protein including the ApoE1 receptor was developed. Efficient cellular uptake of the novel fusion protein was mediated by a mannose-6-phosphate-independent mechanism. The novel findings described here elucidate some of the cellular mechanisms that impede the cure of KD patients by HSPCT and concomitantly open new directions to enhance the therapeutic efficacy of HSPCT protocols for KD. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.
authors.affiliation: Gene Therapy Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Peirong
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Internal Medicine, Washington University in St. Louis, School of Medicine, St Louis, Missouri.
authors.forename: Yedda
authors.initials: Y
authors.lastname: Li
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Nana
authors.initials: N
authors.lastname: Nikolaishvili-Feinberg
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois Chicago, Chicago, Illinois.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scesa
authors.affiliation: Gene Therapy Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.|Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Dao
authors.initials: D
authors.lastname: Pan
authors.affiliation: Biostatistics Core Facility, UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Dominic
authors.initials: D
authors.lastname: Moore
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois Chicago, Chicago, Illinois.
authors.forename: Ernesto R
authors.initials: ER
authors.lastname: Bongarzone
authors.affiliation: Department of Internal Medicine, Washington University in St. Louis, School of Medicine, St Louis, Missouri.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sands
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|Departments of Pathology and Laboratory Medicine and of Neurology, Neurosciences Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Ryan
authors.initials: R
authors.lastname: Miller
authors.affiliation: Gene Therapy Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. kafri@med.unc.edu.
authors.forename: Tal
authors.initials: T
authors.lastname: Kafri
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000963:Antimetabolites / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002066:Busulfan / Q000494:pharmacology; D002461:Cell Line, Transformed; D003523:Cycloserine / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D005698:Galactosylceramidase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D015316:Genetic Therapy / Q000639:trends; D005822:Genetic Vectors / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation / Q000639:trends; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007965:Leukodystrophy, Globoid Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000963:Antimetabolites; D007166:Immunosuppressive Agents; D017527:Receptor, IGF Type 2; D017451:Receptors, Somatomedin; C034304:cation-dependent mannose-6-phosphate receptor; D003523:Cycloserine; D005698:Galactosylceramidase; D002066:Busulfan
keywords: AB_10563203; AB_10611731; AB_10894189; AB_2034021; AB_313497; AB_398535; Galc-AErbd (ApoE receptor binding domain); IMSR_JAX:000845; IMSR_JAX:002014; busulfan conditioning; erythroid-specific promoter; myeloid-specific promoter