title: Mechanism-based combination treatment dramatically increases therapeutic efficacy in murine globoid cell leukodystrophy.
abstract: Globoid cell leukodystrophy (GLD, Krabbe disease) is a lysosomal storage disease (LSD) caused by a deficiency in galactocerebrosidase (GALC) activity. In the absence of GALC activity, the cytotoxic lipid, galactosylsphingosine (psychosine), accumulates in the CNS and peripheral nervous system. Oligodendrocytes and Schwann cells are particularly sensitive to psychosine, thus leading to a demyelinating phenotype. Although hematopoietic stem-cell transplantation provides modest benefit in both presymptomatic children and the murine model (Twitcher), there is no cure for GLD. In addition, GLD has been relatively refractory to virtually every experimental therapy attempted. Here, Twitcher mice were simultaneously treated with CNS-directed gene therapy, substrate reduction therapy, and bone marrow transplantation to target the primary pathogenic mechanism (GALC deficiency) and two secondary consequences of GALC deficiency (psychosine accumulation and neuroinflammation). Simultaneously treating multiple pathogenic targets resulted in an unprecedented increase in life span with improved motor function, persistent GALC expression, nearly normal psychosine levels, and decreased neuroinflammation. Treating the primary pathogenic mechanism and secondary targets will likely improve therapeutic efficacy for other LSDs with complex pathological and clinical presentations.
authors.affiliation: Departments of Internal Medicine.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Hawkins-Salsbury
authors.affiliation: Departments of Internal Medicine.
authors.forename: Lauren
authors.initials: L
authors.lastname: Shea
authors.affiliation: Departments of Internal Medicine.
authors.forename: Xuntian
authors.identifier: http://orcid.org/0000-0001-9048-7294
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Surgery, and.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Hunter
authors.affiliation: Department of Pathology, St Louis University School of Medicine, St Louis, Missouri 63104, and.
authors.forename: A Miguel
authors.initials: AM
authors.lastname: Guzman
authors.affiliation: Departments of Internal Medicine.
authors.forename: Adarsh S
authors.initials: AS
authors.lastname: Reddy
authors.affiliation: Departments of Internal Medicine.
authors.forename: Elizabeth Y
authors.initials: EY
authors.lastname: Qin
authors.affiliation: Departments of Internal Medicine.
authors.forename: Yedda
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Gray
authors.affiliation: Departments of Internal Medicine.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.affiliation: Departments of Internal Medicine, Genetics, Washington University School of Medicine, St Louis, Missouri 63110, msands@dom.wustl.edu.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sands
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D016026:Bone Marrow Transplantation; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003131:Combined Modality Therapy; D003523:Cycloserine / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005698:Galactosylceramidase / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D007965:Leukodystrophy, Globoid Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009048:Motor Skills / Q000187:drug effects; D009186:Myelin Sheath / Q000187:drug effects / Q000502:physiology; D011609:Psychosine / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism
chemical_list: D016207:Cytokines; D011609:Psychosine; D003523:Cycloserine; D005698:Galactosylceramidase
keywords: Krabbe disease; dysmyelination; gene therapy; globoid cell leukodystrophy; lysosomal storage disease