title: Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy.
abstract: As more functional redundancy in mammalian cells is discovered, enhanced expression of genes involved in alternative pathways may become an effective form of gene therapy. X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder with impaired very-long-chain fatty acid metabolism. The X-ALD gene encodes a peroxisomal membrane protein (ALDP) that is part of a small family of related peroxisomal membrane proteins. We show that 4-phenylbutyrate treatment of cells from both X-ALD patients and X-ALD knockout mice results in decreased levels of and increased beta-oxidation of very-long-chain fatty acids; increased expression of the peroxisomal protein ALDRP; and induction of peroxisome proliferation. We also demonstrate that ALDP and ALDRP are functionally related, by ALDRP cDNA complementation of X-ALD fibroblasts. Finally, we demonstrate the in vivo efficacy of dietary 4-phenylbutyrate treatment through its production of a substantial reduction of very-long-chain fatty acid levels in the brain and adrenal glands of X-ALD mice.
authors.affiliation: Kennedy Krieger Institute, Department of Pediatrics, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kemp
authors.forename: H M
authors.initials: HM
authors.lastname: Wei
authors.forename: J F
authors.initials: JF
authors.lastname: Lu
authors.forename: L T
authors.initials: LT
authors.lastname: Braiterman
authors.forename: M C
authors.initials: MC
authors.lastname: McGuinness
authors.forename: A B
authors.initials: AB
authors.lastname: Moser
authors.forename: P A
authors.initials: PA
authors.lastname: Watkins
authors.forename: K D
authors.initials: KD
authors.lastname: Smith
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000326:Adrenoleukodystrophy / Q000235:genetics* / Q000628:therapy*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D017931:DNA Primers; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D015316:Genetic Therapy; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008830:Microbodies / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D005810:Multigene Family; D010654:Phenylbutyrates / Q000494:pharmacology; D011506:Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014960:X Chromosome
chemical_list: C115572:ABCD1 protein, human; C431694:ABCD2 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D010654:Phenylbutyrates; D011506:Proteins; C075773:4-phenylbutyric acid