Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy.
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.
Kemp
S
S
Kennedy Krieger Institute, Department of Pediatrics, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
Wei
H M
HM
Lu
J F
JF
Braiterman
L T
LT
McGuinness
M C
MC
Moser
A B
AB
Watkins
P A
PA
Smith
K D
KD
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
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