Gene redundancy and pharmacological gene therapy: Implications for X-linked
adrenoleukodystrophy
Stephan Kemp, He-Ming Wei, Jyh-Feng Lu, Lelita T Braiterman, Martina C. McGuinness, Ann B. Moser, Paul A. Watkins
& Kirby D. Smith
Kennedy Krieger Institute; Institute of Genetic Medicine
and Departments of Pediatrics and Neurology, The Johns Hopkins School of Medicine,
Baltimore, 707 N. Broadway, Room 400A, Baltimore
, Maryland 21205, USA
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 -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.
-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.
