GENE REDUNDANCY AND PHARMACOLOGICAL GENE-THERAPY - IMPLICATIONS FOR X-LINKED ADRENOLEUKODYSTROPHY

As more functional redundancy in mammalian cells is discovered, enhanc ed 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 met abolism. The X-ALD gene encodes a peroxisomal membrane protein (ALDP) that is part of a small family of related peroxisomal membrane protein s. We show that 4-phenylbutyrate treatment of cells from both X-ALD pa tients and X-ALD knockout mice results in decreased levels of and incr eased beta-oxidation of very-long-chain fatty acids; increased express ion of the peroxisomal protein ALDRP; and induction of peroxisome prol iferation. We also demonstrate that ALDP and ALDRP are functionally re lated, by ALDRP cDNA complementation of X-ALD fibroblasts. Finally, we demonstrate the in vivo efficacy of dietary 4-phenylbutyrate treatmen t through its production of a substantial reduction of very-long-chain fatty acid levels in the brain and adrenal glands of X-ALD mice.