Kemp S, Wei H M, Lu J F, Braiterman L T, McGuinness M C, Moser A B, Watkins P A, Smith K D
Kennedy Krieger Institute, Department of Pediatrics, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
Nat Med. 1998 Nov;4(11):1261-8. doi: 10.1038/3242.
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.
随着在哺乳动物细胞中发现更多的功能冗余，增强参与替代途径的基因表达可能会成为一种有效的基因治疗形式。X连锁肾上腺脑白质营养不良（X-ALD）是一种过氧化物酶体疾病，其极长链脂肪酸代谢受损。X-ALD基因编码一种过氧化物酶体膜蛋白（ALDP），它是相关过氧化物酶体膜蛋白小家族的一部分。我们发现，用4-苯基丁酸处理X-ALD患者和X-ALD基因敲除小鼠的细胞，会导致极长链脂肪酸水平降低以及β-氧化增加；过氧化物酶体蛋白ALDRP的表达增加；以及过氧化物酶体增殖的诱导。我们还通过用ALDRP cDNA互补X-ALD成纤维细胞证明了ALDP和ALDRP在功能上相关。最后，我们通过在X-ALD小鼠的大脑和肾上腺中大幅降低极长链脂肪酸水平，证明了饮食中4-苯基丁酸治疗的体内疗效。
