Gene redundancy and pharmacological gene therapy: Implications for X-linked adrenoleukodystrophy
Gene redundancy and pharmacological gene therapy: Implications for X-linked adrenoleukodystrophy
复制标题
DOI：
10.1038/3242
复制
发表时间：
1998-11-01
期刊：
影响因子：
82.9
通讯作者：
Smith, KD
中科院分区：
文献类型：
--
作者：
Kemp, S;Wei, HM;Smith, KD
随着在哺乳动物细胞中发现更多的功能冗余，参与替代途径的基因的增强表达可能成为基因治疗的有效形式。X-连锁肾上腺脑白质营养不良（X-ALD）是一种过氧化物酶体异常，伴有极长链脂肪酸代谢受损。X-ALD基因编码过氧化物酶体膜蛋白（ALDP），其是相关过氧化物酶体膜蛋白小家族的一部分。我们发现，4-苯基丁酸酯治疗的细胞从X-ALD患者和X-ALD敲除小鼠的结果在水平降低和增加的极长链脂肪酸的β-氧化;增加的过氧化物酶体蛋白ALDRP的表达;和过氧化物酶体增殖的诱导。我们还表明，ALDP和ALDRP功能相关，ALDRP cDNA互补的X-ALD成纤维细胞。最后，我们证明了饮食4-苯丁酸酯治疗的体内功效，通过其生产的X-ALD小鼠的大脑和肾上腺中的极长链脂肪酸水平的大幅降低。
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.