Functional correction of short-chain acyl-CoA dehydrogenase deficiency in transgenic mice: implications for gene therapy of human mitochondrial enzyme deficiencies
Functional correction of short-chain acyl-CoA dehydrogenase deficiency in transgenic mice: implications for gene therapy of human mitochondrial enzyme deficiencies
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DOI：
10.1093/hmg/6.9.1451
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发表时间：
1997-09-01
影响因子：
3.5
通讯作者：
Wood, PA
中科院分区：
文献类型：
--
作者：
Kelly, CL;Rhead, WJ;Wood, PA
我们报道了短链酰基辅酶a脱氢酶（SCAD）转基因在SCAD缺陷小鼠模型中的肝脏特异性表达的治疗效果。在SCAD正常遗传背景和SCAD缺陷背景下，用大鼠白蛋白启动子/增强子驱动小鼠SCAD小基因（ALB-SCAD），在SCAD缺陷背景下产生的三个转基因系中，重组SCAD活性和肝脏线粒体抗原均为正常对照值的7倍，3个品系均显示有机酸尿和脂肪肝明显减少，这是儿童本病代谢异常的敏感指标。这些研究为核编码线粒体酶缺陷的潜在基因治疗提供了重要的基础和实用的治疗信息，并深入了解了该疾病的机制。
We report the therapeutic effects of liver-specific expression of a short-chain acyl-CoA dehydrogenase (SCAD) transgene in the SCAD-deficient mouse model, Transgenic mice were produced with a rat albumin promoter/enhancer driving a mouse SCAD minigene (ALB-SCAD) on both the SCAD normal genetic background and a SCAD-deficient background, In three transgenic lines produced on the SCAD-deficient background, recombinant SCAD activity and antigen in liver mitochondria were found up to 7-fold of normal control values, All three lines showed a markedly reduced organic aciduria and fatty liver, which are sensitive indicators of the metabolic abnormality seen in this disease found in children. We found no detrimental effects of high liver SCAD expression in transgenic mice on either background, These studies provide important basic and practical therapeutic information for the potential gene therapy of nuclear-encoded mitochondrial enzyme deficiencies, as well as insights into the mechanisms of the disease.