Haug S, Braun-Falco M
Division of Environmental Dermatology and Allergy, GSF, National Research Center for Environment and Health, Neuherberg/Technical University Munich, Munich, Germany.
Gene Ther. 2006 Jul;13(13):1021-6. doi: 10.1038/sj.gt.3302743. Epub 2006 Mar 9.
Sjögren-Larsson syndrome (SLS) is an autosomal recessive neurocutaneous disorder caused by mutation in the ALDH3A2 gene that codes for human fatty aldehyde dehydrogenase (FALDH). Sjögren-Larsson syndrome patients lack FALDH, which catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acids. The impaired FALDH activity leads to congenital ichthyosis, mental retardation and spasticity. The current lack of treatment is an impetus to develop gene therapy strategies by introducing functional FALDH into defective cells. We delivered human FALDH into keratinocytes of SLS patients using recombinant adeno-associated virus-2 vectors. Transduction of SLS keratinocytes resulted in an augmentation of FALDH activity comparable to phenotypically normal heterozygous carriers. Toxicity of long-chain aldehydes for FALDH-deficient cells decreased almost to the level of unaffected keratinocytes. Three-dimensional culture of corrected SLS keratinocytes revealed an ameliorated FALDH expression. These studies demonstrate the restoration of FALDH in human SLS cells supporting the concept of gene therapy as a potential future treatment option for SLS.
舍格伦-拉尔松综合征（SLS）是一种常染色体隐性神经皮肤疾病，由编码人类脂肪醛脱氢酶（FALDH）的ALDH3A2基因突变引起。舍格伦-拉尔松综合征患者缺乏FALDH，该酶催化长链脂肪醛氧化为脂肪酸。FALDH活性受损会导致先天性鱼鳞病、智力迟钝和痉挛。目前缺乏有效的治疗方法，这促使人们通过将功能性FALDH导入缺陷细胞来开发基因治疗策略。我们使用重组腺相关病毒2载体将人类FALDH导入SLS患者的角质形成细胞。SLS角质形成细胞的转导导致FALDH活性增强，与表型正常的杂合子携带者相当。长链醛对FALDH缺陷细胞的毒性几乎降至未受影响的角质形成细胞水平。经校正的SLS角质形成细胞的三维培养显示FALDH表达有所改善。这些研究证明了人类SLS细胞中FALDH的恢复，支持了基因治疗作为SLS未来潜在治疗选择的概念。
