Restoration of fatty aldehyde dehydrogenase deficiency in Sjögren-Larsson syndrome.

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.