Impact of laminin 5 beta3 gene versus protein replacement on gene expression patterns in junctional epidermolysis bullosa.

Molecular therapy studies to date have examined only a limited number of corrective parameters. To assess more global impacts on cellular gene expression for two major molecular therapeutic approaches, we compared gene versus protein delivery in the human genetic disease junctional epidermolysis bullosa (JEB). Both gene and protein replacement of the laminin 5 beta3 (beta3) adhesion molecule restored normal growth and adhesion to poorly viable JEB cells. Gene expression profiling was then performed using cDNA microarrays. The expression of more genes was normalized after beta3 gene transfer than after protein transfer. As anticipated for beta3 delivery, many of the genes whose expression was restored to the normal range were those encoding adhesion molecules and hemidesmosome components. Although gene transfer normalized the expression of a higher percentage of genes than did protein transfer, neither approach fully normalized expression of all genes examined. In addition, both approaches disrupted the expression of some genes, but protein transfer altered expression of a larger proportion of the genes studied. Our findings suggest that therapeutic gene and protein delivery may exert different effects on gene expression and thus may have implications for the development and analysis of molecular therapies for the treatment of genetic disorders.