Gene therapy for keratin genodermatoses: striving forward but obstacles persist

D'Alessandro and colleagues have investigated stress responses in keratinocyte cell lines lacking keratin 14 (K14-null mutation). In this issue, they describe the use of this model to assess the extent of phenotypic rescue achievable by wild-type K14 in the absence of a dominant negative mutation. This work provides proof that, in principle, transfection of wild-type K14 on a null background can significantly normalize the cell and reduce stress responses. However, hurdles to gene therapy in vivo persist because the majority of patients with keratin genodermatoses have heterozygous dominant negative mutations, which are more disruptive than those of the null state. Although correction in the laboratory is now relatively routine, gene delivery to the skin of patients and stable correction of mutations remain major challenges.