Prior to testing gene therapy approaches for epidermolysis bullosa simplex (EBS) in humans, it is desirable to utilise a preclinical animal model to determine the safety and efficacy of these approaches. Prof. Roop has recently generated a transgenic mouse model that mimics EBS – Dowling Meara at the genetic level. In the first part of this project Prof. Roop will genetically engineer a mouse model that expresses human keratin 14 (K14) and mimics the human disease, EBS, at both the genetic and symptomatic levels. The genetically engineered mice will be the most realistic and useful animal model for EBS so far developed.

Preliminary data from Prof. Roop’s laboratory suggest a new gene therapy strategy for treating EBS. This suggests that reducing the expression level of the mutant form of keratin 14 to approximately one half the level of normal keratin 14 would eliminate the disease symptoms. Thus, successful gene therapy approaches will not require correction or complete suppression of the mutant gene. Partial suppression of the mutant K14 may be enough.

Dr McLean has developed a novel strategy that employs ribozymes, small artificial genes that switch off other genes, to suppress expression of mutant keratin 14. In the second part of the project, Dr McLean will generate mice that express ribozymes that he has already developed that can switch off the human K14 gene. This will determine whether the ribozyme genes are safe in an actual animal.