European Union funded research Therapeuskin report by Alain Hovnanian

European Union funded research

THERAPEUSKIN 16th November 2005

Therapeuskin report by Alain Hovnanian

A first kick-off meeing was held in Paris in July 2005. A second meeting is planned for January 2006.

Important results have already been obtained. A safe retroviral vector has now been developed by Dr Zanta-Boussif and Olivier Danos at Genethon for genetic transfer of COL7A1 cDNA into keratinocytes and fibroblasts. This vector is a SIN (Self Inactivating) vector, in which the expression of COL7A1 is under the control of its own promoter, which confers physiological regulation of COL7A1 expression. This new vector has now been extensively tested by Matthias Titeux in Alain Hovnanian’s group in Toulouse and was shown to be highly efficient for genetic correction of primary RDEB keratinocytes and fibroblasts in culture. Reconstructed skins made from genetically corrected keratinocytes and/or fibroblasts have been grafted onto immune deficent mice to study long term expression of type VII collagen. Type VII collagen was shown to be secreted and deposited along the basement membrane zone, and anchoring fibrills were formed as shown by electron-microscopy examination of skin equivalent biopsies taken from 2 to 5 months.

In parallel, clinicians (John Dart’s, Alain Hovnanian and Christine Bodemer’s group) have identified additional RDEB patients will residual type VII collagen expression who could enter the first clinical trial.
Dr Yann Barrandon’s group has made significant progresses in the regulatory aspects for setting up a pilot clinical trial in Switzerland. This group has also been involved in the improvement of the transplantation technology through EurosStemCell consortium. The secured retroviral COL7A1 vector has been sent to Dr Barrandon’s group to set up transduction procedures in this laboratory.
Medico-legal aspects of cross-European Gene Therapy clinical trials are being discussed by Dr Dart and Dr Irene Leigh with relevant UK authorities. COL7A1 retroviral vector has also been sent to Dr Leigh’s laboratory to study unlikely oncogenic tranformation.
Dr Moroder’s group is interacting with Hovnanian’s group for biochemical characterisation of the recombinant type VII collagen.

In conclusion, major progresses have been made in the pre-clinical study for ex vivo gene therapy for RDEB using highly secure COL7A1 retroviral vectors. The proof of feasibility has now been clearly obtained. The efforts now aim at investigating the immune tolerance of the newly produced type VII collagen, developing an alternative safe COL7A1-Lentiviral vector, verifying the absence of tumoral complication and finally in preparing a first clinical trail.