A TALEN-based approach to developing safer, more effective treatments for people with EB

Contents:

• Project information
• Lay summary

Investigator: Professor Jakub Tolar, Professor of Paediatrics

Institution: Department of Paediatrics, University of Minnesota, USA

Grant: SRF - $250,000 (01/02/2013 – 31/01/2015)

Lay summary

The fragile skin of people with recessive dystrophic epidermolysis bullosa (RDEB) is caused by a genetic mistake (mutation) that interferes with the normal production of a protein called collagen VII. In normal skin, collagen VII creates fibres that hold the layers of the skin together. In theory, correcting the genetic mistake would result in production of collagen VII and the restoration of the normal function in the skin.

This group is developing a remarkable new technology for correcting genetic mistakes. This technology, called TALEN (Transcription Activator-Like Effector Nuclease), allows them to target the faulty gene, cut it out and insert the correct gene sequence. This should be an improvement on earlier attempts at gene therapy that added the correct genetic material at random.

The researchers use powerful computer software to identify very specific places in the DNA on either side of the faulty section. They then design molecules to recognise these places and attach to them. These molecules also carry a chemical that cuts the DNA and removes the genetic mistake. Analysis of the DNA from current studies has shown they have been successful in removing and replacing the right sections of DNA in EB skin cells.

This group has taken skin cells from RDEB patients and used state-of-the-art techniques to grow them in large numbers in the laboratory. They have also used a technology that gives these cells the properties of stem cells, which can create many different kinds of cells under the correct conditions. Once the gene editing system is optimised, corrected cells from patients can be grown in the lab in to different kinds of cells useful for skin repair and for transplantation.

The technology developed in this study has potentially profound implications for the future of research into RDEB and its treatment.

What is important about this research?

“Support from DEBRA has been critical in allowing us to take innovative directions in looking for better treatments for RDEB, for example using new gene-editing technologies."

Investigator Biography Dr Jakub Tolar is the Director of the Stem Cell Institute and a Professor at the University of Minnesota. His research led to the first use of bone marrow transplant as a therapy for recessive dystrophic epidermolysis bullosa (RDEB). He is now developing new treatments using cells from the RDEB patients themselves. He is exploring both naturally occurring, self-corrected cells and gene-edited cells as protein-producing sources for skin wounds and for whole-body therapy. Dr Tolar and his team are working hard to move these ideas from the laboratory to the clinic.