This is a clinical trial which aims to use gene-corrected grafts to treat chronic wounds of patients with RDEB.
A skin biopsy is taken from the EB patient, which is used to culture cells called keratinocytes and fibroblasts in the laboratory. These are then converted with a viral vector which contains a copy of the COL7AI gene which is faulty in Recessive Dystrophic EB patients. These gene corrected cells are used to produce a full-thickness graft called a skin equivalent, which will be grafted onto chronic wounds.
As the grafts are gene-corrected in all layers, they have the potential to permanently heal the areas they are grafted on to.
The preclinical work for EBGRAFT was made possible through a European Research Grant project called Genegraft. Cure EB is funding the first phase 1/2 clinical trial.
Professor Alain Hovnanian, Head of the research laboratory on genetic skin disease at Imagine Institute, Paris
Professor Fernando Larcher, Universidad Carlos 3 Madrid
Professor John McGrath, Professor of Molecular Dermatology at Guy’s and St Thomas’ NHS Foundation Trust, Kings College London
Data from EBSTEM provides a strong rationale for their routine use in care for children with RDEB. Intravenous infusions of allogeneic cells as the most valuable interim treatment of RDEB until such a time when more definitive therapies that target the underlying genetic pathology becomes available.
Co-funding with NIHR
Dr Anna Martinez GOSH, Professor John McGrath, Mark Lowdell Royal Free
Professor Francesco Dazzi, Kings College London
Professor Paul Veys
Gene Editing for EB
In the laboratory, Professor Qasim’s team has already established proof of concept for gene editing. They now plan to target and repair a range of different Collagen VII gene mutations that affect patients in the UK. Cells will be ‘fixed’, then their ability to make normal skin will be tested. They will also be looking for possible side effects in these experiments.
ONGOING 3 YEAR PROJECT
The UK team at Great Ormond Street and the Institute of Child Health has a world first in using TALENS to cure a baby with Leukaemia, as reported on BBC Health.
Pre Clinical & Gene Editing Trial
Using grafts of autologous gene corrected skin equivalents.
Professor Larcher & Professor Marcela Del Rio at Universidad Carlos III Madrid Spain
Next Generation Genome Sequencing
Developing personalised cell therapies that use gene addition and gene editing techniques. New technology means that we can now try and repair genes, rather than just adding them to existing cells. This technology involves the use of tiny molecular ‘scissors’, which are guided to a particular gene in a very targeted manner in order to cut the section of DNA that needs repairing. This region is then repaired using a ‘patch’ with the right DNA code. The first aim of this project is to generate sets of these molecular ‘scissors’ to correct the majority of the Collagen VII mutations that cause RDEB. The second aim is to increase the body’s response to Collagen VII in RDEB sufferers, to help make up for the fact that people with RDEB have less of it than non-sufferers.
IN COLLABORATION WITH EBRP & EBMRF
DURATION: 5 year project, started 2017
Clinical Development of TXA127
TXA127 has demonstrated substantial anti-fibrotic effects and showed a reduction in the fusion of digits, a symptom in RDEB mice that is analogous to mitten deformity common in patients with severe RDEB. In the first part of the new program, Constant will complete the development of an oral formulation of TXA127. TXA127 is currently delivered as a daily subcutaneous injection, but this is not suitable for patients with EB.
“Cure EB is pleased to assist in this collaboration that will accelerate development of TXA127 for RDEB patients. The development of ‘mitten deformities’ is an extremely severe consequence of RDEB and we thank Constant Pharmaceuticals for the great opportunity to move towards a therapy for RDEB alongside its programs for other conditions” said Sharmila Collins Founder and Trustee, CureEB.
Collaboration with Constant Pharmaceuticals, DEBRA Austria, EBRP
For more details, read the full press release from Constant Pharmaceuticals.
Nanoneedle bandage for topical gene therapy. Research towards developing the nanoneedle bandage as a painless, simple and rapid approach to deliver functional COL7A1 genes to blistered/eroded skin in order to accelerate skin healing. To test application of a bandage to the affected areas, to deliver genes intracellularly over a prolonged time, restoring the integrity and mechanical stability of the dermal-epidermal junction.
Professor Tolar at University of Minnesota and Professor McGrath & Dr Chiappini at Kings College London
Spin Therapeutics RNA derm for EB simplex
Discovery of systemically-administered siRNAs targeting Mutant KRT5 and KRT14 as therapeutics for Epidermolysis Bullosa Simplex.
COLLABORATION WITH EBRP AND EBMRF
Professor Alain Hovnanian MD PhD INSERM Institut Imagine Paris France & Dr Aaron Sato Berkeley CA USA
Potential Gene Therapy for Airway Disease
For amelioration of respiratory symptoms in children with Junctional Epidermolysis Bullosa (JEB). The work here aims to deliver laboratory-based tools to model EB airway disease, as well as to use lentiviral gene editing tools to correct EB-affected airway lining. This proposal is a proof-of-principal project demonstrating the feasibility of combining Lentiviral gene editing with airway Epithelial stem cell therapeutics.
FUNDING IN COLLABORATION WITH DEBRA UK AND DEBRA AUSTRIA
FIBRX Derm is working on a topical gel with Decorin, a natural protein found in humans, to prevent scarring in individuals with Dystrophic EB (DEB). The idea behind this research came from a study of identical twins with RDEB; although both twins had the same genetic mutation in their collagen VII genes, one twin presented with widespread wounds and scars while the other did not. The researchers found that the twin who had less scarring was expressing nearly twice as much Decorin protein than the other. These researchers aim to create a Decorin gel to slow and reverse the process of fibrosis, or scarring, that DEB patients suffer from.
Co-funded with EBRP, EBMRF, Debra US and UK
Jean Tang MD PhD, Mark D’Souza PhD CEO FIBRX Derm Inc Berkley, CA
Developing a non-viral gene therapy for RDEB.
Professor Wenxin Wang t Nova UCD, Dublin, Ireland