Mesenchymal Stromal Cells (Msc’s)
MSC’s are cells isolated from umbilical cord blood, bone marrow and other sources. Sometimes called stem cells they can mature into different cell types and are able to stimulate anti-inflammatory responses. Inflammation is considered a key factor in some of the complications that arise in Recessive Dystrophic Epidermolysis Bullosa (RDEB) such as poor wound healing, itching pain and importantly the particularly aggressive malignant skin cancer that develops.
Phase 1/11 Clinical Trial of Mesenchymal Stromal Cells in RDEB
The EBSTEM trial was the first UK trial aiming to lead to a stem cell treatment for children with RDEB. It sought to establish if stem cells from unrelated donors who do not have EB can benefit children with RDEB in a safe efficacious way. In the EBSTEM trial, these donor stem cells were injected into the blood stream of children with RDEB, on three occasions over the period of one month. The trial led to reduced skin inflammation, reduced blistering and better wound healing.
PUBLISHED 23 APRIL 2015: Journal of Investigative Dermatology, “Potential of Systemic Allogeneic Mesenchymal Stromal Therapy for Children with RDEB.” DOI: https://doi.org/10.1038/jid.2015.158
Professor John McGrath, Kings College London with Great Ormond Street Hospital for Children NHS Trust (London) and collaborating with Utrecht, Netherlands
ADSTEM Clinical Trial
This follow-up study sought to understand if donated stem cells would have similar effects on RDEB symptoms in adults as they had on children’s symptoms in the EBSTEM trial. Results from EBSTEM suggested that individuals responded differently and there may be factors that make them good or poor responders. Studying the safety profile of stem cells in adults with RDEB is important, because they have greater scarring and there is an increased risk of skin cancer.
PUBLISHED AUGUST 2020: Journal of American Academy of Dermatology
Lenticol±F Clinical Trial
Lentiviral-mediated COL7A1 gene-modified cell therapy for RDEB
RDEB sufferers have a faulty version of a gene that produces a protein called Collagen VII. Collagen VII should help skin layers hold together, giving skin its strength. This study took samples of the collagen-producing cells from sufferers, grew them in the laboratory, and introduced a corrected version of the collagen gene using a harmless virus called a lentivirus. When enough cells with the corrected gene had been grown, they were injected back into the sufferer’s skin.
£499,320 TRIAL FUNDING (PRECLINICAL WORK FUNDING FROM DEBRA AUSTRIA €500,000)
PUBLISHED 6 JUNE 2019: JCI Insight, “Safety and early efficacy outcomes for Lentiviral Fibroblast gene therapy in Recessive Dystrophic Epidermolysis Bullosa” DOI: 10.1172/jci.insight.126243
Mesenchymal Stromal Cells engineered to express collagen VII for the treatment of Recessive Dystrophic Epidermolysis Bullosa. The expectation is that patient derived gene modified cells will have a longer lasting effect than donor MSCs. The aim was to assess if they can be manufactured and successfully delivered intravenously to give a systemic treatment for recessive dystrophic epidermolysis bullosa.
£467,185 FUNDING FROM SOHANA RESEARCH FUND
PUBLISHED JANUARY 2020: Journal of Investigative Dermatology, Volume 140, Issue 1, Pages 121–131.e6 “Human Mesenchymal Stromal Cells Engineered to Express Collagen VII Can Restore Anchoring Fibrils in Recessive Dystrophic Epidermolysis Bullosa Skin Graft Chimeras” DOI: https://doi.org/10.1016/j.jid.2019.05.031
Gene editing (or genome editing) is the insertion, deletion or replacement of DNA at a specific site in the genome of an organism or cell. It is usually achieved in the lab using engineered nucleases also known as molecular scissors. This work will not just benefit EB but will in theory be applicable to the people who suffer one of the estimated 5400 genetic disorders in the world, which accounts for 10% of people, 30 million in Europe alone.
based approach to developing safer, more effective treatments for people with EB
Developing a treatment based on a patient’s own cells, corrected in the laboratory for the gene defect, and returned to the EB individual would have the advantage of the absence of severe potential side effects such as the problems of rejection of cells from unrelated donors. The project combined two technologies, iPSC (induced pluripotent stem cells) and TALEN’s (transcription activator-like effector nuclease). The faulty gene is identified, cut out and the correct genetic sequence is inserted.
$250,000 FUNDING FROM SOHANA RESEARCH FUND
PUBLISHED FEBRUARY 2013: Molecular Therapy (2013); Volume 21 Issue 6, 1151–1159 “TALEN-based Gene Correction for Epidermolysis Bullosa” DOI: https://doi.org/10.1038/mt.2013.56
UPDATE: Professor Tolar is currently testing other gene editing techniques
Limbal Stem Cells
for treatment of corneal wounds in Epidermolysis Bullosa
The cornea is the transparent outer surface of the eye that covers the iris and pupil. It is important in bending light that enters the eye into a precise point, which enables clear vision. Most people with RDEB experience corneal erosion, an extremely painful condition that causes loss of corneal clarity and compromises clear vision. When an abrasion occurs, the intense pain and sensitivity to light leaves the RDEB patient without sight for two or three days. The aim of the project is to combine cutting-edge gene correction and stem cell technologies to tackle eye problems associated with RDEB.
PROJECT COMMISSIONED BY THE SOHANA RESEARCH FUND
Stem Cell Regeneration
of the Ocular Surface in RDEB
Following on from Limbal Stem Cell, this project was to develop a 3D cornea with limbal stem cells derived from iPSC in which RDEB mutations in the type vII gene have been edited using CRISPR/Cas9.
Squamous cell carcinoma
Squamous cell carcinoma (SCC) is an aggressive type of skin cancer that is a major cause of death among people with RDEB. Dr South and his team studied the sequences of mutations that arise in SCC to try and understand how they develop. “We’re describing for the first time a mechanism that instigates tissue damage-driven cancers,” said senior author Andrew South, PhD, an associate Professor at Jefferson (Philadelphia University + Thomas Jefferson University) in Jefferson article Researchers Reveal Cause of Aggressive Skin Cancer in Patients with Butterfly Syndrome.
$250,000, 1 YEAR. The Sohana Research Fund (now Cure EB) and EB Research Partnership funded the bulk of the research. Other contributors included Debra International and the National Cancer Institute.
PUBLISHED 21 AUGUST 2018: Raymond J. Cho et al., “APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa,” Science Translational Medicine, DOI:10.1126/scitranslmed.aas9668.
INDUCED PLURIPOTENT STEM CELLS
EB iPS Consortium
iPS stands for ‘induced Pluripotent Stem’ cells. These are reprogrammed from adult cells and could become any other cell in the body. Under this protocol, cells from an individual with EB will be modified with non-viral gene editing method to produce iPS cells with a coorected gene encoding the collagen VII protein. These gene-corrected iPS cells can then be differentiated into other cells such as skin cells known as keratinocyctes. These cells can then be given back to an individual with EB. Read the full press release.
DURATION: 5 YEARS
$850,000 in 2017. FUNDED IN COLLABORATION WITH EBRP AND EBMRF
Professor Antony Oro, Stanford University
Professor Dennis Roop, University of Colorado Anshutz Medical Campus
Dr Angela Christiano, Columbia University Medical Center
Related to EB iPSC
Developing a therapeutic apporach for delivering stem cells systemically to treat fragile internal epithelia in RDEB
Dennis Roop, Ganna Bilousova, Anna Bruckner University of Colorado
Testing an alternative approach to delivering iPSC derived keratinocytes and fibroblasts
Dennis Roop, Ganna Bilousova, Anna Bruckner University of Colorado