Cell and gene research raise hopes for recessive dystrophic EB treatments

Correcting the genetic defect

The most severe form of RDEB is caused by mutations in COL7A1, the gene for collagen type 7 (COL7), the major connective component of the skin, anchoring the epidermis to the dermis. Its absence results in skin that can be so fragile it has been likened to the wings of a butterfly and results in severe blistering after very little trauma.

There is a lot of research on how to correct the underlying genetic defect, either by replacing COL7A1 entirely, repairing the gene, or editing the gene so that COL 7 can be produced in situ and prevent the formation of wounds and heal those that might already be present.

“The excitement is obvious,” said Jakub Tolar, MD, PhD, professor in the department of pediatrics, blood and marrow transplantation, and dean of the University of Minnesota Medical School, Minneapolis, who chaired a session on gene and gene manipulation therapies. “If one can go and correct that information, it follows that everything else is going to be okay,” he said. “Only it’s not. I think that it’s pretty clear that more than gene correction is needed.”

Some of the approaches to replace the faulty gene discussed at the meeting involved taking skin biopsy samples from a healthy area of skin from a patient with RDEB, isolating specific skin cells (fibroblasts, keratinocytes, or both), transferring a healthy copy of the COL7A1 gene into those cells – then expanding the population to form sheets of cells that can be grafted onto the wounds of the same patient.

Clinical trials of gene therapy for RDEB

Clinical trials with these novel gene-corrected, tissue-engineered grafts have already started, including EBGraft, a phase 1/2 open, nonrandomized, proof-of-concept trial using genetically corrected sheets of fibroblasts and keratinocytes, conducted by Alain Hovnanian, MD, PhD, Necker-Enfants Malades Hospital in Paris, and associates.

Then there is the phase 3 VIITAL trial being conducted at Stanford (Calif.) University by Jean Tang, MD, PhD, and colleagues. Recruitment in this open trial, which will enroll 10-15 patients with RDEB, has just started. The aim of the study is to investigate the efficacy and safety of EB-101, an autologous cell therapy that corrects COL7A1 in keratinocytes.

Positive findings from a phase 1/2 study with EB-101 were presented in a poster at the meeting by Emily Gorell, DO, a postdoctoral medical fellow in dermatology, at Stanford University and her associates. The trial included seven patients with RDEB who were treated and followed for 3 to 6 years. Data from that study showed that there were no serious adverse events and 95% of patients’ wounds that were treated (36/38) were healed by at least 50%, based on an Investigator Global Assessment at 6 months. In comparison, none of the untreated wounds had healed by that time point. “There was evidence of C7 [collagen 7] restoration at 2 years in two participants,” and wound healing was associated with both reduced pain and itch, the investigators wrote in the poster.

Another approach to this so-called ‘ex-vivo’ gene therapy is to take the patient’s cells via a small skin biopsy, genetically modify them, expand the population of these modified cells, and then inject them back into the patient. This approach was described by Peter Marinkovich, MD, of the department of dermatology at Stanford University, during an oral presentation and in a poster at the meeting.

Dr. Marinkovich discussed the results of an ongoing phase 1/2 study in which six subjects with RDEB – five adults and one child ­­– were treated intradermally with genetically modified fibroblasts in a preparation currently known as FCX-007.

“Before we had to graft the cells, take the patients into the OR [operating room], with the risks of general anesthesia, but here we don’t have to take the patients to the OR, we just take them into the hospital for a day, inject their wounds and then send them on their way,” Dr. Marinkovich said. Interim findings show that the patients have tolerated the therapy very well up to 52 weeks, he noted.

A greater percentage of wounds were healed by more than 50% following treatment with FCX-007 than those left untreated at weeks 4 (80% versus 20%), 12 (90% versus 44%), 25 (75% versus 50%), and 52 (83% versus 33%).

These results have been used to inform the design of the upcoming phase 3 study, DEFI-RDEB. The multicenter intrapatient randomized, controlled, open-label study is evaluating FCX-007 in the treatment of persistent nonhealing wounds in about 20 people with RDEB.