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The USC Laboratories for Investigative Dermatology under the directorship of Professor Mei Chen has been working on the characterization of the structure and function of type VII collagen since the early 1990s. With her colleague, Dr. David T. Woodley, they have published several strategies for therapy in patients with recessive dystrophic epidermolysis bullosa (RDEB). They have shown that the following therapeutic strategies are possible:
Chen and Woodley focused first on “Protein Therapy” because this did not involve exposing the patient to viral vectors or live cells. Recombinant human type VII collagen was patented with USC and a company called Lotus Tissue Repair, Inc. was formed and funded by Third Rock Ventures. After several technical advances, Lotus was sold to Shire Pharmaceuticals who is currently developing intravenous recombinant human type VII collagen for RDEB patients.
While waiting for Protein Therapy to become a reality, we have published in vitro data, showing that the skin cells of severe hereditary RDEB patients with nonsense mutations in the COL7A1 gene express no type VII collagen in culture. We found, however, that the addition of aminoglycoside antibiotics, such as gentamicin, induces the cultured cells to synthesize and secrete full-length type VII collagen that is functional in a dose-dependent manner.
With these in vitro data in hand and funding from the Epidermolysis Bullosa Research Partnership and the Epidermolysis Bullosa Medical Research Foundation, we recently completed a pilot, double-blind, placebo controlled study of 5 patients with RDEB and nonsense mutations. We wished to translate these in vitro laboratory findings to the dermatology clinic for the treatment of patients. We found that topical 0.1% gentamicin ointment applied three times a day for 2 weeks and sterile gentamicin solution injected intra-dermally into these patients for 2 days generated new type VII collagen and new anchoring fibrils at the patient’s DEJ. In addition, gentamicin administered topically to the erosive skin wound Test Sites stimulated wound closure, improved epidermal-dermal adherence, and reduced the onset of new blister formation. Lastly, none of these patients had any observable gentamicin side effects.
With these exciting in vitro and in vivo clinical trial results, we now wish to expand these observations by treating a wider spectrum of nonsense mutations and optimizing the delivery of topical gentamicin (by using more concentrated ointment, 0.5% rather than 0.1%) and intra-dermal gentamicin (by using a painless microneedle device that can deliver gentamicin to wide areas of the skin). We also wish to examine the effect of intravenous systemic short-term gentamicin treatment. RDEB patients have widespread skin wounds over much of their body including their mouth, esophagus, arms, legs, and trunk. This clinical intravenous strategy has the potential to treat all of the RDEB skin wounds simultaneously in addition to RDEB wounds in inaccessible sites such as the upper third of the esophagus. We are grateful to the Epidermolysis Bullosa Medical Research Foundation and the Epidermolysis Bullosa Research Partnership for providing continued funding to this new study in 2017. We envision that gentamicin-mediated nonsense-suppression therapy may provide a novel, low cost, non-invasive, readily available therapy for RDEB patients harboring nonsense mutations, a population that comprises about 30% of all RDEB patients.
Dr. Woodley & Mei Chen’s research was brought to market, in part, through the EBMRF’s early stage research funding and ultimately through Shire Pharmaceutical’s recent acquisition of Lotus Tissue Repair.
Lotus Tissue Repair was a venture-backed company that raised $35 million to bring USC’s protein replacement therapy to the EB community.
The EBMRF announced that David T. Woodley, M.D. and Mei Chen, PhD of the Department of Dermatology at The Keck School of Medicine at the University of Southern California were recipients of a $150,000 Grant for their research of Epidermolysis Bullosa.
The EBMRF awarded the grant to further expand Dr. Woodley and Dr. Chen’s cutting-edge research into protein replacement therapy for treatment of patients with recessive dystrophic Epidermolysis Bullosa (RDEB). Dr. Woodley’s project proposes a clinical trial to treat RDEB patients with recombinant type VII collagen as well as a strategy for bringing this novel protein to market.
Dr. Mei Chen and Dr. David Woodley at the USC Laboratories for Investigative Dermatology had proposed initially using “Protein Therapy” for patients with dystrophic epidermolysis bullosa (DEB) as a temporizing measure until “Gene Therapy” is fully developed and proven safe. They can produce milligram quantities of full-length recombinant, human type VII collagen and they now wish to make their recombinant, human, type VII collagen by so-called “Good Manufacturing Practices” (GMP) so that it is suitable for administration to human beings. “We believe that Protein Therapy is something that will work right now and can help patients with DEB because it worked so well in the DEB mouse model.” said Dr. Chen.
Dr. Woodley added: “Doctors have great experience injecting type I collagen into the upper dermis of patients for photo aged skin. The collagen persists for about 6 months. Therefore, we do not see any technical hurdles to administering intradermal injections of our recombinant human type VII collagen into DEB patients.” In addition, the injection into patients of a purified protein will not involve cells or viruses which are both large safety issues with the Federal Drug Administration. “We believe the FDA will more likely approve Protein Therapy relatively quickly compared with cell or gene therapy, and protein therapy will answer many essential questions that are essential for gene therapy. In the first Phase I study with “Protein Therapy”, the investigators plan on injecting 100 micrograms of the protein into four quadrants of a 6 cm by 6 cm test site. This will be compared with a similarly sized control site that will not be injected. The investigators will examine new blister formation and open wounds in the two sites. They will also take biopsies from the sites and examine the amount of type VII collagen and the number of anchoring fibrils at the junction between the epidermis and dermis. If human DEB patients are similar to the DEB mouse model, one would expect a cessation of new blister formation, less open wounds, and the expression of type VII collagen and anchoring fibrils in the injected site. Drs. Chen and Woodley were quick to point out that one of the main goals of a Phase I trial is patient safety. Therefore, DEB patients who enroll in the study will be monitored in many ways during and after administration of the collagen. “Of course, in addition to proving safety, Dr. Chen and I are very hopeful that Protein Therapy will also prove to be efficacious and improve the skin blistering and skin fragility in the patient’s test sites.” said Dr. Woodley.
The EBMRF is grateful to DebRA of America for their support and resources in awarding this grant.