DURHAM, N.C.—Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited disease that results from mutations in the COL7A1 gene, which is essential to the production of type VII collagen (C7) in the skin. Mild cases of RDEB are characterized by blistering that primarily affects the hands, feet, knees and elbows. In severe cases, however, patients experience external and internal blistering.
“The level within the skin layers at which the defect occurs, and therefore at which the shearing happens, is so deep that it is equivalent to a third-degree burn and is incredibly painful. External skin and internal skin are affected, leading to blistering in the mouth and esophagus … and on the surface of the eyes,” Cure EB reports on its website. “For a sufferer, this means that eating is always painful. Swallowing can be very difficult due to scarring of the esophagus, necessitating balloon dilatation to allow food to pass. Many children and adults are fed via a gastrostomy tube to allow adequate nutrition … If the UV protective layer of the cornea is sheared off, the eye is vulnerable to UV light. The intense pain that this causes leads to a sufferer closing his/her eyes, rendering them temporarily blind ‘til healing occurs.”
The constant skin damage leads to scarring, which can become bad enough to impact mobility. The disease also increases the likelihood of developing skin cancer, as the Cure EB site notes that “the majority of sufferers will succumb to a malignant skin cancer, squamous cell carcinoma, before the age of thirty-five.” There is no cure for RDEB, and treatment consists primarily of symptom management and efforts to prevent blisters.
Researchers at New York Medical College, among other institutions, showed that the administration of human placental-derived stem cells (HPDSCs) generated promising results in animal models of this progressive disease. The research was published in STEM CELLS Translational Medicine in an article titled “Efficacy of Human Placental Derived Stem Cells in Collagen VII Knockout (Recessive Dystrophic Epidermolysis Bullosa) Animal Model.”
HPDSCs, as noted in the paper, “are a source of stem cells obtained by Celgene Cellular Therapeutics (CCT)’s proprietary process involving perfusion of donated full‐term placentas and depletion of red blood cells, nonviable cells, and tissue debris.”
“We had recently shown how human cord blood-derived stem cells promote wound healing and ameliorate the blistering in a RDEB mouse model,” said Dr. Mitchell Cairo, who led the investigation. “In this latest study, we found that the therapeutic effects of a different type of stem cell—human placental derived stem cells—were even more remarkable. HPDSCs contain a much higher level of both hematopoietic and non-hematopoietic stem and progenitor cells than cord blood and are low in T cell content. HPDSCs are currently being used to safely treat humans with malignant and non-malignant diseases [NCT 01586455].” Cairo is the chief of pediatric hematology, oncology and stem cell transplantation at New York Medical College.
The team found that one dose of the HPDSCs together with unrelated cord blood extended the median life span of mouse models from two days to seven days. When a second group was given an additional dose, the median life span was extended to 18 days. In addition, the authors wrote that “after intrahepatic administration, HPDSCs engrafted short‐term in the organs affected by RDEB, that is, skin and gastrointestinal tract of col7a1−/− mice, increased adhesion at the DEJ [dermal‐epidermal junction] and deposited C7 even at 4 months after administration of HPDSCs, without inducing anti‐C7 antibodies.”
The lack of an immune reaction is a great result, according to Cairo, who notes that “[I]mmunogenicity against C7 would not be a favorable situation in the patients with RDEB. One reason [for the lack of antibody response] is that the C7 secreted by HPDSCs was directly deposited at the basement membrane zone, without getting into circulation. The second is that the level of C7 from HPDSCs is still low, especially compared to the C7 protein therapy,” which is delivered via IV and did induce an antibody response.
The authors did caution that “It has to be noted that the anchoring fibrils were still far from normal in the skin of HPDSC-treated RDEB mice. Kühl et al. recently determined the half-life of C7 in the skin to be approximately 1 month and the disappearance of anchoring fibrils followed the rate of C7 loss.”
“The C7 is an essential structure protein for anchoring fibrils; even with a [plentiful] quantity of C7, anchoring fibrils need time (more than a year) to mature,” Cairo explains. “The incomplete rescue of anchoring fibril formation after HPDSC administration is likely due to decreasing amounts of C7 over time, as a result of short-term engraftment (persisted for about a month) of HPDSCs. We hypothesize that continuous treatment with HPDSCs will provide a sustained level of C7 for the anchoring fibril formation and [maturation].”
When asked about the benefits of stem cell therapy over gene therapy for RDEB, he says that “There has been significant advance in the gene therapy for RDEB—for example, gene-corrected autologous skin graft, for the outside (skin) treatment. However, there is still limited progress for the gene therapy that can be applied for systemic treatment. It is also important to consider the timing and cost of a treatment (availability and whether it requires ex-vivo manipulation), possibility of multiple treatments and the method of administration (ideally minimum invasive) to the patients with RDEB.”
“The advantage of stem cell therapies using HPDSCs is that HPDSC is an easily accessible, cost-effective and minimum invasive cell product in patients with RDEB,” Cairo continues. “In comparison to autologous cellular therapy requiring genetic editing of iPSCs or other pluripotent stem cells, no genetic editing is required of any kind, and there are no risks of tumorigenicity or teratoma formation. There is little risk to DNA damage and unexpected genetic or environmental-induced morbidities, as HPDSCs are prepared immediately from healthy, full-term placenta without any other manipulation or in-vitro culturing.”
As for the team’s next step, Cairo tells DDNews that they hope to explore the long-term effects of HPDSCs, “particularly on suppressing fibrosis and mitten deformity,” and their mechanism of action in RDEB mice.
“There are unlimited supplies of placentas for the preparation of HPDSCs. However, without ex-vivo expansion, the cell dose per HPDSC unit is not unrestricted. Therefore, for a potential need for multiple infusions of HPDSCs in patients, we will also investigate the feasibility and efficacy of infusing multi-unit HPDSCs in RDEB mice,” he adds.