We found that the infusion of allogeneic bone marrow can partially correct the C7 deficiency and improve skin and mucosal integrity in patients with recessive dystrophic epidermolysis bullosa. The observation that partial C7 correction is associated with a clinical benefit is consistent with previous work showing that a C7 level as low as 10% of the wild-type level of expression is associated with stability of the skin.20
The rates of recovery and ultimate outcomes varied among the surviving patients. Patients 4 and 5 had rapid and substantial clinical improvement relative to baseline, whereas Patient 1 had slow improvement, with only a modest overall benefit, and Patient 7 had a recurrence of blistering after an early period (days 30 to 60) of almost no blistering.
Unexpectedly, we detected substantial proportions of donor cells in the skin and mucosa after treatment; these proportions varied over time and with the location of the biopsy site. Many of the donor cells were located some distance away from blood vessels, and many were hematopoietic in origin (CD45+ cells). Although more work needs to be done to determine the identity of the CD45−CD31− donor cells, we favor the possibility that these healthy donor cells residing in the skin secrete C7 and that the secreted C7 is subsequently incorporated into the lamina densa at the dermal–epidermal junction.
The effect of new C7 on the morphologic features of anchoring fibrils, however, is not clear. Because all the patients except Patient 6 had mutant C7 expression at baseline (with Patients 4, 5, and 7 having higher levels of expression than Patients 1 and 3), it is possible that small amounts of newly formed C7 assembled with wild-type C7 early after transplantation to form a trimer and thus improved mucocutaneous integrity. This hypothesis also predicts that the C7 gene dose (i.e., the zygosity status of the donor) could influence the rate of improvement and is consistent with the blunted overall clinical outcome in Patient 1, who had a heterozygous donor with only one normal C7 gene. An initial scaffold of rudimentary anchoring fibrils in the host might be necessary for optimal deposition of wild-type C7 from the allogeneic cells, but it is clear that a clinical response does not depend on the presence of increased numbers of anchoring fibrils. Our data are limited to assessments of skin-biopsy specimens obtained within the first year after transplantation. Although rare anchoring-fibril–like structures were seen in Patient 4, the development of anchoring fibrils that fulfill the established ultrastructural criteria may require a longer interval after bone marrow infusion. Together, our findings suggest that the infusion of bone marrow from a healthy donor can ameliorate recessive dystrophic epidermolysis bullosa in humans, as has previously been shown in the mouse model of the disorder. Substantial efforts are under way to understand the physiology of the apparent clinical response after bone marrow transplantation and to identify the stem-cell population responsible for this effect.
Despite the apparent beneficial effect of bone marrow stem cells in patients with recessive dystrophic epidermolysis bullosa, allogeneic bone marrow transplantation remains a high-risk procedure typically reserved for patients with imminently life-threatening disease, such as those with high-risk lymphohematopoietic malignant disease.21
Before this clinical trial, it was not known whether patients with preexisting mucocutaneous disease could tolerate the conventional conditioning regimens used as preparation for allogeneic bone marrow transplantation. Although grade 3 mucositis occurred in all the patients in our study, as is typical for patients without preexisting mucocutaneous disease, only one patient had severe cutaneous toxicity. Notably, no patient had uncontrolled cellulitis, despite pretransplantation bacterial or fungal skin colonization. Clearly, the risks of bone marrow transplantation need to be weighed against the risks and benefits of alternative innovative therapies now being explored (e.g., injections of C7 protein or ex vivo grafting of allogeneic or gene-corrected autologous cells).17,22-35
Although these measures may prove to ameliorate morbidity, recessive dystrophic epidermolysis bullosa is a systemic disease, and the benefits of these other interventions have thus far been brief or limited to small areas of skin. Therefore, new approaches, such as the one we describe here, are being explored. Already, we and others are considering modifications to enhance safety, such as the coinfusion of mesenchymal stromal cells or the use of reduced-dose conditioning before bone marrow transplantation, recognizing that the latter approach may increase the risk of opportunistic infection as a result of delayed immune reconstitution brought about by the additional immunosuppression.
In summary, our data suggest that the infusion of allogeneic bone marrow stem cells can lead to increased C7 deposition and reduced blistering in patients with severe recessive dystrophic epidermolysis bullosa. However, the unique skin and mucosal membrane defects of this disease pose a particular challenge to any bone marrow transplantation program. Clearly, much remains to be learned regarding the mechanism of the apparent functional correction as well as the long-term risks and benefits of this therapeutic approach, including the risk of squamous-cell carcinoma, which may occur after chemotherapy or as a result of incomplete correction of the underlying disease. Despite the potential benefits of marrow transplantation, it is a high-risk therapeutic approach that could shorten the expected survival of patients with recessive dystrophic epidermolysis bullosa, particularly those with less severe clinical manifestations. Nevertheless, the results to date support the study of stem-cell–based approaches for patients who have the severest forms of epidermolysis bullosa.