CHICAGO – Bone marrow transplantation is evolving as a promising treatment for patients with the most severe forms of epidermolysis bullosa.

“Is this a cure? It’s not,” Dr. Jakub Tolar, MD, PhD, said at the World Congress of Pediatric Dermatology. “It is, however, a path toward understanding how we can treat this grave disorder in a systemic way.”

Early efforts to treat the cutaneous manifestations of recessive dystrophic epidermolysis bullosa (EB) with cellular therapy involved the use of intradermal injections of allogeneic fibroblasts and mesenchymal stromal cells. Today, bone marrow transplantation (BMT) is the most widely used stem cell therapy for patients with severe EB, but it has its limitations, including the requirement for a human leukocyte antigen–matched donor, and the risk of morbidity and mortality. “This is a risky endeavor,” said Dr. Tolar, who directs the Minnesota Stem Cell Institute at the University of Minnesota, Minneapolis, which is the first of several places in the world that offer blood and marrow transplant as a treatment for patients with recessive dystrophic EB and junctional EB. He discussed outcomes from 30 patients with recessive dystrophic EB who have been treated at the University of Minnesota Masonic Children’s Hospital to date. “Overall survival is 77%, which is tragic if you look at it from where you sit, but it is a lifesaving measure for many patients and within the survival range of diagnoses that we use transplant for, like leukemia and other genetic disorders,” he said. “The important thing is that we have seen de novo expression of type 7 collagen in some patients.”

The University of Minnesota BMT Team has also observed a correlation between the engraftment in the blood and engraftment in the skin. “We have skin engraftment as high as 50%, which is good,” Dr. Tolar said. “The more donor cells engrafted in the skin, the more types of collagen you express.”

The clinicians have also been able to reduce the amount of chemotherapy and radiation patients require prior to transplant, for the BMT to work and skin to heal. “We were able to make it so that the last 11 patients are surviving and having benefit from the transplant, with the exception of one,” Dr. Tolar said. “How does this work? We still don’t entirely know. This is not a shot in the dark, however, this is the continuation of a very long process where we were first able to show that bone marrow transplant is an efficient stem cell therapy for leukemia, and about 20 years ago for the lysosomal enzyme deficiencies.” Their hunt for the cell that travels from the bone marrow to skin and produces type 7 collagen is continuing. “What haunts me is that BMT, which works in recessive dystrophic EB, works only in some types of junctional EB, those with alpha-3 chain deficiency of laminin 322.” he continued. “There has been no benefit to bone marrow transplantation for children with mutations of beta-3 chain of laminin 322, so we have closed enrollment for this one form of junctional EB. Survival in this group was 40%. Other types of junctional EB continue to be eligible for the study.”

Dr. Tolar recommended keratinocyte-driven or thymic epithelium cell type–driven therapy for patients with mutations of beta-3. “The deficiency of thymic function seems to be key in the inability to benefit from BMT in this form of junctional EB,” he said. “We have seen children who have engrafted, their skin got better, and then they died of infection many months after transplant. When we look at the immune profile and the thymic epithelial cells, they are both deficient – very abnormal.”

Despite current challenges, Dr. Tolar expressed optimism about the future of BMT in EB patients. “We have the same approach that we have in cancer care: deep empathy for all patients, radical international collaboration, and rapid laboratory and clinical prototyping,” he said. “It’s time to move from two-dimensional science to three-dimensional science; we need to study all aspects of EB simultaneously, from gene to cell to tissue to individual to patient population, and to understand the properties of the whole EB pathobiology that emerge at each level of biological complexity. By connecting information from these layers of disease network, we can better understand EB and create comb

One of the 30 patients with recessive dystrophic EB treated by Dr. Tolar, Elisa McCann, shown approximately two years posttransplant.

inatorial therapies that are specifically designed for how each individual – with their unique genetics, presentation of EB, and disease stage – would respond to them. As investigators around the world respond to the urgency of the needs of patients and their families, we are seeing new discoveries and new innovations in EB therapy every day.”

Dr. Tolar reported having no financial disclosures.

dbrunk@frontlinemedcom.com

Bone marrow transplantation for epidermolysis bullosa continues to evolve