‘Therapeutic reprogramming’ may lead to treatment for epidermolysis bullosa, a blistering skin disease
Induced pluripotent stem cells made from patients with a form of blistering skin disease can be genetically corrected and used to grow back healthy skin cells in laboratory dishes, researchers at the Stanford University School of Medicine have found. They’ve termed the new technique “therapeutic reprogramming.”
The skin cells formed normal human skin when grafted onto the backs of laboratory mice, they said.
The findings represent a major advance in the battle against the disease, epidermolysis bullosa, in which the top layer of skin, called the epidermis, sloughs off with the slightest friction, leaving open wounds that are difficult to heal. Severely stricken children who survive into their late teens or early 20s often die from invasive squamous cell carcinoma, a skin cancer that can arise during repeated cycles of skin wounding and healing.
“Epidermolysis bullosa is a truly horrible, debilitating skin disease in which the top layer of skin is not properly anchored to the underlying layers,” said Anthony Oro, MD, PhD, professor of dermatology. “When they are born, the trauma of birth rips away their skin, and they continue to suffer severe skin wounds that require constant bandaging and medical attention throughout their lives.”
Stanford has one of the largest epidermolysis bullosa clinics in the world, with an extremely active and engaged population of patients and their families eager to help researchers. The Stanford Department of Dermatology has been working to find new treatments for the disease for over 20 years. The latest advance, in which researchers replaced the mutated, disease-causing gene in the donor-made induced pluripotent stem cells with a healthy version, was funded by an $11.7 million grant from the California Institute for Regenerative Medicine.
New avenue of treatment
“This treatment approach represents an entirely new paradigm for this disease,” Oro said. “Normally, treatment has been confined to surgical approaches to repair damaged skin, or medical approaches to prevent and repair damage. But by replacing the faulty gene with a correct version in stem cells, and then converting those corrected stem cells to keratinocytes, we have the possibility of achieving a permanent fix — replacing damaged areas with healthy, perfectly matched skin grafts.”
Oro is one of the two senior authors of a paper, published n Science Translational Medicine, describing the research. Vittorio Sebastiano, PhD, an assistant professor of obstetrics and gynecology, and research associate Hanson Zhen share lead authorship.
The Stanford paper will be one of three in that journal issue to focus on gene therapy approaches for epidermolysis bullosa, also known as EB. All three studies use similar approaches, but each are in some ways unique. Unlike the other studies, the Stanford approach uses induced pluripotent stem cells, or iPS cells, from human patients and directly replaces the faulty gene with new copy.
Other Stanford co-authors are Alfred Lane, MD, emeritus professor of dermatology and of pediatrics; postdoctoral scholars Sandra Melo, PhD, Jiang Li, PhD, Susie Lee, PhD, Lingjie Li, PhD, Leszek Lisowski, PhD, and Pei Wang, PhD; senior research scientist Zurab Siprashvili, PhD; instructor Thomas Leung, MD, PhD; program manager Andrea Tichy, PhD; bioinformatician Jiang Li; research assistant Elizaveta Bashirova; graduate student Bahareh Haddad Derafshi; and undergraduate student John Hawkins.
Lane is the principal investigator on the CIRM grant; Oro and Wernig are the co-principal investigators. Oro and Wernig are both members of the Stanford Cancer Institute.
The study was funded by CIRM, the Children’s Health Research Institute, the Howard Hughes Medical Institute, the New York Stem Cell Foundation-Robertson Investigator Program and the National Institutes of Health (grant ARO55914).