Imagine skin so fragile that rubbing or scratching it can lead to severe blistering and massive wounds. Patients with a rare genetic disease known as junctional epidermolysis bullosa (JEB) suffer from just this painful phenomenon. JEB patients have mutations in a protein known as laminin-332, which is necessary to physically attach the top layer of skin to the lower layers. When this protein is not functional, friction, such as that from rubbing or scratching, can separate these layers and form blisters which may compromise critical skin functions such as protection, regulation, and sensation. There is no known cure for JEB, and while patients with the most severe form of JEB occasionally survive into their teens, the majority die from this disease during their first year of life.

Treatment Breakthrough
In a clinical breakthrough, a team led by Michele de Luca from the Center for Regenerative Medicine in Modena, Italy recently published a treatment for JEB in the journal Nature. Researchers isolated stem cells from a JEB patient and repaired them by adding a corrected form of the mutated gene. In the lab, they grew sheets of healthy skin from the repaired cells, which, stunningly, were used to replace the majority of the patient’s skin (see this STAT article for a detailed description). 

This first-of-its-kind treatment was performed on a 7-year-old boy with severe JEB who had lost approximately 80% of his skin. Doctors treating this young patient had exhausted all approved medical options and successfully petitioned the ethical review board at Ruhr-University in Bochum, Germany to approve the compassionate use of this experimental cell and gene therapy for this single patient.

The treatment began by obtaining cells from a biopsy of the boy’s unblistered skin. These cells then received a functional version of the laminin gene through a gene therapy procedure. Genetically-corrected cells were then expanded in the laboratory to form sheets of skin to obtain the nearly 400 million cells that were grafted onto the patient.

Within a month of transplanting the skin grafts, the patient exhibited nearly complete restoration of all the affected areas. At the conclusion of the study, almost two years later, the regenerated skin was firmly adhered to the underlying layers, exhibiting molecular markers of normal skin, and withstanding stress without blistering. In this groundbreaking achievement, a combination of cell and gene therapy restored the function of a critical protein, which enabled regeneration of 80% of the patient’s skin. 

Skin Regeneration
Skin is the largest organ in the body and has many critical functions. It is a barrier that helps regulate temperature and hydration levels, sense the environment, and offer protection from infection and physical damage. Skin cells in the epidermis, or outer layer of skin, naturally slough off and are constantly being replaced. Skin cells are replenished by epidermal stem cells, which can produce all of the cell types that make up the skin, including hair follicles and sweat glands.

While researchers knew that stem cells replenish the skin during normal growth and aging, prior to this study researchers did not know what cell type was responsible for driving regeneration during a skin transplant. Epidermal stem cells have been grown in the lab for decades, but they have not been shown to incorporate into a patient’s skin and generate the full complement of cell types.  

To determine which cell type drives regeneration during a skin transplant, scientists analyzed the regenerated skin over the course of eight months. While most of the nearly 400 million transplanted cells died after the procedure, the long-lived epidermal stem cells were found to be those responsible for sustaining the skin graft and the long-term maintenance and regeneration of the patient’s skin (see January 2018 blog post  for similar findings about blood stem cells in transplantation).

Moving Forward After Proof-of-Principle Success
The success of this gene and cell therapy treatment is a significant breakthrough, with important implications for the future use of these technologies. This proof-of-principle study involved only one patient, however, and additional clinical studies need to be performed so that results can be replicated and long-term safety assessed before this treatment is routinely used in the clinic. While one potential long-term risk of this treatment is the formation of cancer, this patient has not developed tumors to date.

Based on this initial success, researchers hope that this type of gene therapy has the potential to prevent, rather than repair, skin blistering in JEB patients. One day this novel therapy may be able to cure patients with a variety of types of epidermolysis bullosa, helping them regain a normal quality of life.