Research, Science, Science Fridays

The First Successful Gene Therapy for the Worst Disease You’ve Never Heard Of

In October 2015, a 7-year old boy received life-saving surgeries involving skin grafts made from his own modified skin cells in the first successful gene therapy to-date for junctional epidermolysis bullosa (JEB).

Thanks to his disease, the boy had lost about 60% of his skin, and subsequently contracted multiple infections that quickly turned septic. The procedure was a resounding success: the grafted skin regenerated and covered his body within 1 month, and he was able to return to school last March.

What is epidermolysis bullosa?

JEB is an often-fatal form of epidermolysis bullosa, a family of connective tissue disorders that causes the outer layer of the skin – the epidermis – to blister and slough off at even the slightest touch. Indeed, those born with this disorder have been nicknamed “butterfly children” for their incredibly sensitive skin.

Each of the five main types of this disease is caused by a different set of inherited mutations to crucial proteins responsible for anchoring the epidermis to the underlying tissue. Of the different mutations associated with JEB, the LAMB3 mutation is the most common, causing about 70% of all JEB cases. These mutations give rise to either dysfunctional proteins or missing proteins altogether, resulting in chronic injuries that are prone to infection. Some forms of EB can even result in aggressive skin cancer, if not lethal in infancy. The only treatment for EB is dressing and redressing wounds every day, a process that is both painful and costly, with bandage costs approaching $100,000 a year.

Until now.

The New Treatment

The use of skin grafts isn’t new. Skin grafting has been used to treat severe burns and other injuries since the 19th century. But the treatment for this case of JEB is the first of its kind to succeed on such a large scale without requiring additional procedures.

Developed by Michele De Luca, Reggio Emilia, and colleagues in Italy, the new treatment is based on a simple premise: introduce a healthy copy of the mutated gene into cultures of cells isolated from an area of healthy skin, and graft the modified cultured cells onto the patient.

Here’s how it works:

grafting procedure
Skin cells are grown in culture and then infected with a retrovirus carrying healthy copies of the LAMB3 (laminin 332) gene, which is missing from the boy’s skin cells. The genome of each skin cell gains this new gene, and the cells are grown on gels made of fibrin (which act as a scaffold for the cells to adhere to). These fibrin gels are then grafted or transplanted onto injured areas.

Did it work?

Since the boy’s skin cells were missing the LAMB3 gene, they were missing the laminin 332 protein. Laminins are crucial players in the structure of the basal lamina, a thin mat of protein networks that support the epidermis and anchor it to the deeper layers of the skin (the dermis).

To see if the grafted skin cells kept producing laminin 332, the researchers analyzed samples of the cells under a special microscope. They looked for the inserted laminin 332 using a specific marker that fluoresces green and compared the results to two other sets of cells: 1) the boy’s cells before the surgeries, and 2) healthy cells from a healthy person without JEB.

LAMB3 expression differences
Normal healthy skin has a distinct layer – the basal lamina – between the epidermis and dermis. Laminin 332 is highly expressed in this layer. The boy’s skin prior to surgery, in the top right, has virtually no laminin 332. Between 4 and 12 months after surgery, the protein comes back, and the skin layers improve greatly over time.

A New Model

After the surgeries, the researchers kept tabs on the grafted cells to see which ones helped regenerate the boy’s skin over time. While most of the cells disappeared over time, one small population of cells remained to contribute to the long-term renewal of the epidermis. These long-lived cells, called holoclones, were found to be stem cells. (The short-lived cells that provide the initial boost of skin growth are called meroclones and paraclones.)

Old model: All of the epidermal cells have the same potential to produce different cell types directly.

New model: Specific epidermal cells have the potential to produce populations of transient progenitor cells that then give rise to different cell types as needed.

Paving the Way for EB Patients

Approximately 500,000 people worldwide have epidermolysis bullosa (EB). This new gene therapy has the potential to treat other types of EB besides JEB, and has also pointed out the importance of long-lived stem cells in graft cultures.

Although promising, this treatment may not work for all EB patients. More than half have a different form of the disease, called epidermolysis bullosa simplex, which is caused by mutations that result in a dysfunctional protein rather than a missing protein. Fortunately, hope still remains thanks to new genetic technologies like base-editing. Affectionately called CRISPR 2.0, base editing can precisely change single DNA bases. Whether this new approach can be used to treat EB remains to be seen.


  1. Servick, K. “A boy with a rare disease gets new skin, thanks to gene-corrected stem cells.” (2017).
  2. Mullin, E. “Gene-Therapy Grafts Have Repaired a Child’s Devastating Skin Disorder.” (2017).
  3. Mullin, E. “Gene Therapy Offers Hope for ‘Worst Disease You’ve Never Heard Of.'” (2016).

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