Stem Cell-Based Gene Therapy Restores Normal Skin Function

Michele De Luca from the University of Modena, Italy and his collaborator Reggio Emilia have used a stem cell-based gene therapy to treat an inherited skin disorder.

Epidermolysis bullosa is a painful skin disorder that causes the skin to be very fragile and blister easily. These blisters can lead to life-threatening infections. Unfortunately, no cure exists for this condition and most treatments try to alleviate the symptoms and infections.

Stem cell-based therapy seems to be one of the best ways to treat this disease, there are no clinical studies that have examined the long-term outcomes of such a treatment.

However, De Luca and his colleagues have examined a particular patients with epidermolysis bullosa who was treated with a stem cell-based gene therapy nearly seven years ago as part of a clinical trial.

The treatment of this patient has established that transplantation of a small quantity of stem cells into the skin on this patient’s legs restored normal skin function without causing any adverse side effects.

“These findings pave the way for the future safe use of epidermal stem cells for combined cell and gene therapy of epidermolysis bullosa and other genetic skin diseases,” said Michele De Luca.

De Luca and his research team found that their treatment of their patient, named Claudio, caused the skin covering his upper legs to looker normal and show no signs of blisters. To treat Claudio, De Luca and his colleague extracted skin cells from Claudio’s palm, used genetic engineering techniques to correct the genetic defect in the cells, and then transplanted these cells back into the skin of his upper legs. This was part of a clinical trial conducted at the University of Modena.

Claudio’s legs also showed no signs of tumors and the small number of transplanted cells sufficiently repaired Claudio’s skin long-term. Keep in mind that Claudio’s skin cells had undergone approximately 80 cycles of cell division and still had many of the features of palm skin cells, they show proper elasticity and strength and did not blister.

“This finding suggests that adult stem cell primarily regenerate the tissue in which they normally reside, with little plasticity to regenerate other tissues,” De Luca said. “This calls into question the supposed plasticity of adult stem cells and highlights the need to carefully chose the right type of stem cell for therapeutic tissue regeneration.”

I think De Luca slightly overstates his case here. Certainly choosing the right stem cells is crucial for successful stem cell treatments, but to take stem cells from skin, which are dedicated to making skin and expect them to form other tissues is unreasonable. However, several experiments have shown that stem cells from hair follicles and form neural tissues and several other cell types as well (see Jaks V, Kasper M, Toftgård R. The hair follicle-a stem cell zoo. Exp Cell Res. 2010 May 1;316(8):1422-8).

Adult stem cells have limited plasticity to be sure, but their plasticity is far greater than originally thought and a wealth of experiments have established that.

Despite these quibbles, this is a remarkable experiment that illustrates the feasibility and safety of such a treatment.  A larger problem is that large quantities of cells will be required to treat a person.  It is doubtful that small skin biopsies around the body can provide enough cells to treat the whole person.  Therefore, this might a case for induced pluripotent skin cells, which seriously complicates this treatment strategy.

New Skin for Claudio

Michele De Luca from the University of Modena and Reggio Emilia in Italy specialize in culturing skin cells to make sheets of skin layers in culture that can be transplanted onto the bodies of patients with skin injuries or skin diseases. Patients with full-thickness burns or other types of injuries can benefit greatly from this type of therapy. Dr. De Luca is also interested in a genetic disease known as epidermolysis bullosa (EB). EB is really a group of diseases of the skin characterized by blistering in response to minor injury, heat, or friction from rubbing, scratching or even adhesive tape. There are four main types of EB and most of them are inherited.

Dr, De Luca had a patient named Claudio who suffered from EB. Claudio had been tortured all his life with huge open wounds all over his body. Dr. De Luca was able to grow Claudio’s skin in culture and form large sheets of skin, but, unfortunately, these skin sheets were just as abnormal his Claudio’s native skin, and the transplanted sheets would have done little good.

To solve this problem, Dr. De Luca used gene therapy to fix the genetic problem in Claudio’s skin cells. Claudio suffered from a mutation in the gene that encodes Laminin 5, a cell adhesion protein that is essential for getting the skin layers to stick together.  In order to fix this mutation, De Luca used a completely novel method for placing genes into cells that included viruses that inactivate themselves once they insert into the genome of the cultured cells, but the inserted gene is still under the control of sequences that cause it to be expressed only in skin cells.

After introducing a normal copy of the laminin 5 gene into Claudio’s cultured skin cells, Dr. De Luca was able to grow Claudio’s skin in cultured into tough, resilient, skin sheets that were then transplanted onto Claudio’s legs. The transplanted skin provided large swaths of normal skin that did not suffer from open wounds or pain. The grafts have now been in place and stable for several years.

The combination of two technologies, gene therapy and tissue engineering gave Claudio a new lease on life. Unfortunately, because genetically engineered cells are, legally speaking, drugs, many new safety criteria must be met before this technology is ready for use in an off-the-shelf kind of treatment for patients.