A 7-year-old boy suffering from a rare and often lethal genetic skin disease has made a dramatic recovery after receiving an experimental cell and gene therapy. The boy’s disease, junctional epidermolysis bullosa (JEB), is caused by mutations in the genes encoding the basement membrane component laminin-332 and causes extremely fragile skin that is prone to blisters and tearing. This results in chronic, painful, and untreatable skin wounds that lead to recurrent infections, impair quality of life, and predispose patients to skin cancer.
In 2015, a child with JEB contracted bacterial infections that caused him to lose approximately two-thirds of his skin. After traditional treatments proved unsuccessful, the boy’s family and physicians decided to embark on an experimental therapy.
The research team, led by Michele De Luca of the University of Modena and Reggio Emilia in Italy, used autologous transgenic keratinocyte cultures to successfully regenerate an entire, fully functional epidermis. In brief, the team took a 4 cm2 sample of the boy’s skin to establish primary keratinocyte cultures. These cells were then transduced with a retroviral vector to insert the normal form of the defective gene (LAMB3) into his DNA. The engineered cells were grown into sheets of skin and grafted onto the boy’s body. Ultimately, 80% of his skin was replaced with the healthy tissue. Two years after his treatment, he continues to have healthy skin and lead a normal life.
While this case is a celebrated advancement for the field and a glimpse of hope for those with JEB, the approach is not without its potential drawbacks. One possible complication with gene therapy is the potential for insertional genotoxicity. Because the vector integrates into the host DNA, there is concern that it might disrupt essential genes or activate genes that cause cancer. There is precedent for this issue; a retrovirus-based gene therapy to treat X-linked severe combined immunodeficiency (X-SCID) in the early 2000s inadvertently led to the development of leukemia in some of the patients treated during the trial. Luckily, the current study found no evidence of such adverse events.
Furthermore, there is the scale-out challenge associated with autologous cell therapies. The various forms of epidermolysis bullosa affect approximately 500,000 people worldwide. How does one increase the manufacturing operational scale for many patients when each patient’s starting sample is unique?
Despite the hurdles that remain for scientists and manufacturers, this study highlights the promise of regenerative medicine and the life-changing impact of ex vivo cell and gene therapies. The article, titled “Regeneration of the entire human epidermis using transgenic stem cells,” was published in Nature.