Long-Term Stability and Safety of Transgenic Cultured Epidermal Stem Cells in Gene Therapy of Junctional Epidermolysis Bullosa

Abstract

SummaryWe report a long-term follow-up (6.5 years) of a phase I/II clinical trial envisaging the use of autologous genetically modified cultured epidermal stem cells for gene therapy of junctional epidermolysis bullosa, a devastating genetic skin disease. The critical goals of the trial were to evaluate the safety and long-term persistence of genetically modified epidermis. A normal epidermal-dermal junction was restored and the regenerated transgenic epidermis was found to be fully functional and virtually indistinguishable from a normal control. The epidermis was sustained by a discrete number of long-lasting, self-renewing transgenic epidermal stem cells that maintained the memory of the donor site, whereas the vast majority of transduced transit-amplifying progenitors were lost within the first few months after grafting. These data pave the way for the safe use of epidermal stem cells in combined cell and gene therapy for genetic skin diseases.

Translating the combination of gene therapy and tissue engineering for treating recessive dystrophic epidermolysis bullosa

“…The transgene was expressed during the 21-month follow-up and the epidermis was fully functional and did not form blisters. This proof of principle suggests that this strategy could be applied to other EB types (De Rosa et al, 2014;Hirsch et al, 2017;Mavilio et al, 2006).…”

“…This percentage might have been insufficient to target stem cells and the harsh infection condition could have led to cellular differentiation. In comparison, more than 90 % of keratinocytes are transduced in the JEB studies with a gentle transduction procedure (De Rosa et al, 2014;Hirsch et al, 2017;Mavilio et al, 2006). This important difference in viral transduction is due to the extended length of the COL7A1 cDNA that prevents the generation of high-titer vector batches.…”

Genetic Diseases, Immunology, Viruses, and Gene Therapy

“…Recently I read with pride several articles describing encouraging clinical data from gene therapy trials in children with the diseases metachromaticleukodystrophy (Biffi et al, 2013) and epidermolysis bullosa (De Rosa et al, 2014), both of which had such an influence on me as a medical student. Our research group plans to leverage the successful experiences of liver-directed gene therapy with AAV8 for hemophilia B into clinical trials of AAV8 gene therapy for patients with FH and OTC deficiency.…”

Novel and emerging therapies in the treatment of recessive dystrophic epidermolysis bullosa

“…Of note, follow up for more than 8 years has shown sustained synthesis of laminin-332 protein with no evidence of blistering, inflammation, tumourigenesis or immune response in the grafted area (117). In a second case, the same RV gene therapy protocol was used in an Austrian junctional EB patient in whom ex vivo skin gene therapy targeting autologous epidermal stem cells was used to produce five skin sheets each measuring 5 × 7 cm that were grafted onto wounded areas on the patient's thighs; clinical responses in this patient are still being evaluated (118).…”