RDEB gene-edited skin

Pre-clinical and clinical trial for using gene-edited skin in Recessive Dystrophic Epidermolysis Bullosa

Lay summary

This study uses human skin taken from patients with Recessive Dystrophic Epidermolysis Bullosa (RDEB) and uses genetic engineering to correct the faulty gene for Collagen VII which causes the skin fragility in RDEB. This bioengineered skin will then be grafted back on to patients.

Prior to any human studies, trials will be carried out in mice to assess the effectiveness of the gene-corrected skin grafts as well as their safety. If this is successful, two patients will receive bioengineered skin grafts and be followed up for 12 months to monitor safety, efficacy and feasibility of the treatment. The patients will then receive lifelong follow-up to capture any possible long-term side effects.

Scientific Summary

The primary objective of this first-in-human gene editing phase I/II clinical trial is to evaluate the feasibility, safety and preliminary efficacy of an ex vivo therapeutic approach for RDEB using an autologous bioengineered skin containing patient epidermal stem cells and fibroblasts edited through a non-viral CRISPR/Cas9-mediated precise excision of mutant COL7A1 exon 80. Because RDEB is recessive, one functional copy of COL7A1 is sufficient to prevent a disease skin phenotype in carriers. Thus, a non-viral strategy employing a dual sgRNA-guided Cas9 nuclease delivered as a ribonucleoprotein complex by electroporation to precisely excise mutant COL7A1 exon 80 in RDEB epidermal stem cells and fibroblasts (harbouring at least one mutation leading to a PTC or out‐of‐frame insertions or deletions), has the potential to restore functional C7, AF formation and normal adherence of the epidermis to the dermis.

Two patients (aged between 6 and 18 years) will be grafted with ≥300cm2 of a gene-edited bioengineered skin and will be followed up for 12 months post-grafting. All patients with RDEB are followed up on a lifelong basis, and we will therefore be able to capture any long-term possible adverse effects related to the IMP.

Prior to the clinical work, pre-clinical studies in mice will be carried out:

• To assess efficacy of skin equivalents,
• To evaluate the tumorigenic effect of patient cells corrected by gene editing,
• To monitor histopathology and cell biodistribution,
• To monitor biosafety (genotoxicity).