1:Universidad Carlos III de Madrid (UC3M); 2:CIEMAT/CIBERER; 3:Instituto de Investigación Sanitaria de la Fundacion Jiménez Díaz (IIS-FJD); 4:Great Ormond Street Hospital for Children NHS Foundation Trust/UCL

Recessive dystrophic epidermolysis bullosa (RDEB) is a skin fragility disease caused by loss of functional type VII collagen (C7), a dermo-epidermal adhesive protein, leading to chronic blistering, progressive fibrosis and cancer. A premature termination codon-causing mutation in exon 80 of COL7A1 gene, c.6527insC, is highly prevalent (close to 50% of pathogenic alleles) in the Spanish RDEB patient population. Deletion of small, repetitive sequence-encoding exons in the triple helix-forming region of COL7A1 gene results in functional C7 proteins fit for anchoring fibrils formation at the dermal-epidermal junction. 

We previously demonstrated in a proof of concept study that COL7A1 exon 80 deletion/skipping strategy based on the use of paired guideRNAs leading CRISPR/Cas9 action was an effective approach to rescue the RDEB phenotype (Bonafont et al, Mol. Ther. 2019; 27:986-998) Subsequently, an autologous bioengineered skin populated with RDEB cells (keratinocytes and fibroblasts) edited by exon 80 removal, an advanced medicinal therapy product (AMTP),  received the orphan drug designation (EU/3/20/2253) by the EMA.

We show here the pre-clinical results of efficacy and toxicological studies, including tumorigenicity, histopathology, biodistribution and on-target/off-target genotoxicity which confirm that this cell-and-gene therapy AMTP is a safe and effective approach for patients living with this devastating genodermatosis, suitable to be explored in the context of a clinical trial.