A study demonstrates the viability of the gene editing strategy for epidermolysis dystrophic recessive epidermolysis

A group of researchers from the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (Networking Center for Biomedical Research on Rare Diseases), Universidad Carlos III de Madrid (UC3M), the Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas ( CIEMAT) (Center for Research on Energy, Environment and Technology) and the Institute for Research on Public Health Jiménez Díaz (IIS-FJD) led a study demonstrating the viability of a genes for epidermolysis bullosa dystrophic recessive (also called butterfly chilidren) CRISPR / Cas9 tool in the preclinical models of this disease.

With this approach, published in the prestigious journal Molecular Therapy, an unusually high number of patient cells have been corrected (over 80%), obtaining two properties sought after in the development of new treatments: biosafety and efficacy therapeutic. "This work allows us to lay the foundation for a rapid transfer to clinical trials," said Marcela del Río, co-author of the study and professor at UC3M's bioengineering department.

Recessive dystrophic epidermolysis bullosa, an aggressive subtype of epidermolysis bullosa, is a rare disease resulting in severe skin fragility, characterized by the continuous formation of erosions and vesicles on the skin and internal mucosa, as well as fibrosis and various complications such as pseudo-syndactyly (finger fusion) and increased risk of developing metastatic squamous cell carcinoma. Coping with this disease is a challenge for health professionals and a significant effort by patients and their families.

This disease, of genetic origin, is caused by mutations of the gene COL7A1, which encodes collagen type VII (C7), a protein essential for dermo-epidermal adhesion. In Spain, one of these mutations, located in exon 80 of the gene (present in about 50% of the Spanish patient cohort), has a high prevalence, which justifies the development of a precision therapy targeting this region of the gene.

Gene editing with CRISPR / Cas9

The authors of this study have applied the CRISPR / Cas9 gene editing tool, which is used in this case to safely and accurately remove stem cells from the skin of patients exon 80 of the COL7A1 gene, which contains the pathogenic mutation. This leads to the production, from the edited cells, of a functional variant of C7.

The transplantation of a bioengineering skin equivalent carrying the patient's cells "cured" with the help of this new technology has been shown to be able to regenerate completely normal tissues in a reliable preclinical model of the disease. .

Until now, the CRISPR / Cas9 molecular tool lacked the necessary levels of efficacy for realistic clinical applications using adult stem cells, such as hematopoietic or cutaneous (epidermal) stem cells. Therefore, these strategies could not compete with conventional gene addition therapy using viral vectors. "However, this study showed that the new non-viral gene editing approach developed was even more effective than the viral gene addition therapy for dystrophic epidermolysis bullosa recessive," the report said. co-author of the study, Fernando Larcher of CIEMAT. In addition to its effectiveness, the strategy has proven safe due to the absence of adverse effects on the patient's genome.

In this work, in which José Bonafont, a researcher-in-training at UC3M, participated in his doctoral thesis, scientists from the Centro Nacional de Investigaciones Oncológicas (Spanish National Center for Cancer Research – CNIO) collaborated. The study was made possible thanks to funding from DEBRA International (United Kingdom); Era Net Erare (European Union); Spanish Acción Estratégica en Salud (ISCIII); Spanish plan for evaluation of scientific and technical research and innovation; and also from the Community of Madrid (CAM).