FANEDIT: Gene editing as a novel therapeutic strategy in Fanconi anemia

Fanconi anemia is a DNA repair syndrome characterized by congenital abnormalities, cancer predisposition and early onset of bone marrow failure in the patients. Allogenic hematopoietic stem cell (HSC) transplantation is currently the only curative treatment for the bone marrow failure in Fanconi anemia (FA). However, only 25% of the patients have a suitable donor (human leukocyte antigen (HLA)-identical donor) and severe side effects are associated to this treatment, specially increased incidence of squamous cell carcinoma. Recent studies from FANEDIT members have shown the feasibility to correct hematopoietic stem cells from FA-A patients using lentiviral vectors. Strikingly, corrected cells engrafted in the patients in the absence of any conditioning and showed a marked proliferative advantage. Although lentiviral vector therapy has demonstrated to be safe in different clinical trials, the possibility to precisely correct the mutation in the patient would be the ideal therapeutic strategy. Thanks to the advance in gene editing strategies in this new project we aim to go one step further in the development of safer and more precise gene therapy strategies that allow the correction of the different mutations described in the 22 different genes involved in the disease. For this purpose, novel gene editing strategies and delivery systems will be tested in FA HSCs. Importantly, safety studies using different platforms will be conducted to identify the best-suited programmable nucleases for further clinical development.