Gene editing as a novel therapeutic strategy in Fanconi anemia

点击翻译按钮获取中文摘要

Fanconi anemia (FA) is a DNA repair syndrome characterized by congenital abnormalities, cancer predisposition and early onset of bone marrow failure in the patients. Allogeneic hematopoietic stem cell (HSC) transplantation is currently the only curative treatment for the bone marrow failure in FA. However, only 25% of the patients have a suitable human leukocyte antigen (HLA)-identical donor and severe side effects are associated with this treatment, such as 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. Given the unprecedented advances in gene editing and the proliferative advantage that corrected FA HSCs possess as compared to non-corrected cells, we aim to go one step further and to develop safer and more precise gene therapy strategies to correct different mutations described in FA 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 genome editing tools for further clinical development.