Gene editing as a novel therapeutic strategy in Fanconi anemia

范可尼贫血（FA）是一种DNA修复综合征，以先天性异常、癌症易感性和患者早发性骨髓衰竭为特征。同种异体造血干细胞（HSC）移植是目前治疗FA患者骨髓衰竭的唯一有效方法。然而，只有25%的患者有合适的人类白细胞抗原（HLA）相同的供体，并且与这种治疗相关的严重副作用，例如鳞状细胞癌的发病率增加。FANEDIT成员最近的研究表明，使用慢病毒载体纠正FA-A患者的造血干细胞是可行的。引人注目的是，在没有任何条件作用的情况下，移植到患者体内的校正细胞显示出明显的增殖优势。尽管慢病毒载体疗法在不同的临床试验中被证明是安全的，但精确纠正患者突变的可能性将是理想的治疗策略。鉴于基因编辑的前所未有的进步和与非校正细胞相比，校正后的FA造血干细胞具有增殖优势，我们的目标是更进一步，开发更安全、更精确的基因治疗策略，以校正与该疾病相关的FA基因中描述的不同突变。为此，新的基因编辑策略和传递系统将在FA造血干细胞中进行测试。重要的是，将使用不同的平台进行安全性研究，以确定最适合的基因组编辑工具，用于进一步的临床开发。

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.