临床试验表明，通过慢病毒介导的基因治疗可以改善非条件性范可尼贫血（FA）患者骨髓衰竭（BMF），这是由于纠正了FA HSPC的增殖优势，然而，目前尚不清楚基因治疗是否能够恢复患病的HSPCs受影响的分子通路。我们在基因治疗治疗FA患者的骨髓中进行了改正和未改正HSPCs的嵌合群体的单细胞RNA测序。我们的研究表明，基因治疗可以使FA HSPCs的转录标记逆转，这时候，FA HSPCs的转录计划类似于健康的供体HSPCs的转录计划。这包括了TGF-β和p21的表达下调，这在FA HSPCs中通常是上调的；以及DNA损伤响应和端粒维护通路的上调。我们的结果首次展示了基因治疗改善患有遗传病的病人HSPC转录计划缺陷的潜力，这种情况下是BMF和癌症易感性FA。

Clinical trials have shown that lentiviral-mediated gene therapy can ameliorate bone marrow failure (BMF) in non-conditioned Fanconi anemia (FA) patients resulting from the proliferative advantage of corrected FA HSPCs, however it is yet unknown if gene therapy can revert affected molecular pathways in diseased HSPCs. Single-cell RNA sequencing was performed in chimeric populations of corrected and uncorrected HSPCs coexisting in the BM of gene therapy treated FA patients. Our study demonstrates that gene therapy reverts the transcriptional signature of FA HSPCs, which then resembles the transcriptional program of healthy donor HSPCs. This includes a downregulated expression of TGF-β and p21, typically upregulated in FA HSPCs, and upregulation of DNA damage response and telomere maintenance pathways. Our results show for the first time the potential of gene therapy to rescue defects in the HSPC transcriptional program from patients with inherited diseases, in this case in FA characterized by BMF and cancer predisposition.