Multiple sulfatase deficiency (MSD) is a severe, lysosomal storage disorder caused by pathogenic variants in the gene SUMF1, encoding the sulfatase modifying factor formylglycine-generating enzyme. Patients with MSD exhibit functional deficiencies in all cellular sulfatases. The inability of sulfatases to break down their substrates leads to progressive and multi-systemic complications in patients, similar to those seen in single-sulfatase disorders such as metachromatic leukodystrophy and mucopolysaccharidoses IIIA. Here, we aimed to determine if hematopoietic stem cell transplantation with ex vivo SUMF1 lentiviral gene therapy could improve outcomes in a clinically relevant mouse model of MSD. We first tested our approach in MSD patient-derived cells and found that our SUMF1 lentiviral vector improved protein expression, sulfatase activities, and glycosaminoglycan accumulation. In vivo, we found that our gene therapy approach rescued biochemical deficits, including sulfatase activity and glycosaminoglycan accumulation, in affected organs of MSD mice treated post-symptom onset. In addition, treated mice demonstrated improved neuroinflammation and neurocognitive function. Together, these findings suggest that SUMF1 HSCT-GT can improve both biochemical and functional disease markers in the MSD mouse.

中文翻译：

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造血干细胞基因治疗改善了临床相关多元硫酸酯酶缺乏症小鼠模型的预后


多重硫酸酯酶缺乏症 （MSD） 是一种严重的溶酶体贮积症，由编码硫酸酯酶修饰因子甲酰甘氨酸生成酶的基因 SUMF1 的致病性变异引起。MSD 患者在所有细胞硫酸酯酶中均表现出功能缺陷。硫酸酯酶无法分解其底物导致患者出现进行性和多系统并发症，类似于异染性脑白质营养不良和粘多糖病 IIIA 等单一硫酸酯酶疾病中观察到的并发症。在这里，我们旨在确定使用离 体 SUMF1 慢病毒基因疗法进行造血干细胞移植是否可以改善临床相关 MSD 小鼠模型的预后。我们首先在 MSD 患者来源的细胞中测试了我们的方法，发现我们的 SUMF1 慢病毒载体改善了蛋白质表达、硫酸酯酶活性和糖胺聚糖积累。在 体内，我们发现我们的基因治疗方法挽救了症状发作后接受治疗的 MSD 小鼠受影响器官的生化缺陷，包括硫酸酯酶活性和糖胺聚糖积累。此外，接受治疗的小鼠表现出神经炎症和神经认知功能的改善。总之，这些发现表明 SUMF1 HSCT-GT 可以改善 MSD 小鼠的生化和功能疾病标志物。