Mucopolysaccharidosis type I (MPS-I), a lysosomal storage disorder caused by a deficiency of alpha-L-iduronidase enzyme, results in the progressive accumulation of glycosaminoglycans and consequent multiorgan dysfunction. Despite the effectiveness of hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) in correcting clinical manifestations related to visceral organs, complete improvement of musculoskeletal and neurocognitive defects remains an unmet challenge and provides an impact on patients' quality of life. We tested the therapeutic efficacy of combining HSCT and ERT in the neonatal period. Using a mouse model of MPS-I, we demonstrated that the combination therapy improved clinical manifestations in organs usually refractory to current treatment. Moreover, combination with HSCT prevented the production of anti-IDUA antibodies that negatively impact ERT efficacy. The added benefits of combining both treatments also resulted in a reduction of skeletal anomalies and a trend towards decreased neuroinflammation and metabolic abnormalities. As currently there are limited therapeutic options for MPS-I patients, our findings suggest that the combination of HSCT and ERT during the neonatal period may provide a further step forward in the treatment of this rare disease.

I型粘多糖贮积病（MPS-I）是由α-L-艾杜糖醛酸酶缺乏引起的溶酶体贮积病，导致糖胺聚糖的逐步积累和随之而来的多器官功能障碍。尽管造血干细胞移植（HSCT）和酶替代疗法（ERT）在纠正与内脏器官相关的临床表现方面有效，但肌肉骨骼和神经认知缺陷的全面改善仍是一项尚未得到解决的挑战，并会影响患者的生活质量。我们测试了HSCT和ERT联合在新生儿期的治疗效果。使用MPS-1的小鼠模型，我们证明了联合治疗改善了通常对当前治疗无效的器官的临床表现。此外，与HSCT的联合使用可防止产生对ERT效力产生负面影响的抗IDUA抗体。两种治疗方法相结合的附加好处还可以减少骨骼异常，并减少神经炎症和代谢异常。由于目前MPS-I患者的治疗选择有限，我们的研究结果表明，新生儿期HSCT和ERT的联合使用可为这种罕见疾病的治疗提供进一步的发展。