Immune response to therapeutic enzymes poses a detriment to patient safety and treatment outcome. Enzyme replacement therapy (ERT) is a standard therapeutic option for some types of mucopolysaccharidoses, including Morquio A syndrome caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency. Current protocols tolerize patients using cytotoxic immunosuppressives, which can cause adverse effects. Here we show development of tolerance in Morquio A mice via oral delivery of peptide or GALNS for 10 days prior to ERT. Our results show that using an immunodominant peptide (I10) or the complete GALNS enzyme to orally induce tolerance to GALNS prior to ERT resulted in several improvements to ERT in mice: (a) decreased splenocyte proliferation after in vitro GALNS stimulation, (b) modulation of the cytokine secretion profile, (c) decrease in GALNS-specific IgG or IgE in plasma, (d) decreased GAG storage in liver, and (e) fewer circulating immune complexes in plasma. This model could be extrapolated to other lysosomal storage disorders in which immune response hinders ERT.

中文翻译：

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口服免疫疗法可耐受小鼠对Morquio A综合征的酶替代疗法

对治疗性酶的免疫反应不利于患者的安全性和治疗效果。酶替代疗法（ERT）是某些类型的粘多糖酶的标准治疗选择，包括N-乙酰半乳糖胺-6-硫酸盐硫酸酯酶（GALNS）缺乏引起的Morquio A综合征。当前的方案使用细胞毒性免疫抑制剂耐受患者，这可能引起不良反应。在这里，我们显示了在ERT前10天通过口服肽或GALNS口服给药，在Morquio A小鼠中产生了耐受性。我们的结果表明，在ERT之前使用免疫优势肽（I10）或完整的GALNS酶口服诱导对GALNS的耐受性可导致小鼠ERT改善：（a）体外GALNS刺激后脾细胞增殖减少；（b）调节细胞因子分泌特征 （c）血浆中GALNS特异性IgG或IgE降低，（d）肝脏中GAG储存降低，和（e）血浆中循环免疫复合物减少。该模型可以推断为其他溶酶体贮积病，其中免疫反应阻碍ERT。