Mucopolysaccharidosis type VII (MPS7) is a lysosomal storage disorder (LSD) resulting from mutations in the β-glucuronidase gene, leading to multiorgan dysfunction and fetal demise. While postnatal enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation have resulted in some phenotypic improvements, prenatal treatment might take advantage of a unique developmental window to penetrate the blood-brain barrier or induce tolerance to the missing protein, addressing two important shortcomings of postnatal therapy for multiple LSDs. We performed in utero ERT (IUERT) at E14.5 in MPS7 mice and improved survival of affected mice to birth. IUERT penetrated brain microglia, whereas postnatal administration did not, and neurological testing (after IUERT plus postnatal administration) showed decreased microglial inflammation and improved grip strength in treated mice. IUERT prevented antienzyme antibody development even after multiple repeated postnatal challenges. To test a more durable treatment strategy, we performed in utero hematopoietic stem cell transplantation (IUHCT) using congenic CX3C chemokine receptor 1-green fluorescent protein (CX3CR1-GFP) mice as donors, such that donor-derived microglia are identified by GFP expression. In wild-type recipients, hematopoietic chimerism resulted in microglial engraftment throughout the brain without irradiation or conditioning; the transcriptomes of donor and host microglia were similar. IUHCT in MPS7 mice enabled cross-correction of liver Kupffer cells and improved phenotype in multiple tissues. Engrafted microglia were seen in chimeric mice, with decreased inflammation near donor microglia. These results suggest that fetal therapy with IUERT and/or IUHCT could overcome the shortcomings of current treatment strategies to improve phenotype in MPS7 and other LSDs.

中文翻译：

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胎儿治疗后的耐受诱导和小胶质细胞植入，无条件治疗VII型粘多糖贮积症小鼠。

VII型粘多糖贮积病（MPS7）是一种溶酶体贮积病（LSD），是由β-葡萄糖醛酸苷酶基因突变引起的，导致多器官功能障碍和胎儿死亡。虽然产后酶替代疗法（ERT）和造血干细胞移植已带来一些表型改善，但产前治疗可能会利用独特的发育窗口来穿透血脑屏障或诱导对缺失蛋白的耐受性，从而解决了两个重要缺点多种LSD的产后治疗。我们在E14.5的MPS7小鼠的子宫内ERT（IUERT）中进行了实验，并提高了患病小鼠的存活率。IUERT穿透了脑小胶质细胞，而产后给药则没有，和神经学测试（IUERT加产后给药后）显示，治疗的小鼠小胶质细胞炎症减少，握力增强。即使在多次重复的出生后挑战后，IUERT仍能阻止抗酶抗体的产生。为了测试更持久的治疗策略，我们在子宫造血干细胞移植（IUHCT）中进行了研究，使用同基因CX3C趋化因子受体1-绿色荧光蛋白（CX3CR1-GFP）小鼠作为供体，从而通过GFP表达鉴定了供体来源的小胶质细胞。在野生型受体中，造血嵌合现象导致小胶质细胞植入整个大脑，而无辐射或无条件。供体和宿主小胶质细胞的转录组相似。MPS7小鼠中的IUHCT能够交叉纠正肝Kupffer细胞并改善多种组织的表型。在嵌合小鼠中观察到了植入的小胶质细胞，在供体小胶质细胞附近炎症减少了。这些结果表明，用IUERT和/或IUHCT进行胎儿治疗可以克服目前改善MPS7和其他LSDs表型的治疗策略的缺点。