Eli and Edythe Broad Center of Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
Sci Transl Med. 2020 Feb 26;12(532). doi: 10.1126/scitranslmed.aay8980.
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.
黏多糖贮积症 VII 型（MPS7）是一种溶酶体贮积症（LSD），由β-葡萄糖醛酸酶基因突变引起，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经取得了一些表型改善，但产前治疗可能利用独特的发育窗口穿透血脑屏障或诱导对缺失蛋白的耐受，解决了多种 LSD 产后治疗的两个重要缺陷。我们在 MPS7 小鼠的 E14.5 进行了宫内 ERT（IUERT），并提高了受影响小鼠的存活率至出生。IUERT 穿透了大脑小胶质细胞，而产后给药则没有，神经学测试（在 IUERT 加产后给药后）显示治疗小鼠的小胶质细胞炎症减少和握力增强。IUERT 甚至在多次重复产后挑战后也能防止抗酶抗体的产生。为了测试更持久的治疗策略，我们使用同源 CX3C 趋化因子受体 1-绿色荧光蛋白（CX3CR1-GFP）小鼠作为供体进行了宫内造血干细胞移植（IUHCT），这样供体衍生的小胶质细胞可以通过 GFP 表达来识别。在野生型受体中，造血嵌合导致整个大脑中的小胶质细胞移植，而无需照射或调理；供体和宿主小胶质细胞的转录组相似。MPS7 小鼠的 IUHCT 使肝脏枯否细胞能够交叉校正，并改善了多种组织的表型。在嵌合小鼠中可以看到移植的小胶质细胞，在供体小胶质细胞附近炎症减少。这些结果表明，使用 IUERT 和/或 IUHCT 的胎儿治疗可以克服当前治疗策略的缺陷，改善 MPS7 和其他 LSD 的表型。
