Research ArticleLysosomal Storage Diseases

Tolerance induction and microglial engraftment after fetal therapy without conditioning in mice with mucopolysaccharidosis type VII

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Science Translational Medicine  26 Feb 2020:
Vol. 12, Issue 532, eaay8980
DOI: 10.1126/scitranslmed.aay8980

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When treating at birth is too late

Mucopolysaccharidosis type VII (MPS7) is a rare and severe lysosomal storage disorder, which causes dysfunction of multiple organs including the brain and may be associated with undiagnosed cases of fetal death. By the time of birth, the organ damage may already be severe and the fetus may not survive at all. Thus, the prenatal period provides the most promising opportunity for intervention. Nguyen et al. assessed two prenatal approaches, in utero enzyme replacement therapy and in utero hematopoietic stem cell transplantation, and demonstrated the potential of these treatments to improve survival and functional outcomes in a mouse model of MPS7.


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.

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