O27: MICROGLIAL CORRECTION AFTER FETAL THERAPY WITHOUT CONDITIONING IN MICE WITH MUCOPOLYSACCHARIDOSIS TYPE VII

Abstract Introduction Mucopolysaccharidosis type 7 (MPS7) is a lysosomal storage disorder typically fatal in utero. Postnatal enzyme replacement therapy (ERT) to replace missing glucuronidase (GUS) does not penetrate the blood-brain barrier (BBB). We investigated whether utero ERT (IUERT) specifically targets brain microglia (natural GUS storehouses and key inflammation mediators) hematopoietic stem cell transplantation (IUHSCT) results microglial engraftment as strategy for permanent correction. Methods performed IUERT by injecting into MPS7 fetuses mid-gestation, analyzed tissue homogenates (via colorimetric substrate) flow cytometry) activity after 4-7 days. IUHSCT transplanting HSCs mid-gestation from CX3CR1-GFP donors. examined blood, bone marrow, engraftment. assessed staining CD68. RNA sequencing characterize engrafted microglia. Results resulted detectable activity. Flow cytometry showed that was near wild-type levels, brains harvested adulthood had decreased via CD68 immunohistochemistry. multilineage of cells blood bone. Confocal microscopy revealed multifocal donor-derived indicated were nearly identical endogenous chimeras evidence reduced donor Conclusion Both are complementary treatment modalities can BBB ameliorate neurologic manifestations diseases such MPS7. These lay foundation future studies using molecular therapies well other disorders.