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

Abstract

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.

Fetal therapies and trials for lysosomal storage diseases: a survey of attitudes of parents and patients

“…Additionally, in utero ERT penetrated brain microglia and led to decreased microglial inflammation and improved neurological testing, such as grip strength, compared to mice only treated postnatally. Most importantly, in utero ERT prevented the development of anti-enzyme antibodies [ 13 ], consistent with prior reports of inducing immune tolerance after in utero administration of an antigen [ 14 – 17 ]. Based on these results and the severe unmet medical need in this group of patients, we have obtained an Investigational New Drug approval from the United States Food and Drug Administration to perform in utero ERT for fetuses with various LSDs for which an intravenous ERT is available (NCT04532047), including MPS 1, 2, 4a, 6, 7, neuronopathic Gaucher, Infantile-onset Pompe disease, and Wolman disease.…”

“…These limitations could potentially be addressed by in utero administration of ERT. We recently demonstrated that in utero ERT in a mouse model of MPS 7 improved survival of affected mice to birth [ 13 ]. Additionally, in utero ERT penetrated brain microglia and led to decreased microglial inflammation and improved neurological testing, such as grip strength, compared to mice only treated postnatally.…”

Ostm1 from Mouse to Human: Insights into Osteoclast Maturation

“…Alternatively, a novel protocol tested in mice consists in transfusion of monocytic cells that can rescue bone marrow development in an early onset of osteopetrosis in the absence of HSCT [ 108 ]. As validation of this concept, microglial engraftment through single in utero transplant in the mouse can improve some of the brain phenotype described in lysosomal storage disease [ 109 ] and could possibly alleviate neuronal defects due to osteopetrosis. In fact, based on the implication of Ostm1 in neuronal homeostasis, curative treatment of OSTM1 patients is still challenging and consensus guidelines are being established [ 110 ].…”

Mucopolysaccharidosis type VII presenting as neonatal cholestasis

“…Lentiviral-mediated gene therapy is effective in reversing established skeletal pathology in murine MPS VII [13]. Similarly, animal experiments suggest that fetal therapy with IUERT and/or IUHCT could overcome the shortcomings of current treatment strategies to improve phenotype in MPS VII and other LSDs [14].…”