In-utero cell transplantation for hypophosphatasia with gene-edited hESC-derived MSCs in a murine model

The perinatal severe form of hypophosphatasia (HPP), caused by a deficiency in tissue-nonspecific alkaline phosphatase (TNAP), which is involved in bone metabolism, is a disease that manifests during fetal development. However, no established treatment can be performed in utero, and invasive treatment must be continued for a lifetime immediately after birth due to irreversible thoracic hypoplasia. We have developed an ex vivo in-utero gene cell therapy as a new treatment that can intervene at the fetal stage. We transduced the hALPL-D10 gene into human embryonic stem cell-derived mesenchymal stem cells to generate cells that overexpress TNAP. We transplanted the cells into the fetuses of HPP mice without immunosuppression by total body irradiation. The primary strength of this methodology lies in the fact that all experiments were conducted using immunocompetent animals with human cells. Compared to the untreated group, the treated group showed an extended survival rate ( p = 0.005). In addition, the treated group showed significant weight gain (day 0 [ p = 0.024], day 7 [ p < 0.001], and day 14 [ p = 0.017]) and improvement in bone lesions. Ex vivo in-utero gene cell therapy may be a new option for treating patients with HPP during gestation.