Abstract
In utero gene therapy (IUGT) to the fetal hematopoietic compartment could be used to treat congenital blood disorders such as β-thalassemia. A humanised mouse model of β-thalassemia was used, in which heterozygous animals are anaemic with splenomegaly and extramedullary hematopoiesis. Intrahepatic in utero injections of a β globin-expressing lentiviral vector (GLOBE), were performed in fetuses at E13.5 of gestation. We analysed animals at 12 and 32 weeks of age, for vector copy number in bone marrow, peripheral blood liver and spleen and we performed integration site analysis. Compared to noninjected heterozygous animals IUGT normalised blood haemoglobin levels and spleen weight. Integration site analysis showed polyclonality. The left ventricular ejection fraction measured using magnetic resonance imaging (MRI) in treated heterozygous animals was similar to that of normal non-β-thalassemic mice but significantly higher than untreated heterozygous thalassemia mice suggesting that IUGT ameliorated poor cardiac function. GLOBE LV-mediated IUGT normalised the haematological and anatomical phenotype in a heterozygous humanised model of β-thalassemia.
Highlights
In utero gene therapy (IUGT) to the fetal hematopoietic compartment could be used to treat congenital blood disorders such as β-thalassemia
We show the phenotypic correction of the heterozygous animals using in utero gene therapy (IUGT) approach through prenatal intrahepatic injection of the globin-expressing lentiviral vector (GLOBE) LV
In order to identify the true fetal and dam survival after in utero gene therapy delivery we analysed the fetuses at E18 after IUGT in two dams
Summary
In utero gene therapy (IUGT) to the fetal hematopoietic compartment could be used to treat congenital blood disorders such as β-thalassemia. TM requires regular blood transfusions and if left untreated is a life-threatening condition for which the only curative therapy - allogeneic haematopoietic stem cell (HSC) transplantation - is limited to a small percentage of patients with available HSC donors. Fetal therapy of an affected fetus would avoid termination of pregnancy, early death or life-threatening complications for patients with no compatible donor This would have an impact where α-and β-thalassemia are most prevalent, even where termination of pregnancy may not be available, and blood transfusions are prohibitively expensive[5]
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