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A comparison of intrauterine haemopoietic cell transplantation and lentiviral gene transfer for the correction of severe β-thalassaemia in a HbbTh3/+ murine model

Dighe, NM; Tan, KW; Tan, LG; Shaw, SSW; Buckley, SMK; Sandikin, D; Johana, N; ... Mattar, CNZ; + view all (2018) A comparison of intrauterine haemopoietic cell transplantation and lentiviral gene transfer for the correction of severe β-thalassaemia in a HbbTh3/+ murine model. Experimental Hematology , 62 10.1016/j.exphem.2018.03.006. Green open access

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Abstract

Major haemoglobinopathies place tremendous strain on global resources. Intrauterine haemopoietic cell (IUHCT) and gene (IUGT) therapies can potentially reduce perinatal morbidities with greater efficacy than postnatal therapy alone. We performed both procedures in the thalassaemic HbbTh3/+ murine model. Intraperitoneal delivery of coisogenic cells at E13-14 produced dose-dependent chimerism. High-dose adult bone marrow (BM) cells maintained 0.2-3.1% chimerism over ~24 weeks and treated heterozygotes demonstrated higher chimerism than wild-type pups (1.6 vs. 0.7%). Fetal liver cells produced higher chimerism compared to adult BM when transplanted at the same doses, maintaining 1.8-2.4% chimerism over ~32 weeks. We boosted transplanted mice postnatally with adult BM cells following busulfan conditioning. Engraftment was maintained at >1% only in recipients which were chimeric prior to boosting. IUHCT-treated non-chimeras and non-IUHCT mice showed micro- or no chimerism. Additional fludarabine treatment produced higher chimerism than busulfan alone. Engraftment was more effective following higher starting chimerism prior to boosting and in heterozygotes. Chimeric heterozygotes expressed 2.2-15.1% donor cells with eventual decline at 24 weeks (vs. <1% in non-chimeras) and demonstrated improved haematological indices and smaller spleens compared to untreated heterozygotes. Intravenous delivery of GLOBE lentiviral-vector expressing HBB (human β-globin) resulted in vector concentration of 0.001-0.6 copies/cell. Most haematological indices were higher in treated than untreated heterozygotes including haemoglobin and mean corpuscular volume, though still lower than in wild-types. Thus both direct IUGT and IUHCT strategies can be used to achieve haematological improvement but require further dose optimisation. IUHCT will be useful combined with postnatal transplantation to further enhance engraftment.

Type: Article
Title: A comparison of intrauterine haemopoietic cell transplantation and lentiviral gene transfer for the correction of severe β-thalassaemia in a HbbTh3/+ murine model
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.exphem.2018.03.006
Publisher version: https://doi.org/10.1016/j.exphem.2018.03.006
Language: English
Additional information: User License: Creative Commons Attribution (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0/).
Keywords: Thalassaemia, intrauterine gene therapy, haemopoietic stem cell, intrauterine cell therapy, postnatal transplantation, fludarabine, HbbTh3/+ mouse, GLOBE vector
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health > Maternal and Fetal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10046704
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