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

TY - JOUR

T1 - A comparison of intrauterine haemopoietic cell transplantation and lentiviral gene transfer for the correction of severe β-thalassaemia in a HbbTh3/+ murine model

AU - Dighe, Niraja M.

AU - Tan, Kang Wei

AU - Tan, Lay Geok

AU - Shaw, Steven S.W.

AU - Buckley, Suzanne M.K.

AU - Sandikin, Dedy

AU - Johana, Nuryanti

AU - Tan, Yi-Wan

AU - Biswas, Arijit

AU - Choolani, Mahesh

AU - Waddington, Simon N.

AU - Antoniou, Michael N.

AU - Chan, Jerry K.Y.

AU - Mattar, Citra N.Z.

PY - 2018/3/29

Y1 - 2018/3/29

N2 -  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.

AB -  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.

KW - Thalassaemia

KW - intrauterine gene therapy

KW - haemopoietic stem cell

KW - intrauterine cell therapy

KW - postnatal transplantation

KW - fludarabine

KW - HbbTh3/+ mouse

KW - GLOBE vector

U2 - 10.1016/j.exphem.2018.03.006

DO - 10.1016/j.exphem.2018.03.006

M3 - Article

SN - 0301-472X

JO - Experimental Hematology

JF - Experimental Hematology

ER -