In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques

Panicos Shangaris; Stavros P. Loukogeorgakis; Sindhu Subramaniam; Christina Flouri; Laurence H. Jackson; Wei Wang; Michael P. Blundell; Shanrun Liu; Simon Eaton; Nahla Bakhamis; Durrgah Latchumi Ramachandra; Panayiotis Maghsoudlou; Luca Urbani; Simon N. Waddington; Ayad Eddaoudi; Joy Archer; Michael N. Antoniou; Daniel J. Stuckey; Manfred Schmidt; Adrian J. Thrasher; Thomas M. Ryan; Paolo De Coppi; Anna L. David

doi:10.1038/s41598-019-48078-4

In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques

Panicos Shangaris, Stavros P. Loukogeorgakis, Sindhu Subramaniam, Christina Flouri, Laurence H. Jackson, Wei Wang, Michael P. Blundell, Shanrun Liu, Simon Eaton, Nahla Bakhamis, Durrgah Latchumi Ramachandra, Panayiotis Maghsoudlou, Luca Urbani, Simon N. Waddington, Ayad Eddaoudi, Joy Archer, Michael N. Antoniou, Daniel J. Stuckey, Manfred Schmidt, Adrian J. ThrasherThomas M. Ryan, Paolo De Coppi, Anna L. David

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

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.

Original language	English
Article number	11592
Journal	Scientific Reports
Volume	9
Issue number	1
Early online date	12 Aug 2019
DOIs	https://doi.org/10.1038/s41598-019-48078-4
Publication status	Published - 1 Dec 2019

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Shangaris, P., Loukogeorgakis, S. P., Subramaniam, S., Flouri, C., Jackson, L. H., Wang, W., Blundell, M. P., Liu, S., Eaton, S., Bakhamis, N., Ramachandra, D. L., Maghsoudlou, P., Urbani, L., Waddington, S. N., Eddaoudi, A., Archer, J., Antoniou, M. N., Stuckey, D. J., Schmidt, M., ... David, A. L. (2019). In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques. Scientific Reports, 9(1), Article 11592. https://doi.org/10.1038/s41598-019-48078-4

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title = "In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques",

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.",

author = "Panicos Shangaris and Loukogeorgakis, {Stavros P.} and Sindhu Subramaniam and Christina Flouri and Jackson, {Laurence H.} and Wei Wang and Blundell, {Michael P.} and Shanrun Liu and Simon Eaton and Nahla Bakhamis and Ramachandra, {Durrgah Latchumi} and Panayiotis Maghsoudlou and Luca Urbani and Waddington, {Simon N.} and Ayad Eddaoudi and Joy Archer and Antoniou, {Michael N.} and Stuckey, {Daniel J.} and Manfred Schmidt and Thrasher, {Adrian J.} and Ryan, {Thomas M.} and Coppi, {Paolo De} and David, {Anna L.}",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41598-019-48078-4",

language = "English",

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Shangaris, P, Loukogeorgakis, SP, Subramaniam, S, Flouri, C , Jackson, LH , Wang, W, Blundell, MP, Liu, S, Eaton, S, Bakhamis, N, Ramachandra, DL, Maghsoudlou, P, Urbani, L, Waddington, SN, Eddaoudi, A, Archer, J, Antoniou, MN, Stuckey, DJ, Schmidt, M, Thrasher, AJ, Ryan, TM, Coppi, PD & David, AL 2019, 'In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques', Scientific Reports, vol. 9, no. 1, 11592. https://doi.org/10.1038/s41598-019-48078-4

In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques. / Shangaris, Panicos; Loukogeorgakis, Stavros P.; Subramaniam, Sindhu et al.
In: Scientific Reports, Vol. 9, No. 1, 11592, 01.12.2019.

Research output: Contribution to journal › Article › peer-review

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T1 - In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques

AU - Shangaris, Panicos

AU - Loukogeorgakis, Stavros P.

AU - Subramaniam, Sindhu

AU - Flouri, Christina

AU - Jackson, Laurence H.

AU - Wang, Wei

AU - Blundell, Michael P.

AU - Liu, Shanrun

AU - Eaton, Simon

AU - Bakhamis, Nahla

AU - Ramachandra, Durrgah Latchumi

AU - Maghsoudlou, Panayiotis

AU - Urbani, Luca

AU - Waddington, Simon N.

AU - Eddaoudi, Ayad

AU - Archer, Joy

AU - Antoniou, Michael N.

AU - Stuckey, Daniel J.

AU - Schmidt, Manfred

AU - Thrasher, Adrian J.

AU - Ryan, Thomas M.

AU - Coppi, Paolo De

AU - David, Anna L.

PY - 2019/12/1

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N2 - 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.

AB - 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.

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DO - 10.1038/s41598-019-48078-4

M3 - Article

SN - 2045-2322

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JO - Scientific Reports

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IS - 1

M1 - 11592

ER -

In Utero Gene Therapy (IUGT) Using GLOBE Lentiviral Vector Phenotypically Corrects the Heterozygous Humanised Mouse Model and Its Progress Can Be Monitored Using MRI Techniques

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