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P51

Developing stem cell and gene therapy for VPS33B deficiency

M Nazari(1,3) A C Cozmescu(1,3) A L Mudde(1) S Caetano-Silva(1) D Perocheau(1) S Gurung(1) L Touramanidou(1) J Baruteau(1,2,3) C Booth(1,2) P Gissen(1,2,3)

1:UCL Institute of Child Health; 2:Great Ormond Street Hospital for Children; 3:NIHR Great Ormond Street Hospital Biomedical Research Centre

Arthrogryposis Renal dysfunction and Cholestasis syndrome (ARC) is an autosomal recessive multisystem disorder caused by mutations in VPS33B or VIPAS39. Most patients die of severe infections or bleeding <18 months of age. VPS33B-VIPAR complex regulate protein trafficking and biosynthesis of specialised organelles. Bleeding defects in ARC result from abnormal platelet α‐granules synthesis in megakaryocytes. Infections in ARC may be due to a defect in phagosome-lysosome and endosome-lysosome fusions in macrophages and other immune cells.


In this project we aim to develop ex vivo gene therapy to prevent fatal consequence of ARC such as bleeding and infections. Ex vivo lentiviral gene therapy of haematopoietic stem cells (HSC) has shown promise in humans and animal models of genetic disorders affecting immune and haematological systems for over two decades. We have developed a lentiviral vector LV.EF1α.VPS33B and tested it in a tamoxifen inducible ERT2-Cre-VPS33Bfl/fl mouse model. When induced post developmentally, this mouse model displays the bone marrow abnormalities mimicking those observed in ARC patients.


1 week post tamoxifen induction some of the knock-out mice were sacrificed, HSC were treated with LV.EF1α.VPS33B and infused into surviving tamoxifen induced Vps33bfl/fl-ERT2 mice after irradiation to secure engraftment. A 6-fold increase in the expression of VPS33B was detected in treated mice compared to the wild type mice with >2 vector copy number per cell. The treated mice demonstrated improvement in skin phenotype, normalisation of the spleen size and survival for the first time, providing proof of concept for this treatment approach in ARC.

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