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A systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders

Author

Listed:
  • Francesca Tucci

    (IRCCS San Raffaele Scientific Institute
    IRCCS San Raffaele Scientific Institute)

  • Stefania Galimberti

    (University of Milano — Bicocca)

  • Luigi Naldini

    (IRCCS San Raffaele Scientific Institute
    Vita-Salute San Raffaele University)

  • Maria Grazia Valsecchi

    (University of Milano — Bicocca)

  • Alessandro Aiuti

    (IRCCS San Raffaele Scientific Institute
    IRCCS San Raffaele Scientific Institute
    Vita-Salute San Raffaele University)

Abstract

Ex-vivo gene therapy (GT) with hematopoietic stem and progenitor cells (HSPCs) engineered with integrating vectors is a promising treatment for monogenic diseases, but lack of centralized databases is hampering an overall outcomes assessment. Here we aim to provide a comprehensive assessment of the short and long term safety of HSPC-GT from trials using different vector platforms. We review systematically the literature on HSPC-GT to describe survival, genotoxicity and engraftment of gene corrected cells. From 1995 to 2020, 55 trials for 14 diseases met inclusion criteria and 406 patients with primary immunodeficiencies (55.2%), metabolic diseases (17.0%), haemoglobinopathies (24.4%) and bone marrow failures (3.4%) were treated with gammaretroviral vector (γRV) (29.1%), self-inactivating γRV (2.2%) or lentiviral vectors (LV) (68.7%). The pooled overall incidence rate of death is 0.9 per 100 person-years of observation (PYO) (95% CI = 0.37–2.17). There are 21 genotoxic events out of 1504.02 PYO, which occurred in γRV trials (0.99 events per 100 PYO, 95% CI = 0.18–5.43) for primary immunodeficiencies. Pooled rate of engraftment is 86.7% (95% CI = 67.1–95.5%) for γRV and 98.7% (95% CI = 94.5–99.7%) for LV HSPC-GT (p = 0.005). Our analyses show stable reconstitution of haematopoiesis in most recipients with superior engraftment and safer profile in patients receiving LV-transduced HSPCs.

Suggested Citation

  • Francesca Tucci & Stefania Galimberti & Luigi Naldini & Maria Grazia Valsecchi & Alessandro Aiuti, 2022. "A systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28762-2
    DOI: 10.1038/s41467-022-28762-2
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    References listed on IDEAS

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    1. Marina Cavazzana-Calvo & Emmanuel Payen & Olivier Negre & Gary Wang & Kathleen Hehir & Floriane Fusil & Julian Down & Maria Denaro & Troy Brady & Karen Westerman & Resy Cavallesco & Beatrix Gillet-Leg, 2010. "Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia," Nature, Nature, vol. 467(7313), pages 318-322, September.
    2. Aneal Khan & Dwayne L. Barber & Ju Huang & C. Anthony Rupar & Jack W. Rip & Christiane Auray-Blais & Michel Boutin & Pamela O’Hoski & Kristy Gargulak & William M. McKillop & Graeme Fraser & Syed Wasim, 2021. "Lentivirus-mediated gene therapy for Fabry disease," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
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    1. Jianli Tao & Daniel E. Bauer & Roberto Chiarle, 2023. "Assessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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