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Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges

Nature Reviews Drug Discovery (2019) | Download Citation


Pioneering gene therapy trials have shown that the genetic engineering of haematopoietic stem and progenitor cells can be an alternative to allogeneic transplantation in the treatment of primary immunodeficiencies. Early trials also highlighted the risk of insertional mutagenesis and oncogene transactivation associated with the first generation of gammaretroviral vectors. These events prompted the development of safer, self-inactivating lentiviral or gammaretroviral vectors. These lentiviral vectors have been successfully used to treat over 200 patients with 10 different haematological disorders (including primary immunodeficiencies, haemoglobinopathies and metabolic disorders) and for the generation of chimeric antigen receptor-T cells for cancer therapy. However, several challenges, such as effective reconstitution during inflammation, remain if gene therapy is to be extended to more complex diseases in which haematopoietic stem and progenitor cells can be altered by the disease environment. We discuss the progress made and future challenges for gene therapy and contrast gene therapy with gene-editing strategies.

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The authors thank the researchers whose works were not discussed owing to space limitations. M.C., I.A.-S. and E.S. are grateful to members of the human haematolymphopoiesis laboratory at the Imagine Institute and of the biotherapy department in Necker’s Hospital for their commitment allowing clinical development. A.M. thanks members of her laboratory at the Imagine Institute. F.D.B. thanks members of his laboratory at the University of Pennsylvania School of Medicine. M.C., I.A.-S. and E.S. are supported by grants from the European Research Council (ERC Regenerative Therapy 269037 and Gene for Cure 693762), the EU Seventh Framework Programme (Net4CGD 305011), the EU H2020 research and innovation programme (SCIDNET 666908), the Clinical Research Hospital Programme (PHRC) (Ministry of Health and Social Affairs), Assistance Publique-Hôpitaux de Paris, INSERM, the French National Research Agency under the Investments for the Future programme (ANR-01-A0-IAHU) and Bluebird Bio. A.M. is supported by grants from the Agence nationale de la recherche (ANR-16-CE18-0004 and ANR-10-IAHU-01 ‘Investissements d’avenir’ programme). F.D.B.’s laboratory is supported by grants from the US National Institutes of Health (NIH) (AI 052845–13, AI 082020-05A1, AI 045008–15, U19AI117950-01 and UMIAI126620) and the Penn Center for AIDS Research.

Author information


  1. Biotherapy Department, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

    • Marina Cavazzana
  2. Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France

    • Marina Cavazzana
  3. INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis, Paris, France

    • Marina Cavazzana
    • , Isabelle André-Schmutz
    •  & Emmanuelle Six
  4. Paris Descartes–Sorbonne Paris Cité University, Imagine Institute, Paris, France

    • Marina Cavazzana
    • , Annarita Miccio
    • , Isabelle André-Schmutz
    •  & Emmanuelle Six
  5. Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    • Frederic D. Bushman
  6. Laboratory of Chromatin and Gene Regulation During Development,, INSERM UMR1163, Imagine Institute, Paris, France

    • Annarita Miccio


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Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Marina Cavazzana.


Haematopoietic stem and progenitor cells

(HSPCs). A heterogeneous cell population that can be isolated using the surface marker CD34 and comprises both the most immature haematopoietic stem cells responsible for long-term engraftment and haematopoietic progenitors that have lost self-renewal capacity, are more restricted in term of lineage potential and are responsible for short-term engraftment.

Enzyme replacement therapy

(ERT). A medical treatment aiming to replace a missing protein. In the case of severe combined immunodeficiency caused by adenosine deaminase (ADA) deficiency, pegademase bovine ADA is used.

Patient conditioning

The treatments used to prepare a patient for haematopoietic stem and progenitor cell transplantation. The conditioning regimen may include chemotherapy, monoclonal antibody therapy and radiation. It helps make room in the patient’s bone marrow for new haematopoietic stem cells and to prevent rejection in case of allogeneic transplantation.

Haematopoietic stem cell

(HSC). A cell defined by the capacity to self-renew and the ability to ensure continuous production of all blood lineages for the entire life of an individual.


This bone marrow puncture is a medical test that consists of taking a bone marrow sample from the hip or the sternum. Once the extract has been smeared onto slides, the laboratory analyses the cellular composition of the sample.


A form of chronic lung disease defined as the abnormal irreversible dilatation of the bronchi in which the elastic and muscular tissues are destroyed by acute or chronic inflammation and infection.


Regional lymphadenitis, a severe disseminated disease, following bacillus Calmette–Guérin vaccination.

Ochs score

For Wiskott–Aldrich syndrome, the widely used clinical severity score developed by Ochs (ranging from 1 to 5). A score of 5 is associated with severe disease (autoimmunity, infections, inflammation and/or malignancy).

Vector copy number

(VCN). The average number of integrated therapeutic vector copies per cell in a given population. The VCN can be used to evaluate the transduction and/or correction level in this population.

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