Abstract
Haematopoietic stem and progenitor cell (HSPC) gene therapy has emerged as an effective treatment modality for monogenic disorders of the blood system such as primary immunodeficiencies and β-thalassaemia. Medicinal products based on autologous HSPCs corrected using lentiviral and gammaretroviral vectors have now been approved for clinical use, and the site-specific genome modification of HSPCs using gene editing techniques such as CRISPR–Cas9 has shown great clinical promise. Preclinical studies have shown engineered HSPCs could also be used to cross-correct non-haematopoietic cells in neurodegenerative metabolic diseases. Here, we review the most recent advances in HSPC gene therapy and discuss emerging strategies for using HSPC gene therapy for a range of diseases.
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Acknowledgements
The authors thank Fondazione Telethon and the European Commission (SCIDNET, E-Rare EUROCID) for support. A.A. is the recipient of the Else Kröner Fresenius Prize for Medical Research 2020. A.J.T. is supported by the Wellcome Trust and the UK National Institute for Health Research biomedical research centres at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. A.A. and A.T. are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (project ID no. 739543) and the Inborn Error Working Party of EBMT. The authors thank F. Tucci for her help with the preparation of Table 1 and M. E. Bernardo, F. Fumagalli, A. Gritti and S. Scala, for their critical review of the figures and manuscript.
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The San Raffaele Telethon Institute for Gene Therapy is a joint venture between Fondazione Telethon and Ospedale San Raffaele. Gene therapies for adenosine deaminase-deficient severe combined immunodeficiency, Wiskott–Aldrich syndrome, metachromatic leukodystrophy, β-thalassaemia and mucopolysaccharidosis type I developed at the San Raffaele Telethon Institute for Gene Therapy were licensed to Orchard Therapeutics in 2018 and 2019. A.A. is the principal investigator in the above-mentioned clinical trials. A.J.T has equity in and is on the scientific advisory board for Orchard Therapeutics and receives consultancy payments from Rocket Pharmaceuticals.
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Related links
New gene therapy to treat rare genetic disorder metachromatic leukodystrophy: https://www.ema.europa.eu/en/news/new-gene-therapy-treat-rare-genetic-disorder-metachromatic-leukodystrophy
Potential adverse reaction to gene therapy in a patient treated with Strimvelis for the treatment of ADA-SCID: https://www.telethon.it/en/stories-and-news/news/from-telethonfoundation/potential-adverse-event-after-gene-therapy-for-ada-scid
Glossary
- Allogeneic
-
Relating to or denoting that the source of cells, tissues or organs for transplant is from an individual genetically different from the recipient.
- Primary immunodeficiencies
-
(PIDs). Mendelian genetic disorders caused by defects in the development and/or function of immune cells. Currently, more than 300 genes have been identified that cause adaptive and/or innate immune cell defects.
- Chronic granulomatous disease
-
(CGD). A disease caused by dysfunction of the phagocyte NADPH oxidase, a membrane-bound enzyme complex required for effective killing of bacteria and fungi.
- Leukapheresis
-
A procedure that separates white blood cells, including haematopoietic stem cells, from the blood. White cells are collected from the donor and other blood fractions are returned to the circulation.
- Mobilizing agents
-
Drugs that induce transient mobilization of haematopoietic stem cells from the bone marrow to the circulation so that they can be collected by leukapheresis.
- Myeloablative conditioning
-
High-dose chemotherapy that destroys haematopoietic cells in the bone marrow and severely reduces the number of blood cells. Usually followed by haematopoietic stem and progenitor cell transplantation or gene therapy to rebuild the bone marrow.
- Oligoclonality
-
A quality associated with clones derived from one or a few cells or molecules.
- Iron chelation therapy
-
Pharmacological depletion of toxic iron accumulation in organs.
- Stress erythropoiesis
-
The rapid development of new red blood cells stimulated in response to acute anaemia.
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Ferrari, G., Thrasher, A.J. & Aiuti, A. Gene therapy using haematopoietic stem and progenitor cells. Nat Rev Genet 22, 216–234 (2021). https://doi.org/10.1038/s41576-020-00298-5
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DOI: https://doi.org/10.1038/s41576-020-00298-5
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