The limited gene transfer efficiency into HSPCs and the occurrence of adverse events due insertional mutagenesis in γRV trials accelerated the development of self-inactivating lentiviral vectors (LV) as a delivery platform enabling more effective and safe insertion of therapeutic genes into HSPCs. The first integrating vectors to be employed were derived from gamma-retroviruses (γRV). For metabolic disorders, myeloid cells are engineered to express supraphysiological levels of the defective enzyme, which allows functional reconstitution of scavenger activity within various tissues and cross-correction of resident non-hematopoietic cells, including in the central nervous system 2. In the case of PID and haemoglobinopathies, expression of the healthy gene reestablishes normal differentiation and/or function of mature cells such as immune cells or red blood cells. To date, HSPC-GT works primarily through two mechanisms of action. After reinfusion, gene corrected HSPCs undergo self-renewal and transfer an healthy copy of the gene to daughter blood cells. Integrating viral vectors stably transfer the therapeutic gene into the cromatin of the patients’ own HSPCs collected from the bone marrow or peripheral blood after mobilization. Other products are in advanced stage of development in the EU and US. Recently three ATMPs based on HSPC-GT have been approved for the EU market for the treatment of Adenosine Deaminase Severe Combined Immunodeficiency (ADA-SCID), beta thalassemia and metachromatic leukodystrophy (MLD), respectively 2. Autologous HSPC gene therapy (GT), which belongs to the group of medicinal products classified as advanced therapies medicinal product (ATMP) 1, is designed to overcome the main limitations related to allogeneic HSPC transplantation (HSCT), such as the availability of a compatible donor, the risk of graft versus host disease (GvHD) and need of post-HSCT immunosuppression, while providing comparable or sometime even superior therapeutic benefit. In the past two decades, gene transfer into hematopoietic stem/progenitor cells (HSPCs) has emerged as a promising treatment for several monogenic diseases, including primary immunodeficiencies (PID), metabolic disorders, haemoglobinopathies and bone marrow failures. Our analyses show stable reconstitution of haematopoiesis in most recipients with superior engraftment and safer profile in patients receiving LV-transduced HSPCs. 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. The pooled overall incidence rate of death is 0.9 per 100 person-years of observation (PYO) (95% CI = 0.37–2.17). 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%). We review systematically the literature on HSPC-GT to describe survival, genotoxicity and engraftment of gene corrected cells. Here we aim to provide a comprehensive assessment of the short and long term safety of HSPC-GT from trials using different vector platforms. 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.
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