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

Ex-vivo gene therapy with hematopoietic stem and progenitor cells (HSPCs) is a promising treatment for monogenic diseases. Here the authors report a systematic review and meta-analysis of available evidence assessing clinical outcomes of HSPC gene therapy from clinical trials. 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 (gamma RV) (29.1%), self-inactivating gamma RV (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 gamma RV 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 gamma RV 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.

Automated summary

Ex-vivo gene therapy with hematopoietic stem and progenitor cells (HSPCs) is a promising treatment for monogenic diseases. This systematic review and meta-analysis provide comprehensive assessment on the safety and efficacy of HSPC gene therapy using different vector platforms. The analysis shows stable reconstitution of hematopoiesis in most recipients, with superior engraftment and safer profile in patients receiving lentiviral vectors.