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Meta-Analysis
. 2022 Mar 14;13(1):1315.
doi: 10.1038/s41467-022-28762-2.

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

Francesca Tucci #  1   2 , Stefania Galimberti #  3 , Luigi Naldini  2   4 , Maria Grazia Valsecchi  3 , Alessandro Aiuti  5   6   7
Affiliations
Meta-Analysis

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

Francesca Tucci et al. Nat Commun. .

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.

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Conflict of interest statement

A.A. is PI of clinical trials sponsored by Orchard Therapeutics, which licensed gene therapy products for ADA-SCID, WAS, MLD, Beta-thalassemia, and MPS originally developed at SR-TIGET. A.A. is a member of Committee for Advanced Therapies (CAT) and his views are personal and may not be understood or quoted as being made on behalf of the European Medicines Agency (EMA). L.N. is an inventor on pending and issued patents on LV technology filed by the Salk Institute, Cell Genesys, Telethon Foundation, and/or San Raffaele Scientific Institute. The other authors have no competing interests.

Figures

Fig. 1
Fig. 1. PRISMA diagram detailing the search strategy.
PRISMA diagram detailing the search strategy of articles for inclusion in the meta-analysis.
Fig. 2
Fig. 2. Forest plot of the incidence rate of mortality by vector type, i.e., (A) γRV, (B) LV, (C) SIN-γRV, and overall.
The squares indicate the incidence rate of mortality and their size reflects the study sample size, while the horizontal lines represent 95% Confidence Intervals (CI). The diamond denotes the summary effect size from the random-effects model for all or subgroups of studies (from a meta-regression model), and the width of the diamond depicts the overall 95% CI. The indices of heterogeneity (I2 and τ2) refer to the overall analysis or to the single subgroups, and pLRT is the p value for the test of residual heterogeneity, while pQM refers to the test on vector type as moderator. All tests were two-tailed. Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Forest plot of the incidence rate of genotoxicity by vector type, i.e., (A) γRV, (B) LV, (C) SIN-γRV, and overall.
The squares indicate the incidence rate of genotoxicity and their size reflects the study sample size, while the horizontal lines represent 95% Confidence Intervals (CI). The diamond denotes the summary effect size from the random-effects model for all or subgroups of studies (from a meta-regression model), and the width of the diamond depicts the overall 95% CI. The indices of heterogeneity (I2 and τ2) refer to the overall analysis or to the single subgroups, and pLRT is the p-value for the test of residual heterogeneity, while pQM refers to the test on vector type as moderator. All tests were two-tailed. Source data are provided as a Source Data file.
Fig. 4
Fig. 4. Aalen-Johansen crude cumulative incidence rate of genotoxicity (A) overall and stratified by (B) vector type and (C) disease using γRV.
The result of the Gray test (two-tailed) is also reported. Source data are provided as a Source Data file.
Fig. 5
Fig. 5. Forest plot of the rate of engraftment by vector type, i.e., (A) γRV, (B) LV, (C) SIN-γRV, and overall.
The squares indicate the rate of engraftment and their size reflects the study sample size, while the horizontal lines represent 95% Confidence Intervals (CI). The diamond denotes the summary effect size from the random-effects model for all or subgroups of studies (from a meta-regression model), and the width of the diamond depicts the overall 95% CI. The indices of heterogeneity (I2 and τ2) refer to the overall analysis or to the single subgroups, and pLRT is the p value for the test of residual heterogeneity, while pQM refers to the test on vector type as moderator. All tests were two-tailed. Source data are provided as a Source Data file.
See this image and copyright information in PMC

References

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