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Clonal tracking in gene therapy patients reveals a diversity of human hematopoietic differentiation programs

Six, E; Guilloux, A; Denis, A; Lecoules, A; Magnani, A; Vilette, R; Male, F; ... Bushman, F; + view all (2020) Clonal tracking in gene therapy patients reveals a diversity of human hematopoietic differentiation programs. Blood 10.1182/blood.2019002350. (In press).

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Abstract

In gene therapy with human hematopoietic stem and progenitor cells (HSPCs), each gene-corrected cell and its progeny are marked in a unique way by the integrating vector. This feature enables lineages to be tracked by sampling blood cells and using DNA sequencing to identify the vector integration sites. Here, we studied five cell lineages (granulocytes, monocytes, T cells, B cells, and natural killer cells) in patients having undergone HSPC gene therapy for Wiskott-Aldrich syndrome or beta hemoglobinopathies. We found that the estimated minimum number of active, repopulating HSPCs (which ranged from 2,000 to 50,000) was correlated with the number of HSPCs per kg infused. We sought to quantify the lineage output and dynamics of gene-modified clones; this is usually challenging because of (i) sparse sampling of the various cell types during the analytical procedure, (ii) contamination during cell isolation, and (iii) different levels of vector marking in the various lineages. We therefore measured the residual contamination and corrected our statistical models accordingly, in order to provide a rigorous analysis of the HSPC lineage output. A cluster analysis of the HSPC lineage output highlighted the existence of several stable, distinct differentiation programs, including myeloid-dominant, lymphoid-dominant and balanced cell subsets. Our study evidenced the heterogeneous nature of the cell lineage output from HSPCs, and provided methods for analyzing these complex data.

Type: Article
Title: Clonal tracking in gene therapy patients reveals a diversity of human hematopoietic differentiation programs
Location: United States
DOI: 10.1182/blood.2019002350
Publisher version: https://doi.org/10.1182/blood.2019002350
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Gene therapy, cell separation, hemoglobinopathies, sequence analysis, dna, wiskott-aldrich syndrome
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10093495
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