Clonal reconstruction from co-occurrence of vector integration sites accurately quantifies expanding clones in vivo

Sebastian Wagner, Christoph Baldow, Andrea Calabria, Laura Rudilosso, Pierangela Gallina, Eugenio Montini, Daniela Cesana and Ingmar Glauche ()
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Sebastian Wagner: Technische Universität Dresden
Christoph Baldow: Technische Universität Dresden
Andrea Calabria: IRCCS Ospedale San Raffaele
Laura Rudilosso: IRCCS Ospedale San Raffaele
Pierangela Gallina: IRCCS Ospedale San Raffaele
Eugenio Montini: IRCCS Ospedale San Raffaele
Daniela Cesana: IRCCS Ospedale San Raffaele
Ingmar Glauche: Technische Universität Dresden

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract High transduction rates of viral vectors in gene therapies (GT) and experimental hematopoiesis ensure a high frequency of gene delivery, although multiple integration events can occur in the same cell. Therefore, tracing of integration sites (IS) leads to mis-quantification of the true clonal spectrum and limits safety considerations in GT. Hence, we use correlations between repeated measurements of IS abundances to estimate their mutual similarity and identify clusters of co-occurring IS, for which we assume a clonal origin. We evaluate the performance, robustness and specificity of our methodology using clonal simulations. The reconstruction methods, implemented and provided as an R-package, are further applied to experimental clonal mixes and preclinical models of hematopoietic GT. Our results demonstrate that clonal reconstruction from IS data allows to overcome systematic biases in the clonal quantification as an essential prerequisite for the assessment of safety and long-term efficacy of GT involving integrative vectors.

Date: 2022
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DOI: 10.1038/s41467-022-31292-6

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