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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Sebastian Wagner & Christoph Baldow & Andrea Calabria & Laura Rudilosso & Pierangela Gallina & Eugenio Montini & Daniela Cesana & Ingmar Glauche, 2022. "Clonal reconstruction from co-occurrence of vector integration sites accurately quantifies expanding clones in vivo," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31292-6
    DOI: 10.1038/s41467-022-31292-6
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    References listed on IDEAS

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    2. Yao Xiao & Xueqing Wang & Hongjiu Zhang & Peter J. Ulintz & Hongyang Li & Yuanfang Guan, 2020. "FastClone is a probabilistic tool for deconvoluting tumor heterogeneity in bulk-sequencing samples," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    3. Marina Cavazzana-Calvo & Emmanuel Payen & Olivier Negre & Gary Wang & Kathleen Hehir & Floriane Fusil & Julian Down & Maria Denaro & Troy Brady & Karen Westerman & Resy Cavallesco & Beatrix Gillet-Leg, 2010. "Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia," Nature, Nature, vol. 467(7313), pages 318-322, September.
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