San Raffaele Telethon Institute for Gene Therapy

Vector Integration Core

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manager

Eugenio Montini

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Insertional mutagenesis is one of the major hurdles of gene therapy with integrating vectors.  Analysis of genomic vector integration sites (IS) present in cells from gene therapy patients and preclinical models in vivo allows the detection of cells that have acquired a selective advantage as a result of oncogene activation caused by nearby vector insertions. Indeed, since vector IS are stable genetic marks, distinctive for each independently transduced cell and its progeny, their characterization allows to track thousands of transduced cell clones over time, in different tissues or cell lineages, evaluate the clonal composition of the engrafted population, identify the genes targeted by vector integrations and quantify the relative abundance of clones harboring a specific IS in order to detect or exclude clonal expansions.  

Therefore, the analyses of IS is crucial to monitor the biological unfolding and ultimate safety of the administered gene therapies.

Activities

The Vector Integration Core has set up state of the art procedures, bioinformatics pipelines and rigorous statistical analyses to perform genome-wide profiling of vector integration sites and monitor the behavior of transduced cell clones in:

  • pre-clinical safety studies performed under research grade or Good Laboratory Practice;
  • clinical gene therapy pharmacovigilance studies;
  • basic scientific projects.

The Vector Integration Core has been fundamental to address the safety and the clonal dynamics of hematopoietic reconstitution in several preclinical models and clinical trials such as for Metachromatic Leukodystrophy and Wiskott-Aldrich and others carried out at SR-Tiget.