Coherence analysis discriminates between retroviral integration patterns in CD34+ cells transduced under differing clinical trial conditions

Claus V. Hallwirth, Gagan Garg, Timothy J. Peters, Belinda A. Kramer, Nirav V. Malani, Jessica Hyman, Xiaoan Ruan, Samantha L. Ginn, Nicola A. Hetherington, Lavanya Veeravalli, Atif Shahab, Shoba Ranganathan, Chia Lin Wei, Christopher Liddle, Adrian J. Thrasher, Frederic D. Bushman, Michael J. Buckley, Ian E. Alexander*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Unequivocal demonstration of the therapeutic utility of γ-retroviral vectors for gene therapy applications targeting the hematopoietic system was accompanied by instances of insertional mutagenesis. These events stimulated the ongoing development of putatively safer integrating vector systems and analysis methods to characterize and compare integration site (IS) biosafety profiles. Continuing advances in next-generation sequencing technologies are driving the generation of ever-more complex IS datasets. Available bioinformatic tools to compare such datasets focus on the association of integration sites (ISs) with selected genomic and epigenetic features, and the choice of these features determines the ability to discriminate between datasets. We describe the scalable application of point-process coherence analysis (CA) to compare patterns produced by vector ISs across genomic intervals, uncoupled from association with genomic features. To explore the utility of CA in the context of an unresolved question, we asked whether the differing transduction conditions used in the initial Paris and London SCID-X1 gene therapy trials result in divergent genome-wide integration profiles. We tested a transduction carried out under each condition, and showed that CA could indeed resolve differences in IS distributions. Existence of these differences was confirmed by the application of established methods to compare integration datasets.

Original languageEnglish
Article number15015
Pages (from-to)1-10
Number of pages10
JournalMolecular Therapy - Methods and Clinical Development
Publication statusPublished - 29 Apr 2015

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