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

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

SUBMITTER: Wagner S 

PROVIDER: S-EPMC9240075 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature