Title:
NON-RANDOMNESS IN THE CLUSTERING OR GENOMIC EVENTS DETECTS INSERTIONAL MUTAGENESIS IN CLINICAL GENE THERAPY
Document Type and Number:
WIPO Patent Application WO2008071682
Kind Code:
A8
Abstract:
Features such as mutations or structural characteristics can be non-randomly distributed within a genomic DNA. As an example, insertional mutagenesis is of great importance in cancer research, preclinical and clinical retroviral vector gene therapy. Even when detectable side effects of vector integration are absent,the presence of insertions at higher than expected frequency at particular loci, termed common integration sites (CIS), is indicative of a biological of the integration at that site, and indicates a selective advantage of the affected cell clones based on their integration site (IS). So far, only computational simulations could assess whether the distribution of IS or other DNA features was significantly different compared to random. These simulations require extensive computational resources and fixed parameters of CIS definition. Here, we show that statistical inferences on the distribution of IS are possible using mathematical formulae to calculate the expected frequency of insertions based on genome size, number of sampled integration sites and CIS window size. P-values can be calculated based on the Poisson-distribution. Thus, for each individual problem a flexible CIS definition can be applied to most effectively identify non-random IS distribution mathematically. We here show that application of these calculations on clinical trials detect subtle, but substantial biological effects of insertion sites on clonal selection of hematopoiesis in humans.
Inventors:
VON KALLE CHRISTOF (DE)
SCHMIDT MANFRED (DE)
SCHMIDT MANFRED (DE)
Application Number:
PCT/EP2007/063666
Publication Date:
December 24, 2008
Filing Date:
December 11, 2007
Export Citation:
Assignee:
DKFZ KREBSFORSCHUNGSZENTRUM (DE)
UNIV RUPRECHT KARLS HEIDELBERG (DE)
ABEL ULRICH (DE)
VON KALLE CHRISTOF (DE)
SCHMIDT MANFRED (DE)
UNIV RUPRECHT KARLS HEIDELBERG (DE)
ABEL ULRICH (DE)
VON KALLE CHRISTOF (DE)
SCHMIDT MANFRED (DE)
International Classes:
G16B40/30
Download PDF:
Previous Patent: ANTIMICROBIAL COMPOSITION FOR FINISHING TEXTILES
Next Patent: FLOW DISTRIBUTOR FOR AN EXHAUST GAS SYSTEM
Next Patent: FLOW DISTRIBUTOR FOR AN EXHAUST GAS SYSTEM