AAV Integration Summary and Implications

AAV Integration Summary and Implications
Highlights From NHF's 16th Workshop on Novel Technologies and Gene Transfer for Hemophilia

AAV integration summary and implications

Frederic D. Bushman, PhD
Professor and Chair
Department of Microbiology
Co-Director Center for Research on Coronaviruses and Other Emerging Pathogens
Co-Director PennCHOP Microbiome Program
Perelman School of Medicine at the University of Pennsylvania

Key Data Points

Notable clonal expansion with integration sites near cancer-associated genes

Clonal expansions observed in 5 of 9 hemophilia A dogs infused with an AAV vector containing a factor VIII (FVIII) transgene. Clonal expansions are indicated by the nearest identified gene. Some of these expansions were found near genes associated with tumorigenesis (eg, the green bar in Linus was located near genes Deleted in Leukemia 2, DLEU2, and DLEU2-like DLEU2L).

Conclusions

  • Stable and sustained FVIII expressed for up to 10 years in a canine model of hemophilia A. An increase in FVIII activity observed was in 2 of 9 dogs.
  • Clonal expansion observed with integrated AAV DNA near cancer-associated genes. Mechanisms of potential insertional activation unknown.
  • No dogs had evidence of tumorigenesis or liver nodules despite the expanded clones
  • It is unclear why two dogs showed increase in FVIII levels, but simplest model may be expanding clone with intact FVIII gene, though this was not identified in the study
  • The great majority of AAV-encoded transgenes are inactivated by mutation, offering an opportunity for optimization

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Supported by educational grants from Bayer, BioMarin, CSL Behring, Freeline Therapeutics Limited, Pfizer Inc., Spark Therapeutics, and uniQure, Inc.

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