A largely random AAV integration profile after LPLD gene therapy

• Published in: Nature medicine Vol. 19; no. 7; pp. 889 - 891
• Main Authors: Kaeppel, Christine, Beattie, Stuart G, Fronza, Raffaele, van Logtenstein, Richard, Salmon, Florence, Schmidt, Sabine, Wolf, Stephan, Nowrouzi, Ali, Glimm, Hanno, von Kalle, Christof, Petry, Harald, Gaudet, Daniel, Schmidt, Manfred
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-07-2013; Nature Publishing Group
• Subjects: 692/308/575; Adeno-associated virus; Adenoviruses; Analysis; Animals; Binding Sites - genetics; Biomedicine; Biotechnology industry; brief-communication; Cancer Research; Clinical trials; Dependovirus - genetics; Dependovirus - physiology; Dependoviruses; Gene therapy; Genetic aspects; Genetic Therapy - adverse effects; Genetic vectors; Genetic Vectors - administration & dosage; Genetic Vectors - adverse effects; Genetic Vectors - genetics; Genetic Vectors - physiology; Health aspects; Humans; Hyperlipoproteinemia Type I - genetics; Infectious Diseases; Injection; Injections, Intramuscular; Lipoprotein lipase; Lipoprotein Lipase - administration & dosage; Lipoprotein Lipase - deficiency; Lipoprotein Lipase - genetics; Metabolic Diseases; Mice; Mice, Inbred C57BL; Models, Biological; Molecular Medicine; Mutagenesis, Insertional - genetics; Mutagenesis, Insertional - physiology; Neurosciences; Physiological aspects; Transcriptome; Virus Integration - genetics; Virus Integration - physiology; Canada
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3230

An adeno-associated virus (AAV) vector encoding a variant of human lipoprotein lipase was recently approved in Europe as the first gene therapy for the treatment of LPL deficiency. Here Manfred Schmidt and his colleagues report their analysis of AAV integration sites after injection of the gene therapy construct in LPL-deficient patients and in mice.
The clinical application of adeno-associated virus vectors (AAVs) is limited because of concerns about AAV integration–mediated tumorigenicity. We performed integration-site analysis after AAV1-LPL
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intramuscular injection in five lipoprotein lipase–deficient subjects, revealing random nuclear integration and hotspots in mitochondria. We conclude that AAV integration is potentially safe and that vector breakage and integration may occur from each position of the vector genome. Future viral integration-site analyses should include the mitochondrial genome.