A largely random AAV integration profile after LPLD gene therapy

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 ther...

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Published inNature 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
LanguageEnglish
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
Online AccessGet full text
ISSN1078-8956
1546-170X
1546-170X
DOI10.1038/nm.3230

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Abstract 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 S447X 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.
AbstractList 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(S447X) 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.
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 super(S447X) 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.
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(S447X) 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.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(S447X) 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.
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 S447X 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.
Audience Academic
Author Petry, Harald
Beattie, Stuart G
Schmidt, Manfred
Salmon, Florence
Glimm, Hanno
Schmidt, Sabine
Fronza, Raffaele
Gaudet, Daniel
Wolf, Stephan
Nowrouzi, Ali
Kaeppel, Christine
van Logtenstein, Richard
von Kalle, Christof
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  organization: Genomics and Proteomics Core Facility, German Cancer Research Center
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  organization: National Center for Tumor Diseases and German Cancer Research Center
BackLink https://www.ncbi.nlm.nih.gov/pubmed/23770691$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright Springer Nature America, Inc. 2013
COPYRIGHT 2013 Nature Publishing Group
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Snippet 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...
The clinical application of adeno-associated virus vectors (AAVs) is limited because of concerns about AAV integration-mediated tumorigenicity. We performed...
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SubjectTerms 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
Title A largely random AAV integration profile after LPLD gene therapy
URI https://link.springer.com/article/10.1038/nm.3230
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