Lymphomagenesis in SCID-X1 Mice Following Lentivirus-mediated Phenotype Correction Independent of Insertional Mutagenesis and γc Overexpression
Identifieur interne : 006F29 ( Main/Exploration ); précédent : 006F28; suivant : 006F30Lymphomagenesis in SCID-X1 Mice Following Lentivirus-mediated Phenotype Correction Independent of Insertional Mutagenesis and γc Overexpression
Auteurs : Samantha L. Ginn [Australie] ; Sophia Hy Liao [Australie] ; Allison P. Dane [Australie] ; Min Hu [Australie] ; Jessica Hyman [Australie] ; John W. Finnie [Australie] ; Maolin Zheng [Australie] ; Marina Cavazzana-Calvo [France] ; Stephen I. Alexander [Australie] ; Adrian J. Thrasher [Royaume-Uni] ; Ian E. Alexander [Australie]Source :
- Molecular Therapy [ 1525-0016 ] ; 2010.
Abstract
The development of leukemia as a consequence of vector-mediated genotoxicity in gene therapy trials for X-linked severe combined immunodeficiency (SCID-X1) has prompted substantial research effort into the design and safety testing of integrating vectors. An important element of vector design is the selection and evaluation of promoter-enhancer elements with sufficient strength to drive reliable immune reconstitution, but minimal propensity for enhancer-mediated insertional mutagenesis. In this study, we set out to explore the effect of promoter-enhancer selection on the efficacy and safety of human immunodeficiency virus-1-derived lentiviral vectors in γc-deficient mice. We observed incomplete or absent T- and B-cell development in mice transplanted with progenitors expressing γc from the phosphoglycerate kinase (PGK) and Wiscott–Aldrich syndrome (WAS) promoters, respectively. In contrast, functional T- and B-cell compartments were restored in mice receiving an equivalent vector containing the elongation factor-1-α (EF1α) promoter; however, 4 of 14 mice reconstituted with this vector subsequently developed lymphoma. Extensive analyses failed to implicate insertional mutagenesis or γc overexpression as the underlying mechanism. These findings highlight the need for detailed mechanistic analysis of tumor readouts in preclinical animal models assessing vector safety, and suggest the existence of other ill-defined risk factors for oncogenesis, including replicative stress, in gene therapy protocols targeting the hematopoietic compartment.
Url:
DOI: 10.1038/mt.2010.50
PubMed: 20354504
PubMed Central: 2890120
Affiliations:
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Ginn</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Liao, Sophia Hy" sort="Liao, Sophia Hy" uniqKey="Liao S" first="Sophia Hy" last="Liao">Sophia Hy Liao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Dane, Allison P" sort="Dane, Allison P" uniqKey="Dane A" first="Allison P" last="Dane">Allison P. 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Ginn</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Liao, Sophia Hy" sort="Liao, Sophia Hy" uniqKey="Liao S" first="Sophia Hy" last="Liao">Sophia Hy Liao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Dane, Allison P" sort="Dane, Allison P" uniqKey="Dane A" first="Allison P" last="Dane">Allison P. Dane</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hu, Min" sort="Hu, Min" uniqKey="Hu M" first="Min" last="Hu">Min Hu</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Kidney Research of The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hyman, Jessica" sort="Hyman, Jessica" uniqKey="Hyman J" first="Jessica" last="Hyman">Jessica Hyman</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Oncology Research Unit of The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Finnie, John W" sort="Finnie, John W" uniqKey="Finnie J" first="John W" last="Finnie">John W. Finnie</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Institute of Medical and Veterinary Science</institution> Adelaide, South Australia,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zheng, Maolin" sort="Zheng, Maolin" uniqKey="Zheng M" first="Maolin" last="Zheng">Maolin Zheng</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Cavazzana Calvo, Marina" sort="Cavazzana Calvo, Marina" uniqKey="Cavazzana Calvo M" first="Marina" last="Cavazzana-Calvo">Marina Cavazzana-Calvo</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Paediatric Immunology and Haematology Unit, Hôpital Necker-Enfants Malades</institution> Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Alexander, Stephen I" sort="Alexander, Stephen I" uniqKey="Alexander S" first="Stephen I" last="Alexander">Stephen I. Alexander</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Kidney Research of The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Thrasher, Adrian J" sort="Thrasher, Adrian J" uniqKey="Thrasher A" first="Adrian J" last="Thrasher">Adrian J. Thrasher</name><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>Institute of Child Health, Great Ormond Street Hospital</institution> London,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Alexander, Ian E" sort="Alexander, Ian E" uniqKey="Alexander I" first="Ian E" last="Alexander">Ian E. Alexander</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Gene Therapy Research Unit of the Children's Medical Research Institute and The Children's Hospital at Westmead</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Discipline of Paediatrics and Child Health, The University of Sydney</institution> Westmead, New South Wales,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Molecular Therapy</title><idno type="ISSN">1525-0016</idno><idno type="eISSN">1525-0024</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The development of leukemia as a consequence of vector-mediated genotoxicity in gene therapy trials for X-linked severe combined immunodeficiency (SCID-X1) has prompted substantial research effort into the design and safety testing of integrating vectors. An important element of vector design is the selection and evaluation of promoter-enhancer elements with sufficient strength to drive reliable immune reconstitution, but minimal propensity for enhancer-mediated insertional mutagenesis. In this study, we set out to explore the effect of promoter-enhancer selection on the efficacy and safety of human immunodeficiency virus-1-derived lentiviral vectors in γc-deficient mice. We observed incomplete or absent T- and B-cell development in mice transplanted with progenitors expressing γc from the phosphoglycerate kinase (PGK) and Wiscott–Aldrich syndrome (WAS) promoters, respectively. In contrast, functional T- and B-cell compartments were restored in mice receiving an equivalent vector containing the elongation factor-1-α (EF1α) promoter; however, 4 of 14 mice reconstituted with this vector subsequently developed lymphoma. Extensive analyses failed to implicate insertional mutagenesis or γc overexpression as the underlying mechanism. These findings highlight the need for detailed mechanistic analysis of tumor readouts in preclinical animal models assessing vector safety, and suggest the existence of other ill-defined risk factors for oncogenesis, including replicative stress, in gene therapy protocols targeting the hematopoietic compartment.</p></div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Royaume-Uni</li></country></list><tree><country name="Australie"><noRegion><name sortKey="Ginn, Samantha L" sort="Ginn, Samantha L" uniqKey="Ginn S" first="Samantha L" last="Ginn">Samantha L. Ginn</name></noRegion><name sortKey="Alexander, Ian E" sort="Alexander, Ian E" uniqKey="Alexander I" first="Ian E" last="Alexander">Ian E. Alexander</name><name sortKey="Alexander, Ian E" sort="Alexander, Ian E" uniqKey="Alexander I" first="Ian E" last="Alexander">Ian E. Alexander</name><name sortKey="Alexander, Stephen I" sort="Alexander, Stephen I" uniqKey="Alexander S" first="Stephen I" last="Alexander">Stephen I. Alexander</name><name sortKey="Dane, Allison P" sort="Dane, Allison P" uniqKey="Dane A" first="Allison P" last="Dane">Allison P. Dane</name><name sortKey="Finnie, John W" sort="Finnie, John W" uniqKey="Finnie J" first="John W" last="Finnie">John W. Finnie</name><name sortKey="Hu, Min" sort="Hu, Min" uniqKey="Hu M" first="Min" last="Hu">Min Hu</name><name sortKey="Hyman, Jessica" sort="Hyman, Jessica" uniqKey="Hyman J" first="Jessica" last="Hyman">Jessica Hyman</name><name sortKey="Liao, Sophia Hy" sort="Liao, Sophia Hy" uniqKey="Liao S" first="Sophia Hy" last="Liao">Sophia Hy Liao</name><name sortKey="Zheng, Maolin" sort="Zheng, Maolin" uniqKey="Zheng M" first="Maolin" last="Zheng">Maolin Zheng</name></country><country name="France"><noRegion><name sortKey="Cavazzana Calvo, Marina" sort="Cavazzana Calvo, Marina" uniqKey="Cavazzana Calvo M" first="Marina" last="Cavazzana-Calvo">Marina Cavazzana-Calvo</name></noRegion></country><country name="Royaume-Uni"><noRegion><name sortKey="Thrasher, Adrian J" sort="Thrasher, Adrian J" uniqKey="Thrasher A" first="Adrian J" last="Thrasher">Adrian J. Thrasher</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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