Recombinant Adeno-Associated Virus-Mediated In Utero Gene Transfer Gives Therapeutic Transgene Expression in the Sheep
Somatic in utero gene therapy aims to treat congenital diseases where pathology develops in perinatal life, thereby preventing permanent damage. The aim of this study was to determine whether delivery of self-complementary (sc) adeno-associated virus (AAV) vector in utero would provide therapeutic l...
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2011
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| Online Access: | http://hdl.handle.net/10725/3970 http://dx.doi.org/10.1089/hum.2010.007. http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://online.liebertpub.com/doi/abs/10.1089/hum.2010.007 |
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| _version_ | 1864513462547251200 |
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| author | Abi Nader, Khalil |
| author2 | David, Anna L. McIntosh, Jenny Peebles, Donald Cook, Terry Waddington, Simon Weisz, Boaz |
| author2_role | author author author author author author |
| author_facet | Abi Nader, Khalil David, Anna L. McIntosh, Jenny Peebles, Donald Cook, Terry Waddington, Simon Weisz, Boaz |
| author_role | author |
| dc.creator.none.fl_str_mv | Abi Nader, Khalil David, Anna L. McIntosh, Jenny Peebles, Donald Cook, Terry Waddington, Simon Weisz, Boaz |
| dc.date.none.fl_str_mv | 2011 2016-06-07T11:00:45Z 2016-06-07T11:00:45Z 2016-06-07 |
| dc.identifier.none.fl_str_mv | 1043-0342 http://hdl.handle.net/10725/3970 http://dx.doi.org/10.1089/hum.2010.007. David, A. L., McIntosh, J., Peebles, D. M., Cook, T., Waddington, S., Weisz, B., ... & Nathwani, A. C. (2010). Recombinant adeno-associated virus-mediated in utero gene transfer gives therapeutic transgene expression in the sheep. Human gene therapy, 22(4), 419-426. http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://online.liebertpub.com/doi/abs/10.1089/hum.2010.007 |
| dc.language.none.fl_str_mv | en |
| dc.relation.none.fl_str_mv | Human Gene Therapy |
| dc.rights.*.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.title.none.fl_str_mv | Recombinant Adeno-Associated Virus-Mediated In Utero Gene Transfer Gives Therapeutic Transgene Expression in the Sheep |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | Somatic in utero gene therapy aims to treat congenital diseases where pathology develops in perinatal life, thereby preventing permanent damage. The aim of this study was to determine whether delivery of self-complementary (sc) adeno-associated virus (AAV) vector in utero would provide therapeutic long-term transgene expression in a large animal model. We performed ultrasound-guided intraperitoneal injection of scAAV2/8-LP1-human Factor IX (hFIX)co (1 × 1012 vector genomes/kg) in early (n = 4) or late (n = 2) gestation fetal sheep. The highest mean hFIX levels were detected 3 weeks after injection in late gestation (2,055 and 1,687.5 ng/ml, n = 2) and 3 days after injection in early gestation (435 ng/ml, n = 1). Plasma hFIX levels then dropped as fetal liver and lamb weights increased, although low levels were detected 6 months after late gestation injection (75 and 52.5 ng/ml, n = 2). The highest vector levels were detected in the fetal liver and other peritoneal organs; no vector was present in fetal gonads. hFIX mRNA was detectable only in hepatic tissues after early and late gestation injection. Liver function tests and bile acid levels were normal up to a year postnatal; there was no evidence of liver pathology. No functional antibodies to hFIX protein or AAV vector were detectable, although lambs mounted an antibody response after injection of hFIX protein and Freund's adjuvant. In conclusion, hFIX expression is detectable up to 6 months after delivery of scAAV vector to the fetal sheep using a clinically applicable method. This is the first study to show therapeutic long-term hFIX transgene expression after in utero gene transfer in a large animal model. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | LAURepo_5a0ff64c697157ba57f4f03eda1d70db |
| identifier_str_mv | 1043-0342 David, A. L., McIntosh, J., Peebles, D. M., Cook, T., Waddington, S., Weisz, B., ... & Nathwani, A. C. (2010). Recombinant adeno-associated virus-mediated in utero gene transfer gives therapeutic transgene expression in the sheep. Human gene therapy, 22(4), 419-426. |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/3970 |
| publishDate | 2011 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | Recombinant Adeno-Associated Virus-Mediated In Utero Gene Transfer Gives Therapeutic Transgene Expression in the SheepAbi Nader, KhalilDavid, Anna L.McIntosh, JennyPeebles, DonaldCook, TerryWaddington, SimonWeisz, BoazSomatic in utero gene therapy aims to treat congenital diseases where pathology develops in perinatal life, thereby preventing permanent damage. The aim of this study was to determine whether delivery of self-complementary (sc) adeno-associated virus (AAV) vector in utero would provide therapeutic long-term transgene expression in a large animal model. We performed ultrasound-guided intraperitoneal injection of scAAV2/8-LP1-human Factor IX (hFIX)co (1 × 1012 vector genomes/kg) in early (n = 4) or late (n = 2) gestation fetal sheep. The highest mean hFIX levels were detected 3 weeks after injection in late gestation (2,055 and 1,687.5 ng/ml, n = 2) and 3 days after injection in early gestation (435 ng/ml, n = 1). Plasma hFIX levels then dropped as fetal liver and lamb weights increased, although low levels were detected 6 months after late gestation injection (75 and 52.5 ng/ml, n = 2). The highest vector levels were detected in the fetal liver and other peritoneal organs; no vector was present in fetal gonads. hFIX mRNA was detectable only in hepatic tissues after early and late gestation injection. Liver function tests and bile acid levels were normal up to a year postnatal; there was no evidence of liver pathology. No functional antibodies to hFIX protein or AAV vector were detectable, although lambs mounted an antibody response after injection of hFIX protein and Freund's adjuvant. In conclusion, hFIX expression is detectable up to 6 months after delivery of scAAV vector to the fetal sheep using a clinically applicable method. This is the first study to show therapeutic long-term hFIX transgene expression after in utero gene transfer in a large animal model.PublishedN/A2016-06-07T11:00:45Z2016-06-07T11:00:45Z20112016-06-07Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1043-0342http://hdl.handle.net/10725/3970http://dx.doi.org/10.1089/hum.2010.007.David, A. L., McIntosh, J., Peebles, D. M., Cook, T., Waddington, S., Weisz, B., ... & Nathwani, A. C. (2010). Recombinant adeno-associated virus-mediated in utero gene transfer gives therapeutic transgene expression in the sheep. Human gene therapy, 22(4), 419-426.http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.phphttp://online.liebertpub.com/doi/abs/10.1089/hum.2010.007enHuman Gene Therapyinfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/39702021-03-19T10:03:20Z |
| spellingShingle | Recombinant Adeno-Associated Virus-Mediated In Utero Gene Transfer Gives Therapeutic Transgene Expression in the Sheep Abi Nader, Khalil |
| status_str | publishedVersion |
| title | Recombinant Adeno-Associated Virus-Mediated In Utero Gene Transfer Gives Therapeutic Transgene Expression in the Sheep |
| title_full | Recombinant Adeno-Associated Virus-Mediated In Utero Gene Transfer Gives Therapeutic Transgene Expression in the Sheep |
| title_fullStr | Recombinant Adeno-Associated Virus-Mediated In Utero Gene Transfer Gives Therapeutic Transgene Expression in the Sheep |
| title_full_unstemmed | Recombinant Adeno-Associated Virus-Mediated In Utero Gene Transfer Gives Therapeutic Transgene Expression in the Sheep |
| title_short | Recombinant Adeno-Associated Virus-Mediated In Utero Gene Transfer Gives Therapeutic Transgene Expression in the Sheep |
| title_sort | Recombinant Adeno-Associated Virus-Mediated In Utero Gene Transfer Gives Therapeutic Transgene Expression in the Sheep |
| url | http://hdl.handle.net/10725/3970 http://dx.doi.org/10.1089/hum.2010.007. http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://online.liebertpub.com/doi/abs/10.1089/hum.2010.007 |