Performance of AAV8 vectors expressing human factor IX from a hepatic-selective promoter following intravenous injection
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BioMed Central
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Performance of AAV8 vectors expressing human factor IX from a hepatic-selective promoter following intravenous injection into rats Tracey Graham, Jenny McIntosh2, Lorraine M Work1, Amit Nathwani2 and Andrew H Baker*1 Address: 1British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, UK and 2Department of Haematology, University College London, London, UK Email: Tracey Graham - [email protected]; Jenny McIntosh - [email protected]; Lorraine M Work - [email protected]; Amit Nathwani - [email protected]; Andrew H Baker* - [email protected] * Corresponding author
Published: 3 March 2008 Genetic Vaccines and Therapy 2008, 6:9
doi:10.1186/1479-0556-6-9
Received: 28 January 2008 Accepted: 3 March 2008
This article is available from: http://www.gvt-journal.com/content/6/1/9 © 2008 Graham et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: Vectors based on adeno-associated virus-8 (AAV8) have shown efficiency and efficacy for liver-directed gene therapy protocols following intravascular injection, particularly in relation to haemophilia gene therapy. AAV8 has also been proposed for gene therapy targeted at skeletal and cardiac muscle, again via intravascular injection. It is important to assess vector targeting at the level of virion accumulation and transgene expression in multiple species to ascertain potential issues relating to species variation in infectivity profiles. Methods: We used AAV8 vectors expressing human factor IX (FIX) from the liver-specific LP-1 promoter and administered this virus via the intravascular route of injection into 12 week old Wistar Kyoto rats. We assessed FIX levels in serum by ELISA and transgene expression at sacrifice by immunohistochemistry using anti-FIX antibodies. Vector DNA levels in organs we determined by real time PCR. Results: Administration of 1 × 1011 or 5 × 1011 scAAV8-LP1-hFIX vector particles/rat resulted in efficient production of physiological hFIX levels, respectively in blood assessed 4 weeks postinjection. This was maintained for the 4 month duration of the study. At 4 months we observed liver persistence of vector with minimal non-hepatic distribution. Conclusion: Our results demonstrate that AAV8 is a robust vector for delivering therapeutic genes into rat liver following intravascular injection.
Background Adeno-associated viruses (AAV) are attractive vectors for in vivo gene therapy due to their safety profile and ability to achieve long term production of therapeutic genes following cell infection. Intravascular delivery provides a minimally invasive yet versatile approach to gene therapy for applications to correct liver deficiencies or utilise this
organ for production of th
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