Transgene Expression Up to 7 Years in Nonhuman Primates Following Hepatic Transduction with Helper-dependent Adenoviral Vectors

Overview

Journal Hum Gene Ther

Specialties Genetics
Pharmacology

Date 2013 Aug 2

PMID 23902403

Citations 44

Authors

Nicola Brunetti-Pierri

Thomas Ng

David Iannitti

William Cioffi

Gary Stapleton

Mark Law

John Breinholt

Donna Palmer

Nathan Grove

Karen Rice

Cassondra Bauer

Milton Finegold

Arthur Beaudet

Charles Mullins

Philip Ng

Affiliations

Soon will be listed here.

Abstract

Helper-dependent adenoviral vectors (HDAd) have been shown to mediate a considerably longer duration of transgene expression than first-generation adenoviral vectors. We have previously shown that transgene expression from HDAd-transduced hepatocytes can persist at high levels for up to 2.6 years in nonhuman primates following a single-vector administration. Because duration of transgene expression and long-term toxicity are critical for risk:benefit assessment, we have continued to monitor these animals. We report here that transgene expression has persisted for the entire observation period of up to 7 years for all animals without long-term adverse effects. However, in all cases, transgene expression level slowly declined over time to less than 10% of peak values by the end of the observation period but remained 2.3-111-fold above baseline values. These results will provide important information for a more informed risk:benefit assessment before clinical application of HDAd.

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References

Brunetti-Pierri N, Liou A, Patel P, Palmer D, Grove N, Finegold M . Balloon catheter delivery of helper-dependent adenoviral vector results in sustained, therapeutic hFIX expression in rhesus macaques. Mol Ther. 2012; 20(10):1863-70. PMC: 3464633. DOI: 10.1038/mt.2012.143. View

Palmer D, Ng P . Improved system for helper-dependent adenoviral vector production. Mol Ther. 2003; 8(5):846-52. DOI: 10.1016/j.ymthe.2003.08.014. View

Kim I, Jozkowicz A, Piedra P, Oka K, Chan L . Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci U S A. 2001; 98(23):13282-7. PMC: 60862. DOI: 10.1073/pnas.241506298. View

Brunetti-Pierri N, Stapleton G, Law M, Breinholt J, Palmer D, Zuo Y . Efficient, long-term hepatic gene transfer using clinically relevant HDAd doses by balloon occlusion catheter delivery in nonhuman primates. Mol Ther. 2008; 17(2):327-33. PMC: 2835071. DOI: 10.1038/mt.2008.257. View

Martin L, Mahaney M, Bronikowski A, Carey K, Dyke B, Comuzzie A . Lifespan in captive baboons is heritable. Mech Ageing Dev. 2002; 123(11):1461-7. DOI: 10.1016/s0047-6374(02)00083-0. View

McCormack W, Seiler M, Bertin T, Ubhayakar K, Palmer D, Ng P . Helper-dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia A model. J Thromb Haemost. 2006; 4(6):1218-1225. PMC: 3947717. DOI: 10.1111/j.1538-7836.2006.01901.x. View

Croyle M, Chirmule N, Zhang Y, Wilson J . "Stealth" adenoviruses blunt cell-mediated and humoral immune responses against the virus and allow for significant gene expression upon readministration in the lung. J Virol. 2001; 75(10):4792-801. PMC: 114234. DOI: 10.1128/JVI.75.10.4792-4801.2001. View

Hodges B, Taylor K, Chu Q, Scull S, Serriello R, Anderson S . Local delivery of a viral vector mitigates neutralization by antiviral antibodies and results in efficient transduction of rabbit liver. Mol Ther. 2005; 12(6):1043-51. DOI: 10.1016/j.ymthe.2005.06.475. View

Brunetti-Pierri N, Nichols T, McCorquodale S, Merricks E, Palmer D, Beaudet A . Sustained phenotypic correction of canine hemophilia B after systemic administration of helper-dependent adenoviral vector. Hum Gene Ther. 2005; 16(7):811-20. DOI: 10.1089/hum.2005.16.811. View

10.

Brunetti-Pierri N, Palmer D, Mane V, Finegold M, Beaudet A, Ng P . Increased hepatic transduction with reduced systemic dissemination and proinflammatory cytokines following hydrodynamic injection of helper-dependent adenoviral vectors. Mol Ther. 2005; 12(1):99-106. DOI: 10.1016/j.ymthe.2005.03.001. View

11.

Brunetti-Pierri N, Stapleton G, Palmer D, Zuo Y, Mane V, Finegold M . Pseudo-hydrodynamic delivery of helper-dependent adenoviral vectors into non-human primates for liver-directed gene therapy. Mol Ther. 2007; 15(4):732-40. DOI: 10.1038/sj.mt.6300102. View

12.

Brunetti-Pierri N, Ng T, Iannitti D, Palmer D, Beaudet A, Finegold M . Improved hepatic transduction, reduced systemic vector dissemination, and long-term transgene expression by delivering helper-dependent adenoviral vectors into the surgically isolated liver of nonhuman primates. Hum Gene Ther. 2006; 17(4):391-404. DOI: 10.1089/hum.2006.17.391. View

13.

Toietta G, Mane V, Norona W, Finegold M, Ng P, McDonagh A . Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci U S A. 2005; 102(11):3930-5. PMC: 554836. DOI: 10.1073/pnas.0500930102. View

14.

Palmer D, Ng P . Physical and infectious titers of helper-dependent adenoviral vectors: a method of direct comparison to the adenovirus reference material. Mol Ther. 2004; 10(4):792-8. DOI: 10.1016/j.ymthe.2004.06.1013. View