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Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques.
Blood 2002; 100(5):1662-9Blood

Abstract

The feasibility, safety, and efficacy of liver-directed gene transfer was evaluated in 5 male macaques (aged 2.5 to 6.5 years) by using a recombinant adeno-associated viral (rAAV) vector (rAAV-2 CAGG-hFIX) that had previously mediated persistent therapeutic expression of human factor IX (hFIX; 6%-10% of physiologic levels) in murine models. A dose of 4 x 10(12) vector genomes (vgs)/kg of body weight was administered through the hepatic artery or portal vein. Persistence of the rAAV vgs as circular monomers and dimers and high-molecular-weight concatamers was documented in liver tissue by Southern blot analysis for periods of up to 1 year. Vector particles were present in plasma, urine, or saliva for several days after infusion (as shown by polymerase chain reaction analysis), and the vgs were detected in spleen tissue at low copy numbers. An enzyme-linked immunosorption assay capable of detecting between 1% and 25% of normal levels of hFIX in rhesus plasma was developed by using hyperimmune serum from a rhesus monkey that had received an adenoviral vector encoding hFIX. Two macaques having 3 and 40 rAAV genome equivalents/cell, respectively, in liver tissue had 4% and 8% of normal physiologic plasma levels of hFIX, respectively. A level of hFIX that was 3% of normal levels was transiently detected in one other macaque, which had a genome copy number of 25 before abrogation by a neutralizing antibody (inhibitor) to hFIX. This nonhuman-primate model will be useful in further evaluation and development of rAAV vectors for gene therapy of hemophilia B.

Authors+Show Affiliations

Department of Haematology, University College London, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12176886

Citation

Nathwani, Amit C., et al. "Sustained High-level Expression of Human Factor IX (hFIX) After Liver-targeted Delivery of Recombinant Adeno-associated Virus Encoding the hFIX Gene in Rhesus Macaques." Blood, vol. 100, no. 5, 2002, pp. 1662-9.
Nathwani AC, Davidoff AM, Hanawa H, et al. Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques. Blood. 2002;100(5):1662-9.
Nathwani, A. C., Davidoff, A. M., Hanawa, H., Hu, Y., Hoffer, F. A., Nikanorov, A., ... Nienhuis, A. W. (2002). Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques. Blood, 100(5), pp. 1662-9.
Nathwani AC, et al. Sustained High-level Expression of Human Factor IX (hFIX) After Liver-targeted Delivery of Recombinant Adeno-associated Virus Encoding the hFIX Gene in Rhesus Macaques. Blood. 2002 Sep 1;100(5):1662-9. PubMed PMID: 12176886.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques. AU - Nathwani,Amit C, AU - Davidoff,Andrew M, AU - Hanawa,Hideki, AU - Hu,Yunyu, AU - Hoffer,Fredric A, AU - Nikanorov,Alexander, AU - Slaughter,Clive, AU - Ng,Catherine Y C, AU - Zhou,Junfang, AU - Lozier,Jay N, AU - Mandrell,Timothy D, AU - Vanin,Elio F, AU - Nienhuis,Arthur W, PY - 2002/8/15/pubmed PY - 2002/9/14/medline PY - 2002/8/15/entrez SP - 1662 EP - 9 JF - Blood JO - Blood VL - 100 IS - 5 N2 - The feasibility, safety, and efficacy of liver-directed gene transfer was evaluated in 5 male macaques (aged 2.5 to 6.5 years) by using a recombinant adeno-associated viral (rAAV) vector (rAAV-2 CAGG-hFIX) that had previously mediated persistent therapeutic expression of human factor IX (hFIX; 6%-10% of physiologic levels) in murine models. A dose of 4 x 10(12) vector genomes (vgs)/kg of body weight was administered through the hepatic artery or portal vein. Persistence of the rAAV vgs as circular monomers and dimers and high-molecular-weight concatamers was documented in liver tissue by Southern blot analysis for periods of up to 1 year. Vector particles were present in plasma, urine, or saliva for several days after infusion (as shown by polymerase chain reaction analysis), and the vgs were detected in spleen tissue at low copy numbers. An enzyme-linked immunosorption assay capable of detecting between 1% and 25% of normal levels of hFIX in rhesus plasma was developed by using hyperimmune serum from a rhesus monkey that had received an adenoviral vector encoding hFIX. Two macaques having 3 and 40 rAAV genome equivalents/cell, respectively, in liver tissue had 4% and 8% of normal physiologic plasma levels of hFIX, respectively. A level of hFIX that was 3% of normal levels was transiently detected in one other macaque, which had a genome copy number of 25 before abrogation by a neutralizing antibody (inhibitor) to hFIX. This nonhuman-primate model will be useful in further evaluation and development of rAAV vectors for gene therapy of hemophilia B. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/12176886/Sustained_high_level_expression_of_human_factor_IX__hFIX__after_liver_targeted_delivery_of_recombinant_adeno_associated_virus_encoding_the_hFIX_gene_in_rhesus_macaques_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12176886 DB - PRIME DP - Unbound Medicine ER -