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Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved by Sequential Administration of AAV5ch and AAV1.
Mol Ther 2017; 25(8):1831-1842MT

Abstract

In the gene therapy field, re-administration of adeno-associated virus (AAV) is an important topic because a decrease in therapeutic protein expression might occur over time. However, an efficient re-administration with the same AAV serotype is impossible due to serotype-specific, anti-AAV neutralizing antibodies (NABs) that are produced after initial AAV treatment. To address this issue, we explored the feasibility of using chimeric AAV serotype 5 (AAV5ch) and AAV1 for repeated liver-targeted gene delivery. To develop a relevant model, we immunized animals with a high dose of AAV5ch-human secreted embryonic alkaline phosphatase (hSEAP) that generates high levels of anti-AAV5ch NAB. Secondary liver transduction with the same dose of AAV1-human factor IX (hFIX) in the presence of high levels of anti-AAV5ch NAB proved to be successful because expression/activity of both reporter transgenes was observed. This is the first time that two different transgenes are shown to be produced by non-human primate (NHP) liver after sequential administration of clinically relevant doses of both AAV5ch and AAV1. The levels of transgene proteins achieved after delivery with AAV5ch and AAV1 illustrate the possibility of both serotypes for liver targeting. Furthermore, transgene DNA and RNA biodistribution patterns provided insight into the potential cause of decrease or loss of transgene protein expression over time in NHPs.

Authors+Show Affiliations

Research Department at uniQure biopharma B.V., 1105 BP Amsterdam, the Netherlands. Electronic address: a.majowicz@uniqure.com.Gene Therapy and Hepatology Department at CIMA, University of Navarra, Pamplona 31008, Spain.Gene Therapy and Hepatology Department at CIMA, University of Navarra, Pamplona 31008, Spain.Gene Therapy and Hepatology Department at CIMA, University of Navarra, Pamplona 31008, Spain.Gene Therapy and Hepatology Department at CIMA, University of Navarra, Pamplona 31008, Spain.Research Department at uniQure biopharma B.V., 1105 BP Amsterdam, the Netherlands.Research Department at uniQure biopharma B.V., 1105 BP Amsterdam, the Netherlands.

Pub Type(s)

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

Language

eng

PubMed ID

28596114

Citation

Majowicz, Anna, et al. "Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved By Sequential Administration of AAV5ch and AAV1." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 25, no. 8, 2017, pp. 1831-1842.
Majowicz A, Salas D, Zabaleta N, et al. Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved by Sequential Administration of AAV5ch and AAV1. Mol Ther. 2017;25(8):1831-1842.
Majowicz, A., Salas, D., Zabaleta, N., Rodríguez-Garcia, E., González-Aseguinolaza, G., Petry, H., & Ferreira, V. (2017). Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved by Sequential Administration of AAV5ch and AAV1. Molecular Therapy : the Journal of the American Society of Gene Therapy, 25(8), pp. 1831-1842. doi:10.1016/j.ymthe.2017.05.003.
Majowicz A, et al. Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved By Sequential Administration of AAV5ch and AAV1. Mol Ther. 2017 08 2;25(8):1831-1842. PubMed PMID: 28596114.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved by Sequential Administration of AAV5ch and AAV1. AU - Majowicz,Anna, AU - Salas,David, AU - Zabaleta,Nerea, AU - Rodríguez-Garcia,Estefania, AU - González-Aseguinolaza,Gloria, AU - Petry,Harald, AU - Ferreira,Valerie, Y1 - 2017/06/05/ PY - 2016/10/12/received PY - 2017/05/02/revised PY - 2017/05/02/accepted PY - 2017/6/10/pubmed PY - 2018/4/24/medline PY - 2017/6/10/entrez KW - AAV KW - gene therapy KW - re-administration of gene therapy SP - 1831 EP - 1842 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol. Ther. VL - 25 IS - 8 N2 - In the gene therapy field, re-administration of adeno-associated virus (AAV) is an important topic because a decrease in therapeutic protein expression might occur over time. However, an efficient re-administration with the same AAV serotype is impossible due to serotype-specific, anti-AAV neutralizing antibodies (NABs) that are produced after initial AAV treatment. To address this issue, we explored the feasibility of using chimeric AAV serotype 5 (AAV5ch) and AAV1 for repeated liver-targeted gene delivery. To develop a relevant model, we immunized animals with a high dose of AAV5ch-human secreted embryonic alkaline phosphatase (hSEAP) that generates high levels of anti-AAV5ch NAB. Secondary liver transduction with the same dose of AAV1-human factor IX (hFIX) in the presence of high levels of anti-AAV5ch NAB proved to be successful because expression/activity of both reporter transgenes was observed. This is the first time that two different transgenes are shown to be produced by non-human primate (NHP) liver after sequential administration of clinically relevant doses of both AAV5ch and AAV1. The levels of transgene proteins achieved after delivery with AAV5ch and AAV1 illustrate the possibility of both serotypes for liver targeting. Furthermore, transgene DNA and RNA biodistribution patterns provided insight into the potential cause of decrease or loss of transgene protein expression over time in NHPs. SN - 1525-0024 UR - https://www.unboundmedicine.com/medline/citation/28596114/Successful_Repeated_Hepatic_Gene_Delivery_in_Mice_and_Non_human_Primates_Achieved_by_Sequential_Administration_of_AAV5ch_and_AAV1_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(17)30221-6 DB - PRIME DP - Unbound Medicine ER -