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In Utero Transfer of Adeno-Associated Viral Vectors Produces Long-Term Factor IX Levels in a Cynomolgus Macaque Model.
Mol Ther 2017; 25(8):1843-1853MT

Abstract

The safe correction of an inherited bleeding disorder in utero prior to the onset of organ damage is highly desirable. Here, we report long-term transgene expression over more than 6 years without toxicity following a single intrauterine gene transfer (IUGT) at 0.9G using recombinant adeno-associated vector (AAV)-human factor IX (hFIX) in the non-human primate model we have previously described. Four of six treated animals monitored for around 74 months expressed hFIX at therapeutic levels (3.9%-120.0%). Long-term expression was 6-fold higher in males and with AAV8 compared to AAV5, mediated almost completely at this stage by random genome-wide hepatic proviral integrations, with no evidence of hotspots. Post-natal AAV challenge without immunosuppression was evaluated in two animals exhibiting chronic low transgene expression. The brief neutralizing immune reaction elicited had no adverse effect and, although expression was not improved at the dose administered, no clinical toxicity was observed. This long-term surveillance thus confirms the safety of late-gestation AAV-hFIX transfer and demonstrates that postnatal re-administration can be performed without immunosuppression, although it requires dose optimization for the desired expression. Nevertheless, eventual vector genotoxicity and the possibility of germline transmission will require lifelong monitoring and further evaluation of the reproductive function of treated animals.

Authors+Show Affiliations

Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore. Electronic address: citramattar@nus.edu.sgp.Department of Translational Oncology, German Cancer Research Center and National Center for Tumor Diseases, 69120 Heidelberg, Germany.UCL Cancer Institute, University College London, London WC1E 6BT, United Kingdom.Reproductive Medicine, K.K. Women's and Children's Hospital, Singapore 229899, Singapore.Reproductive Medicine, K.K. Women's and Children's Hospital, Singapore 229899, Singapore.UCL Cancer Institute, University College London, London WC1E 6BT, United Kingdom.Department of Translational Oncology, German Cancer Research Center and National Center for Tumor Diseases, 69120 Heidelberg, Germany.Institute for Women's Health, University College London, London WC1E 6BT, United Kingdom; MRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa.Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.Department of Translational Oncology, German Cancer Research Center and National Center for Tumor Diseases, 69120 Heidelberg, Germany.UCL Cancer Institute, University College London, London WC1E 6BT, United Kingdom.Reproductive Medicine, K.K. Women's and Children's Hospital, Singapore 229899, Singapore; Duke-NUS Medical School, Singapore 169857, Singapore. Electronic address: jerrychan@nus.edu.sg.

Pub Type(s)

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

Language

eng

PubMed ID

28462816

Citation

Mattar, Citra N Z., et al. "In Utero Transfer of Adeno-Associated Viral Vectors Produces Long-Term Factor IX Levels in a Cynomolgus Macaque Model." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 25, no. 8, 2017, pp. 1843-1853.
Mattar CNZ, Gil-Farina I, Rosales C, et al. In Utero Transfer of Adeno-Associated Viral Vectors Produces Long-Term Factor IX Levels in a Cynomolgus Macaque Model. Mol Ther. 2017;25(8):1843-1853.
Mattar, C. N. Z., Gil-Farina, I., Rosales, C., Johana, N., Tan, Y. Y. W., McIntosh, J., ... Chan, J. K. Y. (2017). In Utero Transfer of Adeno-Associated Viral Vectors Produces Long-Term Factor IX Levels in a Cynomolgus Macaque Model. Molecular Therapy : the Journal of the American Society of Gene Therapy, 25(8), pp. 1843-1853. doi:10.1016/j.ymthe.2017.04.003.
Mattar CNZ, et al. In Utero Transfer of Adeno-Associated Viral Vectors Produces Long-Term Factor IX Levels in a Cynomolgus Macaque Model. Mol Ther. 2017 08 2;25(8):1843-1853. PubMed PMID: 28462816.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In Utero Transfer of Adeno-Associated Viral Vectors Produces Long-Term Factor IX Levels in a Cynomolgus Macaque Model. AU - Mattar,Citra N Z, AU - Gil-Farina,Irene, AU - Rosales,Cecilia, AU - Johana,Nuryanti, AU - Tan,Yvonne Yi Wan, AU - McIntosh,Jenny, AU - Kaeppel,Christine, AU - Waddington,Simon N, AU - Biswas,Arijit, AU - Choolani,Mahesh, AU - Schmidt,Manfred, AU - Nathwani,Amit C, AU - Chan,Jerry K Y, Y1 - 2017/04/24/ PY - 2017/03/18/received PY - 2017/04/03/revised PY - 2017/04/03/accepted PY - 2017/5/4/pubmed PY - 2018/4/24/medline PY - 2017/5/3/entrez KW - adeno-associated viral vector KW - immune tolerance KW - intrauterine gene transfer KW - long-term expression KW - non-human primate KW - non-responder KW - vector integration SP - 1843 EP - 1853 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol. Ther. VL - 25 IS - 8 N2 - The safe correction of an inherited bleeding disorder in utero prior to the onset of organ damage is highly desirable. Here, we report long-term transgene expression over more than 6 years without toxicity following a single intrauterine gene transfer (IUGT) at 0.9G using recombinant adeno-associated vector (AAV)-human factor IX (hFIX) in the non-human primate model we have previously described. Four of six treated animals monitored for around 74 months expressed hFIX at therapeutic levels (3.9%-120.0%). Long-term expression was 6-fold higher in males and with AAV8 compared to AAV5, mediated almost completely at this stage by random genome-wide hepatic proviral integrations, with no evidence of hotspots. Post-natal AAV challenge without immunosuppression was evaluated in two animals exhibiting chronic low transgene expression. The brief neutralizing immune reaction elicited had no adverse effect and, although expression was not improved at the dose administered, no clinical toxicity was observed. This long-term surveillance thus confirms the safety of late-gestation AAV-hFIX transfer and demonstrates that postnatal re-administration can be performed without immunosuppression, although it requires dose optimization for the desired expression. Nevertheless, eventual vector genotoxicity and the possibility of germline transmission will require lifelong monitoring and further evaluation of the reproductive function of treated animals. SN - 1525-0024 UR - https://www.unboundmedicine.com/medline/citation/28462816/In_Utero_Transfer_of_Adeno_Associated_Viral_Vectors_Produces_Long_Term_Factor_IX_Levels_in_a_Cynomolgus_Macaque_Model_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(17)30162-4 DB - PRIME DP - Unbound Medicine ER -