Loading...
Therapeutic expression of human clotting factors IX and X following adeno-associated viral vector-mediated intrauterine gene transfer in early-gestation fetal macaques
Chan, Jerry K Y Gil-Farina, Irene Johana, Nuryanti Rosales, Cecilia Tan, Yi Wan Ceiler, Jessika Mcintosh, Jenny Ogden, Bryan Waddington, Simon N Schmidt, Manfred
Chan, Jerry K Y
Gil-Farina, Irene
Johana, Nuryanti
Rosales, Cecilia
Tan, Yi Wan
Ceiler, Jessika
Mcintosh, Jenny
Ogden, Bryan
Waddington, Simon N
Schmidt, Manfred
Citations
Altmetric:
Abstract
Adeno-associated viral vectors (AAVs) achieve stable therapeutic expression without long-term toxicity in adults with hemophilia. To avert irreversible complications in congenital disorders producing early pathogenesis, safety and efficacy of AAV-intrauterine gene transfer (IUGT) requires assessment. We therefore performed IUGT of AAV5 or -8 with liver-specific promoter-1 encoding either human coagulation factors IX (hFIX) or X (hFX) into Macaca fascicularis fetuses at ∼0.4 gestation. The initial cohort received 1 × 10 vector genomes (vgs) of AAV5-hFIX ( n = 5; 0.45 × 10 vg/kg birth weight), resulting in ∼3.0% hFIX at birth and 0.6-6.8% over 19-51 mo. The next cohort received 0.2-1 × 10 vg boluses. AAV5-hFX animals ( n = 3; 3.57 × 10 vg/kg) expressed <1% at birth and 9.4-27.9% up to 42 mo. AAV8-hFIX recipients ( n = 3; 2.56 × 10 vg/kg) established 4.2-41.3% expression perinatally and 9.8-25.3% over 46 mo. Expression with AAV8-hFX ( n = 6, 3.12 × 10 vg/kg) increased from <1% perinatally to 9.8-13.4% >35 mo. Low expressers (<1%, n = 3) were postnatally challenged with 2 × 10 vg/kg AAV5 resulting in 2.4-13.2% expression and demonstrating acquired tolerance. Linear amplification-mediated-PCR analysis demonstrated random integration of 57-88% of AAV sequences retrieved from hepatocytes with no events occurring in or near oncogenesis-associated genes. Thus, early-IUGT in macaques produces sustained curative expression related significantly to integrated AAV in the absence of clinical toxicity, supporting its therapeutic potential for early-onset monogenic disorders.-Chan, J. K. Y., Gil-Farina I., Johana, N., Rosales, C., Tan, Y. W., Ceiler, J., Mcintosh, J., Ogden, B., Waddington, S. N., Schmidt, M., Biswas, A., Choolani, M., Nathwani, A. C., Mattar, C. N. Z. Therapeutic expression of human clotting factors IX and X following adeno-associated viral vector-mediated intrauterine gene transfer in early-gestation fetal macaques.
Description
Date
2018-12-05
Journal Title
Journal ISSN
Volume Title
Publisher
Wiley
Collections
Research Projects
Organizational Units
Journal Issue
Keywords
genotoxicity,immune tolerance,nonhuman primate
Citation
Chan JKY, Gil-Farina I, Johana N, Rosales C, Tan YW, Ceiler J, Mcintosh J, Ogden B, Waddington SN, Schmidt M, Biswas A, Choolani M, Nathwani AC, Mattar CNZ. Therapeutic expression of human clotting factors IX and X following adeno-associated viral vector-mediated intrauterine gene transfer in early-gestation fetal macaques. FASEB J. 2019 Mar;33(3):3954-3967. doi: 10.1096/fj.201801391R.