Therapeutic hFIX Activity Achieved after Single AAV5-hFIX Treatment in Hemophilia B Patients and NHPs with Pre-existing Anti-AAV5 NABs
- PMID: 31276009
- PMCID: PMC6586596
- DOI: 10.1016/j.omtm.2019.05.009
Therapeutic hFIX Activity Achieved after Single AAV5-hFIX Treatment in Hemophilia B Patients and NHPs with Pre-existing Anti-AAV5 NABs
Abstract
Currently, individuals with pre-existing neutralizing antibodies (NABs) against adeno-associated virus (AAV) above titer of 5 are excluded from systemic AAV-based clinical trials. In this study we explored the impact of pre-existing anti-AAV5 NABs on the efficacy of AAV5-based gene therapy. AMT-060 (AAV5-human FIX) was evaluated in 10 adults with hemophilia B who tested negative for pre-existing anti-AAV5 NABs using a GFP-based assay. In this study, using a more sensitive luciferase-based assay, we show that 3 of those 10 patients tested positive for anti-AAV5 NABs. However, no relationship was observed between the presence of pre-treatment anti-AAV5 NABs and the therapeutic efficacy of AMT-060. Further studies in non-human primates (NHPs) showed that AAV5 transduction efficacy was similar following AMT-060 treatment, irrespective of the pre-existing anti-AAV5 NABs titers. We show that therapeutic efficacy of AAV5-mediated gene therapy was achieved in humans with pre-existing anti-AAV5 NABs titers up to 340. Whereas in NHPs circulating human factor IX (hFIX) protein was achieved, at a level therapeutic in humans, with pre-existing anti-AAV5 NABs up to 1030. Based on those results, no patients were excluded from the AMT-061 (AAV5-hFIX-Padua) phase IIb clinical trial (n = 3). All three subjects presented pre-existing anti-AAV5 NABs, yet had therapeutic hFIX activity after AMT-061 administration.
Keywords: AAV; FIX; NABs; anti-AAV NABs; gene therapy; hFIX; hemophilia.
Figures







Similar articles
-
Enhanced Factor IX Activity following Administration of AAV5-R338L "Padua" Factor IX versus AAV5 WT Human Factor IX in NHPs.Mol Ther Methods Clin Dev. 2019 Sep 26;15:221-231. doi: 10.1016/j.omtm.2019.09.005. eCollection 2019 Dec 13. Mol Ther Methods Clin Dev. 2019. PMID: 31709273 Free PMC article.
-
Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates.Blood Adv. 2019 Sep 10;3(17):2632-2641. doi: 10.1182/bloodadvances.2019000380. Blood Adv. 2019. PMID: 31501158 Free PMC article.
-
Safety Findings of Dosing Gene Therapy Vectors in NHP With Pre-existing or Treatment-Emergent Anti-capsid Antibodies.Toxicol Pathol. 2023 Jul;51(5):246-256. doi: 10.1177/01926233231202995. Epub 2023 Nov 3. Toxicol Pathol. 2023. PMID: 37921115
-
Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved by Sequential Administration of AAV5ch and AAV1.Mol Ther. 2017 Aug 2;25(8):1831-1842. doi: 10.1016/j.ymthe.2017.05.003. Epub 2017 Jun 5. Mol Ther. 2017. PMID: 28596114 Free PMC article.
-
Theodore E. Woodward Award. AAV-mediated gene transfer for hemophilia.Trans Am Clin Climatol Assoc. 2003;114:337-51; discussion 351-2. Trans Am Clin Climatol Assoc. 2003. PMID: 12813929 Free PMC article. Review.
Cited by
-
Anti-AAV Antibodies in AAV Gene Therapy: Current Challenges and Possible Solutions.Front Immunol. 2021 Mar 17;12:658399. doi: 10.3389/fimmu.2021.658399. eCollection 2021. Front Immunol. 2021. PMID: 33815421 Free PMC article. Review.
-
Characterization of a Bioengineered AAV3B Capsid Variant with Enhanced Hepatocyte Tropism and Immune Evasion.Hum Gene Ther. 2023 Apr;34(7-8):289-302. doi: 10.1089/hum.2022.176. Hum Gene Ther. 2023. PMID: 36950804 Free PMC article.
-
Correlation of antigen expression with epigenetic modifications after rAAV delivery of a human factor IX variant in mice and rhesus macaques.Mol Ther. 2024 Jul 3;32(7):2064-2079. doi: 10.1016/j.ymthe.2024.05.005. Epub 2024 May 7. Mol Ther. 2024. PMID: 38715361 Free PMC article.
-
Sustained high expression of human FVII following AAV8-mediated gene delivery in mice.Mol Ther Methods Clin Dev. 2025 Jun 25;33(3):101523. doi: 10.1016/j.omtm.2025.101523. eCollection 2025 Sep 11. Mol Ther Methods Clin Dev. 2025. PMID: 40697775 Free PMC article.
-
In Vivo Hematopoietic Stem Cell Genome Editing: Perspectives and Limitations.Genes (Basel). 2022 Nov 27;13(12):2222. doi: 10.3390/genes13122222. Genes (Basel). 2022. PMID: 36553489 Free PMC article. Review.
References
-
- Hurlbut G.D., Ziegler R.J., Nietupski J.B., Foley J.W., Woodworth L.A., Meyers E., Bercury S.D., Pande N.N., Souza D.W., Bree M.P. Preexisting immunity and low expression in primates highlight translational challenges for liver-directed AAV8-mediated gene therapy. Mol. Ther. 2010;18:1983–1994. - PMC - PubMed
-
- Jiang H., Couto L.B., Patarroyo-White S., Liu T., Nagy D., Vargas J.A., Zhou S., Scallan C.D., Sommer J., Vijay S. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood. 2006;108:3321–3328. - PMC - PubMed
-
- Manno C.S., Pierce G.F., Arruda V.R., Glader B., Ragni M., Rasko J.J., Ozelo M.C., Hoots K., Blatt P., Konkle B. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med. 2006;12:342–347. - PubMed
-
- Scallan C.D., Jiang H., Liu T., Patarroyo-White S., Sommer J.M., Zhou S., Couto L.B., Pierce G.F. Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice. Blood. 2006;107:1810–1817. - PubMed
LinkOut - more resources
Full Text Sources
Other Literature Sources