Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy
Open accessAbstract
Preclinical studies and initial clinical trials have documented the feasibility of adenoassociated virus (AAV)–mediated gene therapy for hemophilia B. In an 8-year study, inhibitor-prone hemophilia B dogs (n = 2) treated with liver-directed AAV2 factor IX (FIX) gene therapy did not have a single bleed requiring FIX replacement, whereas dogs undergoing muscle-directed gene therapy (n = 3) had a bleed frequency similar to untreated FIX-deficient dogs. Coagulation tests (whole blood clotting time [WBCT], activated clotting time [ACT], and activated partial thromboplastin time [aPTT]) have remained at the upper limits of the normal ranges in the 2 dogs that received liver-directed gene therapy. The FIX activity has remained stable between 4% and 10% in both liver-treated dogs, but is undetectable in the dogs undergoing muscle-directed gene transfer. Integration site analysis by linear amplification–mediated polymerase chain reaction (LAM-PCR) suggested the vector sequences have persisted predominantly in extrachromosomal form. Complete blood count (CBC), serum chemistries, bile acid profile, hepatic magnetic resonance imaging (MRI) and computed tomography (CT) scans, and liver biopsy were normal with no evidence for tumor formation. AAV-mediated liver-directed gene therapy corrected the hemophilia phenotype without toxicity or inhibitor development in the inhibitor-prone null mutation dogs for more than 8 years.
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Clinical data from the first successful systemic AAV trial in HB demonstrate durable expression 8 years postgene transfer.
“Clinical data from the first successful systemic AAV trial, conducted in HB,163,164 mirror observations in canine HA and HB data after AAV-mediated gene transfer, demonstrating durable expression 8 years postgene transfer.139,164,218,219”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [218]
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- Authors
- Niemeyer, G. P., Herzog, R. W., Mount, J., Arruda, V. R., Tillson, D. M., Hathcock, J., van Ginkel, F. W., High, K. A., & Lothrop, C. D.
- Affiliations
- University of Alabama at Birmingham (US)
- University of Florida (US)
- Auburn University (US)
- Children's Hospital of Philadelphia (US)
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2009-01-22
- Volume
- 113
- Issue
- 4
- Pages
- 797-806
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2630266
- OpenAlex
- W2066226950
- Cited by
- 276
- References
- 3
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 13 · 2023: 8 · 2022: 16 · 2021: 17 · 2020: 11 · 2019: 22 · 2018: 10 · 2017: 17 · 2016: 12 · 2015: 18 · 2014: 13 · 2013: 21 · 2012: 23
- FWCI
- 12.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (R24HL086944, 2P01 HL64190, P01HL064190)
- National Institute of Allergy and Infectious Diseases (R01 AI/HL51390, R01AI051390)
- Topics
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- hemophilia B, AAV2, liver-directed gene transfer, long-term follow-up, dogs, coagulation tests, factor IX activity, treatment efficacy and safety
- MeSH terms
- Dependovirus, Animals, Hemophilia B, DNA, Viral, Dogs, Factor IX, Gene Expression Regulation, Genetic Vectors, Immune Tolerance, Liver, RNA, Messenger, Time Factors, Tomography, X-Ray Computed, Genetic Therapy
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