Cited by 345Virus-based gene therapy researchHemophilia Treatment and ResearchRNA Interference and Gene Delivery

Long-term Safety and Efficacy Following Systemic Administration of a Self-complementary AAV Vector Encoding Human FIX Pseudotyped With Serotype 5 and 8 Capsid Proteins

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Nathwani, Amit C, Rosales, Cecilia, McIntosh, Jenny, Rastegarlari, Ghasem, Nathwani, Devhrut, Raj, Deepak, Nawathe, Sushmita, Waddington, Simon N +16 more·2011·Molecular Therapy

Abstract

Adeno-associated virus vectors (AAV) show promise for liver-targeted gene therapy. In this study, we examined the long-term consequences of a single intravenous administration of a self-complementary AAV vector (scAAV2/ 8-LP1-hFIXco) encoding a codon optimized human factor IX (hFIX) gene in 24 nonhuman primates (NHPs). A dose-response relationship between vector titer and transgene expression was observed. Peak hFIX expression following the highest dose of vector (2 × 10(12) pcr-vector genomes (vg)/kg) was 21 ± 3 µg/ml (~420% of normal). Fluorescent in-situ hybridization demonstrated scAAV provirus in almost 100% of hepatocytes at that dose. No perturbations of clinical or laboratory parameters were noted and vector genomes were cleared from bodily fluids by 10 days. Macaques transduced with 2 × 10(11) pcr-vg/kg were followed for the longest period (~5 years), during which time expression of hFIX remained >10% of normal level, despite a gradual decline in transgene copy number and the proportion of transduced hepatocytes. All macaques developed serotype-specific antibodies but no capsid-specific cytotoxic T lymphocytes were detected. The liver was preferentially transduced with 300-fold more proviral copies than extrahepatic tissues. Long-term biochemical, ultrasound imaging, and histologic follow-up of this large cohort of NHP revealed no toxicity. These data support further evaluation of this vector in hemophilia B patients.

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  • FDA's denial of the first biologics licensing application for a hemophilia gene-therapy product submitted by BioMarin Pharmaceutical for a hemophilia A vector requested additional data to address unexplained observations specific to its trial (e.g., questions around durability of expression) that are important for all hemophilia gene-therapy efforts.

    “the FDA’s denial of the first biologics licensing application for a hemophilia gene-therapy product submitted by BioMarin Pharmaceutical for a hemophilia A (HA) vector; whereas the outcome surprised many, the FDA’s requested additional data aim to address unexplained observations thus far specific to its trial (e.g., questions around durability of expression163,164) that are undoubtedly important”
  • 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”

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Authors
Nathwani, A. C., Rosales, C., McIntosh, J., Rastegarlari, G., Nathwani, D., Raj, D., Nawathe, S., Waddington, S. N., Bronson, R., Jackson, S., Donahue, R. E., High, K. A., Mingozzi, F., Ng, C. Y., Zhou, J., Spence, Y., McCarville, M. B., Valentine, M., Allay, J., Coleman, J., Sleep, S., Gray, J. T., Nienhuis, A. W., & Davidoff, A. M.
Affiliations
  • NHS Blood and Transplant (GB)
  • University College London (GB)
  • Dana-Farber/Harvard Cancer Center (US)
  • University of Tennessee Health Science Center (US)
  • National Heart, Lung, and Blood Institute (US)
  • Children's Hospital of Philadelphia (US)
  • St. Jude Children's Research Hospital (US)
Corresponding author
Nawathe, Sushmita
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2011-05
Volume
19
Issue
5
Pages
876-885
ISSN
1525-0016 (ISSN-L)
OpenAlex
W2088410491
Cited by
345
References
43
Citations by year
2026: 10 · 2025: 18 · 2024: 29 · 2023: 24 · 2022: 35 · 2021: 17 · 2020: 19 · 2019: 27 · 2018: 22 · 2017: 22 · 2016: 19 · 2015: 19 · 2014: 15 · 2013: 22 · 2012: 25
FWCI
16.56
Type
journal article
Language
en
Open access
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • National Institute for Health and Care Research (RP-PG-0310-1001)
  • National Heart, Lung, and Blood Institute (HL073838, R01HL094396, R01HL073838)
  • National Cancer Institute (CA027165)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
self-complementary AAV vectors, AAV8, factor IX, hemophilia B, liver-targeted gene therapy, non-human primates, long-term safety, transgene expression, serotype-specific antibodies, cytotoxic T lymphocytes, dose-response relationship
MeSH terms
Dependovirus, Animals, Hemophilia B, Factor IX, Genetic Vectors, Humans, Liver, Macaca, Genetic Therapy, Gene Expression, In Situ Hybridization, Fluorescence, Capsid Proteins, Mice, HEK293 Cells

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