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Publication Detail
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.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Nathwani AC, Rosales C, McIntosh J, Rastegarlari G, Nathwani D, Raj D, Nawathe S, Waddington SN, Bronson R, Jackson S, Donahue RE, High KA, Mingozzi F, Ng CYC, Zhou J, Spence Y, McCarville MB, Valentine M, Allay J, Coleman J, Sleep S, Gray JT, Nienhuis AW, Davidoff AM
  • Publication date:
  • Pagination:
    876, 885
  • Journal:
    Mol Ther
  • Volume:
  • Issue:
  • Status:
  • Country:
    United States
  • PII:
  • Language:
  • Keywords:
    Animals, Capsid Proteins, Dependovirus, Factor IX, Gene Expression, Genetic Therapy, Genetic Vectors, HEK293 Cells, Hemophilia B, Humans, In Situ Hybridization, Fluorescence, Liver, Macaca, Mice
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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