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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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| Authors: | Amit C Nathwani Cecilia Rosales Jenny McIntosh Ghasem Rastegarlari Devhrut Nathwani Deepak Raj Sushmita Nawathe Simon N Waddington Roderick Bronson Scott Jackson Robert E Donahue Katherine A High Federico Mingozzi Catherine YC Ng Junfang Zhou Yunyu Spence M Beth McCarville Marc Valentine James Allay John Coleman Susan Sleep John T Gray Arthur W Nienhuis Andrew M Davidoff |
| Affiliation: | 1. Department of Hematology, University College London Cancer Institute, London, UK;2. NHS Blood and Transplant, London, UK;3. University College London, Institute for Women''s Health, London, UK;4. Rodent Histopathology Core, Dana Farber/Harvard Cancer Center, Boston, Massachusetts, USA;5. Department of Comparative Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA;6. Hematology Branch, NHLBI, Washington, District of Columbia, USA;7. Center for Cellular and Molecular Therapeutics, The Children''s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA;8. Howard Hughes Medical Institute at the Children''s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA;9. Department of Surgery, St Jude Children''s Research Hospital, Memphis, Tennessee, USA;10. Department of Radiological Sciences, St Jude Children''s Research Hospital, Memphis, Tennessee, USA;11. Department of Genetics and Tumor Cell Biology, St Jude Children''s Research Hospital, Memphis, Tennessee, USA;12. Children''s GMP, LLC, St Jude Children''s Research Hospital, Memphis, Tennessee, USA;13. Division of Experimental Hematology, St Jude Children''s Research Hospital, Memphis, Tennessee, USA |
| 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 × 1012 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 × 1011 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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