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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
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
Molecular Therapy, Volume 19, No. 5, Year 2011
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Description
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 3νg/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. © The American Society of Gene and Cell Therapy.
Authors & Co-Authors
Nathwani, Amit Chunilal
United Kingdom, London
University College London
United Kingdom, Bristol
Nhs Blood and Transplant
Rosales, Cecilia
United Kingdom, London
University College London
McIntosh, Jenny H.
United Kingdom, London
University College London
Waddington, Simon N.
United Kingdom, London
University College London
Bronson, Roderick T.
United States, Boston
Dana-farber/harvard Cancer Center
Mingozzi, Federico
United States, Philadelphia
The Children's Hospital of Philadelphia
McCarville, Mary Beth
United States, Memphis
St. Jude Children's Research Hospital
Davidoff, Andrew M.
United States, Boston
Dana-farber/harvard Cancer Center
Statistics
Citations: 280
Authors: 8
Affiliations: 7
Identifiers
Doi:
10.1038/mt.2010.274
ISSN:
15250016
Research Areas
Genetics And Genomics
Study Design
Cohort Study