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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Stable human FIX expression after 0.9G intrauterine gene transfer of self-complementary adeno-associated viral vector 5 and 8 in macaques
Molecular Therapy, Volume 19, No. 11, Year 2011
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Description
Intrauterine gene transfer (IUGT) offers ontological advantages including immune naiveté mediating tolerance to the vector and transgenic products, and effecting a cure before development of irreversible pathology. Despite proof-of-principle in rodent models, expression efficacy with a therapeutic transgene has yet to be demonstrated in a preclinical nonhuman primate (NHP) model. We aimed to determine the efficacy of human Factor IX (hFIX) expression after adeno-associated-viral (AAV)-mediated IUGT in NHP. We injected 1.0-1.95 × 1013 vector genomes (vg)/kg of self-complementary (sc) AAV5 and 8 with a LP1-driven hFIX transgene intravenously in 0.9G late gestation NHP fetuses, leading to widespread transduction with liver tropism. Liver-specific hFIX expression was stably maintained between 8 and 112% of normal activity in injected offspring followed up for 2-22 months. AAV8 induced higher hFIX expression (P = 0.005) and milder immune response than AAV5. Random hepatocellular integration was found with no hotspots. Transplacental spread led to low-level maternal tissue transduction, without evidence of immunotoxicity or germline transduction in maternal oocytes. A single intravenous injection of scAAV-LP1-hFIXco to NHP fetuses in late-gestation produced sustained clinically-relevant levels of hFIX with liver-specific expression and a non-neutralizing immune response. These data are encouraging for conditions where gene transfer has the potential to avert perinatal death and long-term irreversible sequelae. © The American Society of Gene & Cell Therapy.
Authors & Co-Authors
Mattar, Citra Nz
Singapore, Singapore City
National University of Singapore
Nathwani, Amit Chunilal
United Kingdom, London
University College London
Waddington, Simon N.
United Kingdom, London
University College London
Dighe, Niraja M.
Singapore, Singapore City
National University of Singapore
Kaeppel, Christine
Germany, Heidelberg
German Cancer Research Center
Nowrouzi, Ali
Germany, Heidelberg
German Cancer Research Center
McIntosh, Jenny H.
United Kingdom, London
University College London
Johana, Nuryanti Binti
Singapore, Singapore City
National University of Singapore
Ogden, Bryan Emmett
Singapore, Singapore City
Singapore Health Services
Fisk, N. M.
Australia, Brisbane
Uq Centre for Clinical Research
Davidoff, Andrew M.
United States, Memphis
St. Jude Children's Research Hospital
David, Anna Louise
United Kingdom, London
University College London
Peebles, Donald M.
United Kingdom, London
University College London
Von-Kalle, Christof
Germany, Heidelberg
German Cancer Research Center
Schmidt, Manfred C.
Germany, Heidelberg
German Cancer Research Center
Biswas, Arijit
Singapore, Singapore City
National University of Singapore
Choolani, Mahesh A.
Singapore, Singapore City
National University of Singapore
Chan, Jerry Kok Yen
Singapore, Singapore City
National University of Singapore
Singapore, Singapore City
Kk Women's and Children's Hospital
Singapore, Singapore City
Duke-nus Medical School
Statistics
Citations: 54
Authors: 18
Affiliations: 8
Identifiers
Doi:
10.1038/mt.2011.107
ISSN:
15250016
Research Areas
Genetics And Genomics
Maternal And Child Health