title: Balloon catheter delivery of helper-dependent adenoviral vector results in sustained, therapeutic hFIX expression in rhesus macaques.
abstract: Hemophilia B is an excellent candidate for gene therapy because low levels of factor IX (FIX) (≥1%) result in clinically significant improvement of the bleeding diathesis. Helper-dependent adenoviral (HDAd) vectors can mediate long-term transgene expression without chronic toxicity. To determine the potential for HDAd-mediated liver-directed hemophilia B gene therapy, we administered an HDAd expressing hFIX into rhesus macaques through a novel and minimally invasive balloon occlusion catheter-based method that permits preferential, high-efficiency hepatocyte transduction with low, subtoxic vector doses. Animals given 1 × 10(12) and 1 × 10(11) virus particle (vp)/kg achieved therapeutic hFIX levels for the entire observation period (up to 1,029 days). At 3 × 10(10) and 1 × 10(10) vp/kg, only subtherapeutic hFIX levels were achieved which were not sustained long-term. Balloon occlusion administration of HDAd was well tolerated with negligible toxicity. Five of six animals developed inhibitors to hFIX. These results provide important information in assessing the clinical utility of HDAd for hemophilia B gene therapy.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Nicola
authors: N
authors: Brunetti-Pierri
authors: Aimee
authors: A
authors: Liou
authors: Priti
authors: P
authors: Patel
authors: Donna
authors: D
authors: Palmer
authors: Nathan
authors: N
authors: Grove
authors: Milton
authors: M
authors: Finegold
authors: Pasquale
authors: P
authors: Piccolo
authors: Elizabeth
authors: E
authors: Donnachie
authors: Karen
authors: K
authors: Rice
authors: Arthur
authors: A
authors: Beaudet
authors: Charles
authors: C
authors: Mullins
authors: Philip
authors: P
authors: Ng
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002404:Catheterization / Q000379:methods*; D004195:Disease Models, Animal; D005164:Factor IX / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors; D006378:Helper Viruses / Q000235:genetics / Q000378:metabolism; D002836:Hemophilia B / Q000235:genetics / Q000628:therapy*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008253:Macaca mulatta / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes / Q000235:genetics
chemical_list: D005164:Factor IX