title: Gene transfer to hemophilia A mice via oral delivery of FVIII-chitosan nanoparticles.
abstract: Effective oral delivery of a non-viral gene carrier would represent a novel and attractive strategy for therapeutic gene transfer. To evaluate the potential of this approach, we studied the oral gene delivery efficacy of DNA polyplexes composed of chitosan and Factor VIII DNA. Transgene DNA was detected in both local and systemic tissues following oral administration of the chitosan nanoparticles to hemophilia A mice. Functional factor VIII protein was detected in plasma by chromogenic and thrombin generation assays, reaching a peak level of 2-4% FVIII at day 22 after delivery. In addition, a bleeding challenge one month after DNA administration resulted in phenotypic correction in 13/20 mice given 250-600 microg of FVIII DNA in chitosan nanoparticles, compared to 1/13 mice given naked FVIII DNA and 0/6 untreated mice. While further optimization would be required to render this type of delivery system practical for hemophilia A gene therapy, the findings suggest the feasibility of oral, non-viral delivery for gene medicine applications.
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bowman
authors.forename: Rita
authors.initials: R
authors.lastname: Sarkar
authors.forename: Sanj
authors.initials: S
authors.lastname: Raut
authors.forename: Kam W
authors.initials: KW
authors.lastname: Leong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D048271:Chitosan / Q000737:chemistry*; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D005169:Factor VIII / Q000096:biosynthesis* / Q000235:genetics; D005240:Feasibility Studies; D015316:Genetic Therapy / Q000379:methods*; D006467:Hemophilia A / Q000097:blood / Q000235:genetics / Q000628:therapy*; D006487:Hemostasis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D053758:Nanoparticles; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D005169:Factor VIII; D004247:DNA; D048271:Chitosan; D013917:Thrombin