title: Efficient whole-body transduction with trans-splicing adeno-associated viral vectors.
abstract: Limited packaging capacity has hampered adeno-associated virus (AAV)-mediated gene therapy for many common genetic diseases such as cystic fibrosis (CF) and Duchenne muscular dystrophy (DMD). Trans-splicing AAV (tsAAV) vectors double AAV packaging capacity but their transduction efficiency has been too low to be useful. We have recently overcome this hurdle by rational vector design. We have shown that a pair of optimized mini-dystrophin tsAAV vectors can reach the same transduction efficiency as that of a single AAV vector after local injection in dystrophic muscle. However, global gene transfer is required to treat diseases like DMD. To test whether systemic delivery can be achieved with tsAAV vectors, we generated a set of optimized alkaline phosphatase (AP) tsAAV vectors. We delivered AAV serotype 9 pseudotyped AP tsAAV intravenously to newborn mice. Six weeks later, we observed high-level transduction in all body skeletal muscle and the heart, the tissues that are affected in DMD. We also detected efficient transduction in the lung, the primary organ affected in CF. Our results provide the first evidence of whole-body transduction with tsAAV vectors and further raise the hope of tsAAV gene therapy for DMD and CF.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri 65212, USA.
authors.forename: Arkasubhra
authors.initials: A
authors.lastname: Ghosh
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yue
authors.forename: Chun
authors.initials: C
authors.lastname: Long
authors.forename: Brian
authors.initials: B
authors.lastname: Bostick
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Duan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003550:Cystic Fibrosis / Q000235:genetics / Q000628:therapy; D000229:Dependovirus / Q000235:genetics*; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000628:therapy; D009206:Myocardium / Q000378:metabolism; D014161:Transduction, Genetic