title: Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery.
abstract: Duchenne muscular dystrophy is a monogenic disease potentially treatable by gene replacement. Use of recombinant adeno-associated virus (AAV) will ultimately require a vascular approach to broadly transduce muscle cells. We tested the impact of preexisting AAV antibodies on microdystrophin expression following vascular delivery to nonhuman primates. Rhesus macaques were treated by isolated limb perfusion using a fluoroscopically guided catheter. In addition to serostatus stratification, the animals were placed into one of the three immune suppression groups: no immune suppression, prednisone, and triple immune suppression (prednisone, tacrolimus, and mycophenolate mofetil). The animals were analyzed for transgene expression at 3 or 6 months. Microdystrophin expression was visualized in AAV, rhesus serotype 74 sero-negative animals (mean: 48.0 ± 20.8%) that was attenuated in sero-positive animals (19.6 ± 18.7%). Immunosuppression did not affect transgene expression. Importantly, removal of AAV binding antibodies by plasmapheresis in AAV sero-positive animals resulted in high-level transduction (60.8 ± 18.0%), which is comparable with that of AAV sero-negative animals (53.7 ± 7.6%), whereas non-pheresed sero-positive animals demonstrated significantly lower transduction levels (10.1 ± 6.0%). These data support the hypothesis that removal of AAV binding antibodies by plasmapheresis permits successful and sustained gene transfer in the presence of preexisting immunity (natural infection) to AAV.
authors.affiliation: Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio, USA. Electronic address: Louis.Chicoine@nationwidechildrens.org.
authors.forename: L G
authors.initials: LG
authors.lastname: Chicoine
authors.affiliation: Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Montgomery
authors.affiliation: Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Bremer
authors.affiliation: Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Shontz
authors.affiliation: Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Griffin
authors.affiliation: Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: Heller
authors.affiliation: Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lewis
authors.affiliation: Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: V
authors.initials: V
authors.lastname: Malik
authors.affiliation: Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Grose
authors.affiliation: Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Shilling
authors.affiliation: Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Campbell
authors.affiliation: Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Preston
authors.affiliation: Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Coley
authors.affiliation: Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio, USA; Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA.
authors.forename: P T
authors.initials: PT
authors.lastname: Martin
authors.affiliation: Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA; Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio, USA; Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Walker
authors.affiliation: Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Clark
authors.affiliation: Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Neurology, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Sahenk
authors.affiliation: Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio, USA; Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA; Department of Neurology, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA. Electronic address: Jerry.Mendell@nationwidechildrens.org.
authors.forename: J R
authors.initials: JR
authors.lastname: Mendell
authors.affiliation: Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, Columbus, Ohio, USA; Centers for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio, USA; Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA. Electronic address: Louise.Rodino-Klapac@nationwidechildrens.org.
authors.forename: L R
authors.initials: LR
authors.lastname: Rodino-Klapac
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D016189:Dystrophin / Q000235:genetics*; D015870:Gene Expression; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D010956:Plasmapheresis / Q000379:methods; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D016189:Dystrophin; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins