Plasmapheresis Eliminates the Negative Impact of AAV Antibodies on Microdystrophin Gene Expression Following Vascular Delivery

Plasmapheresis Eliminates the Negative Impact of AAV Antibodies on Microdystrophin Gene Expression Following Vascular Delivery

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 expressio...

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Bibliographic Details
Published in:Molecular therapy Vol. 22; no. 2; pp. 338 - 347
Main Authors: Chicoine, LG, Montgomery, CL, Bremer, WG, Shontz, KM, Griffin, DA, Heller, KN, Lewis, S, Malik, V, Grose, WE, Shilling, CJ, Campbell, KJ, Preston, TJ, Coley, BD, Martin, PT, Walker, CM, Clark, KR, Sahenk, Z, Mendell, JR, Rodino-Klapac, LR
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-02-2014
Elsevier Limited
Nature Publishing Group
Subjects:
Adeno-associated virus
Animals
Antibodies
Antibodies, Neutralizing - immunology
Antibodies, Viral - immunology
Apheresis
Biodistribution
Catheters
Dependovirus - genetics
Dependovirus - immunology
Dystrophin - genetics
Gene Expression
Genes, Reporter
Genetic Vectors - administration & dosage
Genetic Vectors - genetics
Genetic Vectors - immunology
Genomes
Glycoproteins
Green Fluorescent Proteins - genetics
Humans
Lymphatic system
Macaca mulatta
Male
Medical screening
Muscle, Skeletal - metabolism
Muscular dystrophy
Mutation
Original
Plasmapheresis - methods
Research centers
Spleen
Transduction, Genetic
Transgenes
Veins & arteries
United States > US
Ohio
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Summary: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.
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ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2013.244