Plasmapheresis eliminates the negative impact of AAV antibodies on micro-dystrophin gene expression following vascular delivery.

1] Departments of Pediatrics and Neurology, The Ohio State University and Nationwide Children's Hospital, Columbus, OH, USA, [2] Centers for Gene Therapy and Vaccines and Immunity at The Research Institute at Nationwide Children's Hospital, Columbus, OH. [3] Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, OH.
Molecular Therapy (Impact Factor: 6.43). 10/2013; DOI: 10.1038/mt.2013.244
Source: PubMed

ABSTRACT Duchenne muscular dystrophy (DMD) is a monogenic disease potentially treatable by gene replacement. Use of recombinant adeno-associated virus will ultimately require a vascular approach to broadly transduce muscle. We tested the impact of pre-existing AAV antibodies on micro-dystrophin expression following vascular delivery to non-human primates. Rhesus macaques were treated by isolated limb perfusion via a fluoroscopically guided catheter. In addition to serostatus stratification, the animals were placed into one of 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. Micro-dystrophin expression was visualized in AAVrh.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 to that of AAV sero-negative animals (53.7 ± 7.6%). While 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 pre-existing immunity (natural infection) to AAV.Molecular Therapy (2013); doi:10.1038/mt.2013.244.

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