Striatal readministration of rAAV vectors reveals an immune response against AAV2 capsids that can be circumvented.

Molecular Therapy : the Journal of the American Society of Gene Therapy
Carmen S PedenRonald J Mandel

Abstract

Recombinant adeno-associated virus (rAAV) expresses no viral genes after transduction. In addition, because the brain is relatively immunoprivileged, intracranial rAAV transduction may be immunologically benign due to a lack of antigen presentation. However, preexposure to AAV allows neutralizing antibodies (nAbs) to block brain transduction and rAAV readministration in the brain leads to an inflammatory response in the second-injection site. In this study, we replicate our striatal rAAV2/2-GDNF readministration results and extend this effect to a second transgene, green fluorescent protein (GFP). Unlike rAAV2/2-GDNF readministration, striatal rAAV2/2-GFP readministration leads to a loss of transgene in the second site in the absence of detectable circulating nAbs. In order to determine whether the transgene or the AAV2 capsid is the antigenic stimulus in brain for the immune response in the second site, we readministered rAAV2/2-GFP using two different rAAV serotypes (rAAV2/2 followed by rAAV2/5). In this case, there was no striatal inflammation or transgene loss detected in the second-injection site. In addition, striatal readministration of rAAV2/5-GFP also resulted in no detectable immune response. Furthermore, delaying rAA...Continue Reading

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Citations

Nov 13, 2009·Gene Therapy·S Nayak, R W Herzog
Aug 27, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Fredric P ManfredssonRonald J Mandel
Jul 29, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Oleg S GorbatyukNicholas Muzyczka
Jul 5, 2012·Molecular Therapy : the Journal of the American Society of Gene Therapy·Guillermo GarauletAntonio Rodríguez
Oct 20, 2009·Human Molecular Genetics·Marie-Anne ColleCaroline Sevin
Jan 5, 2014·PloS One·Paula S Montenegro-MirandaPiter J Bosma
Nov 3, 2014·Annual Review of Virology·R Jude Samulski, Nicholas Muzyczka
Jan 10, 2012·Neurobiology of Disease·Shilpa Ramaswamy, Jeffrey H Kordower
Mar 24, 2020·Brain : a Journal of Neurology·Yaping ChuJeffrey H Kordower
Aug 2, 2018·Bioengineering & Translational Medicine·William F Kaemmerer
Nov 26, 2010·Expert Review of Neurotherapeutics·John ForsayethMichael J Aminoff

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