Research Article
Gene Therapy (2003) 10, 2139–2147. doi:10.1038/sj.gt.3302123
Genetic modifications of the adeno-associated virus type 2 capsid reduce the affinity and the neutralizing effects of human serum antibodies
N A Huttner1, A Girod1, L Perabo1, D Edbauer1, J A Kleinschmidt2, H Büning1 and M Hallek1,3,4
- 1Genzentrum, Ludwig-Maximilians-Universität München, Feodor-Lynen-Stra
e 25, Munich, Germany - 2Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Im Neuenheimer Feld 242, Heidelberg, Germany
- 3Medizinische Klinik III, Klinikum Grohadern, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strae 25, Munich, Germany
- 4GSF-National Research Center for Environment and Health, KKG Gentherapie, Marchioninistrae 25, Munich, Germany
Correspondence: Dr M Hallek, Genzentrum der Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany
Received 27 February 2003; Accepted 23 June 2003.
Abstract
The high prevalence of human serum antibodies against adeno-associated virus type 2 (AAV) vectors represents a potential limitation for in vivo applications. Consequently, the development of AAV vectors able to escape antibody binding and neutralization is of importance. To identify capsid domains which contain major immunogenic epitopes, six AAV capsid mutants carrying peptide insertions in surface exposed loop regions (I-261, I-381, I-447, I-534, I-573, I-587) were analyzed. Two of these mutants, I-534 and I-573, showed an up to 70% reduced affinity for AAV antibodies as compared to wild-type AAV in the majority of serum samples. In addition, AAV mutant I-587 but not wild-type AAV efficiently transduced cells despite the presence of neutralizing antisera. Taken together, the results show that major neutralizing effects of human AAV antisera might be overcome by the use of AAV capsid mutants.
Keywords:
adeno-associated virus, immunogenic epitopes, AAV antibodies, neutralizing antibodies, human serum samples
