117. HSPG Binding Properties of Adeno- Associated Virus Retargeting Mutants and Consequences for Their In Vivo Tropism

Different technologies have been developed to control or redirect tropism of adeno-associated virus of type 2 (AAV-2) by genetic capsid modification. Many of these approaches are based on the introduction of peptide sequences on the viral capsid in order to provide the vector with the ability to bin...

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Bibliographic Details
Published in:	Molecular therapy Vol. 13; no. S1; p. S48
Main Authors:	Goldnau, Daniela, Perabo, Luca, White, Kathryn, Endell, Jan, Humme, Sibille, Work, Lorraine, Jannicki, Hanna, Hallek, Michael, Baker, Andrew H., Buening, Hildegard
Format:	Journal Article
Language:	English
Published:	Milwaukee Elsevier Limited 01-05-2006
Subjects:	Animals Gene therapy Kinetics Liver Spleen Vectors (Biology) Germany
Online Access:	Get full text
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Summary:	Different technologies have been developed to control or redirect tropism of adeno-associated virus of type 2 (AAV-2) by genetic capsid modification. Many of these approaches are based on the introduction of peptide sequences on the viral capsid in order to provide the vector with the ability to bind particular cellular receptors. To obtain selective vectors however, simultaneous abrogation of capsid usage of natural receptors is essential. Insertions at amino acid position 587 of the major capsid protein VP1 ablated the heparan sulphate proteoglycan binding of wild-type AAV in some, but not all previously described AAV targeting vectors.By panning an AAV Display library (Perabo et al, 2003) on heparin columns, we were able to correlate amino acid composition of insertions with heparin-binding phenotype and to propose a model to interpret the responsible molecular mechanisms. Interestingly, in vivo studies allowed us to correlate the inability to bind to heparin with detargeting from liver and spleen in mice after systemic application, whereas AAV targeting mutants who retained the ability to bind to heparin showed an accumulation in liver and spleen comparable to AAV with unmodified capsid.Our data point toward an unspecific HSPG dependent retention of AAV vectors in liver and spleen, which can be overcome by HSPG independent targeting vectors. These results suggest several alternatives to improve efforts to obtain tissue specific AAV targeting vectors.
ISSN:	1525-0016 1525-0024
DOI:	10.1016/j.ymthe.2006.08.137