Editors' ChoiceImmunology

AAV and gene therapy: It’s complicated

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Science Translational Medicine  06 May 2015:
Vol. 7, Issue 286, pp. 286ec72
DOI: 10.1126/scitranslmed.aab3969

Adeno-associated virus (AAV)–mediated gene therapy has gained momentum in the past 10 years, with dozens of ongoing clinical trials and one approved gene therapy product for use in Europe. Intriguingly, though, little is known about which characteristics make AAV immunogenic. AAV safely transduces postmitotic tissues with relatively low immunogenicity compared with other vectors like adenovirus, but both anti-capsid and anti-transgene immune responses and tolerance have been reported following AAV–mediated gene transfer in humans. To date, the molecular interactions between AAV and antigen-presenting cells (APCs), as well as the impact of these interactions on transgene or capsid-specific immunization, are unclear.

Now, Ferrand and colleagues provide new insights into interaction of one frequently used AAV serotype with its receptors and how this contributes to its immune response. The authors investigated the overall contribution of sialic acids—sugar chains on the surface of cells which AAV1 uses to gain cell entry—to the antigenic presentation process in vitro and in mice, using an enzyme to remove sialic acids from various cells. Sialic acid–dependent binding of recombinant AAV1 particles on APCs was essential to trigger the CD4+ T cell response. Sialic acid also increased AAV binding and uptake by APCs and contributed to antigenic presentation of both the capsid and transgene product. In addition, the nanoparticulate structure of the vector itself was sufficient to trigger mobilization and activation of some APCs in the mouse spleen. Therefore, combinations of structural and serotype-specific (sugar-dependent) cell–targeting properties of AAV1 can determine its complex immunogenicity.

These findings may be useful to guide selection of AAV variants depending on the intended level of immunogenicity for either gene therapy or vaccination. In the context of gene therapy, Ferrand et al. provide evidence that AAV’s affinity towards APC is an added constraint in the selection of AAV vectors. One could consider limiting the interaction between a new variant and APC when selecting AAVs based on their preference towards a cell type to achieve high-level gene delivery with little immunogenicity.

M. Ferrand et al., Serotype-specific binding properties and nanoparticle characteristics contribute to the immunogenicity of rAAV1 vectors. Mol. Ther. 10.1038/mt.2015.59 (2015). [Abstract]

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