AI Article Synopsis
- A major challenge in gene therapy is that existing AAV vectors don't specifically target desired tissues, limiting their effectiveness.
- By inserting a short human-derived epitope into AAV surface proteins, researchers can prevent AAVs from attaching to their natural receptors and instead redirect them using specialized bispecific antibodies.
- This new method successfully targets specific proteins present in tumor and fibrotic tissues, paving the way for more effective gene therapies by allowing targeted delivery to relevant cell types.
Article Abstract
A major limiting factor for systemically delivered gene therapies is the lack of novel tissue specific AAV (Adeno-associated virus) derived vectors. Bispecific antibodies can be used to redirect AAVs to specific target receptors. Here, we demonstrate that the insertion of a short linear epitope "2E3" derived from human proprotein-convertase subtilisin/kexin type 9 (PCSK9) into different surface loops of the VP capsid proteins can be used for AAV de-targeting from its natural receptor(s), combined with a bispecific antibody-mediated retargeting. We chose to target a set of distinct disease relevant membrane proteins-fibroblast activation protein (FAP), which is upregulated on activated fibroblasts within the tumor stroma and in fibrotic tissues, as well as programmed death-ligand 1 (PD-L1), which is strongly upregulated in many cancers. Upon incubation with a bispecific antibody recognizing the 2E3 epitope and FAP or PD-L1, the bispecific antibody/rAAV complex was able to selectively transduce receptor positive cells. In summary, we developed a novel, rationally designed vector retargeting platform that can target AAVs to a new set of cellular receptors in a modular fashion. This versatile platform may serve as a valuable tool to investigate the role of disease relevant cell types and basis for novel gene therapy approaches.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347852 | PMC |
| http://dx.doi.org/10.3390/ijms22158355 | DOI Listing |
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