Research ArticleGene Therapy

Restoring the natural tropism of AAV2 vectors for human liver

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Science Translational Medicine  09 Sep 2020:
Vol. 12, Issue 560, eaba3312
DOI: 10.1126/scitranslmed.aba3312

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Improving gene therapy efficacy

Clinical trial results of a gene therapy for hemophilia B reported unexpectedly low success. Cabanes-Creus et al. may have found a reason for this result. They report that the viral vector commonly used for liver-directed gene therapy, adeno-associated virus 2 (AAV2), mutates during culture, resulting in the virus binding more tightly to heparan sulfate proteoglycans (HSPGs). In contrast, naturally occurring AAVs isolated from human liver biopsies did not bind HSPGs tightly and were more successful at infecting human liver cells. However, these naturally occurring AAVs cultured over time also mutated, resulting in greater HSPG binding and decreased liver infection. Thus, naturally occurring AAVs may be more effective as vectors for liver-targeting gene therapies.

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