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Intracellular trafficking of adeno-associated virus (AAV) vectors: challenges and future directions

Gene Therapy volume 28, pages 683–696 (2021)Cite this article

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A Correction to this article was published on 26 March 2021

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Abstract

In the last two decades, recombinant adeno-associated virus has emerged as the most popular gene therapy vector. Recently AAV gene therapy has been approved by the FDA for the treatment of two rare genetic disorders, namely the early childhood blindness disease Leber congenital amaurosis and spinal muscular atrophy (SMA). As is the case for the treatment of SMA, if the AAV vector must be administered systemically, very high vector doses are often required for therapeutic efficacy. But higher vector doses inevitably increase the risk of adverse events. The tragic death of three children in a clinical trial to treat X-linked myotubular myopathy with an AAV vector has thrown this limitation into sharp relief. Regardless of the precise cause(s) that led to the death of the two children, it is critical that we develop better AAV vectors to achieve therapeutic levels of expression with lower vector doses. To transduce successfully a target cell, AAV has to overcome both systemic as well as cellular roadblocks. In this review, we discuss some of the most prominent cellular roadblocks that AAV must get past to deliver successfully its therapeutic payload. We also highlight recent advancements in our knowledge of AAV biology that can potentially be harnessed to improve AAV vector performance and thereby make AAV gene therapy safer.

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Fig. 1: Wild-type AAV genome organization.
Fig. 2: AAV can follow multiple endocytic routes into the cell.
Fig. 3: Intracellular trafficking of AAV to the Golgi.
Fig. 4: AAV must escape into the cytosol prior to nuclear entry.
Fig. 5: Steps following nuclear import that lead to transgene expression.

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Acknowledgements

We would like to thank Dr. Kyle Chamberlain for the critical reading of our manuscript.

Funding

This work was supported by NHLBI grants HL131404 (T.W.) and HL117505 (T.W.).

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  1. Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jalish M. Riyad & Thomas Weber

  2. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jalish M. Riyad & Thomas Weber

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Riyad, J.M., Weber, T. Intracellular trafficking of adeno-associated virus (AAV) vectors: challenges and future directions. Gene Ther 28, 683–696 (2021). https://doi.org/10.1038/s41434-021-00243-z

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