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. 2019 Sep 29;6(1):601-621.
doi: 10.1146/annurev-virology-092818-015530. Epub 2019 Jul 5.

Recombinant Adeno-Associated Virus Gene Therapy in Light of Luxturna (and Zolgensma and Glybera): Where Are We, and How Did We Get Here?

Allison M Keeler  1 , Terence R Flotte  1
Affiliations

Recombinant Adeno-Associated Virus Gene Therapy in Light of Luxturna (and Zolgensma and Glybera): Where Are We, and How Did We Get Here?

Allison M Keeler et al. Annu Rev Virol. .

Abstract

The recent market approvals of recombinant adeno-associated virus (rAAV) gene therapies in Europe and the United States are landmark achievements in the history of modern science. These approvals are also anticipated to herald the emergence of a new class of therapies for monogenic disorders, which had hitherto been considered untreatable. These events can be viewed as stemming from the convergence of several important historical trends: the study of basic virology, the development of genomic technologies, the imperative for translational impact of National Institutes of Health-funded research, and the development of economic models for commercialization of rare disease therapies. In this review, these historical trends are described and the key developments that have enabled clinical rAAV gene therapies are discussed, along with an overview of the current state of the field and future directions.

Keywords: AAV; adeno-associated virus; clinical trial; gene therapy; genetic disease; genome editing.

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Figures

Figure 1
Figure 1
Adeno-associated virus (AAV) replication scheme. The steps in AAV replication and terminal resolution result in flip and flop configurations of inverted terminal repeats (ITR). The 3′ end of the hairpin configuration of the ITR acts as template for leading strand synthesis. Rep-mediated nicking at the trs allows for terminal resolution. Other abbreviations: trs, terminal resolution site, DNA Pol-DNA Polymerase. Figure adapted from Reference .
Figure 2
Figure 2
The wild-type AAV genome contains three parts: noncoding ITRs and two genes, rep and cap. From both alternative splicing and non-AUG start sites, eight different proteins are produced. Four Rep proteins are produced, two from the p5 promoter (Rep78 and Rep68) and two from the p19 promoter (Rep52 and Rep40). Three capsid and AAPs are produced from the p40 promoter. VP2, VP3, and AAP are produced from the same transcript but from different initiation start sites. Abbreviations: AAP, assembly-activating protein; AAV, adeno-associated virus; ITR, inverted terminal repeat.
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