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. 2015 Jun;10(3):281-299.
doi: 10.1586/17469899.2015.1035711. Epub 2015 Apr 10.

Retinal Gene Therapy: Current Progress and Future Prospects

Cristy A Ku  1 , Mark E Pennesi  2
Affiliations

Retinal Gene Therapy: Current Progress and Future Prospects

Cristy A Ku et al. Expert Rev Ophthalmol. 2015 Jun.

Abstract

Clinical trials treating inherited retinal dystrophy caused by RPE65 mutations had put retinal gene therapy at the forefront of gene therapy. Both successes and limitations in these clinical trials have fueled developments in gene vectors, which continue to further advance the field. These novel gene vectors aim to more safely and efficiently transduce retinal cells, expand the gene packaging capacity of AAV, and utilize new strategies to correct the varying mechanisms of dysfunction found with inherited retinal dystrophies. With recent clinical trials and numerous pre-clinical studies utilizing these novel vectors, the future of ocular gene therapy continues to hold vast potential.

Keywords: RPE65; adeno-associated virus; equine infectious anemia virus; gene therapy; inherited retinal dystrophies.

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Conflict of interest statement

Financial and competing interests disclosure

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1
Figure 1
AAV capsid pseudotyping and retinal cell tropism. Production of rAAV involves co-transfection of two plasmids: (1) the transgene cassette with two ITR regions flanking the transgene of choice, and (2) a helper plasmid encoding for the necessary replication (Rep) genes from AAV2 and capsid (Cap) genes from the desired AAV serotype. The retinal cell tropism of each AAV serotype listed below show the most effective retinal cell type transduced in bold. Relative comparisons of transduction efficiency of the RPE and PRs are shown from lowest (*) to highest (***) for particularly effective serotypes [38,42]. Note that information pertaining to transduction efficiencies is representative of murine retina [38,42], but variances between species have been reported [150]. Abbreviations: ITR, inverted terminal repeats; rAAV, recombinant adeno-associated virus; RPE, retinal pigmented epithelium; PR, photoreceptors; GC, ganglion cells; INL, inner nuclear layer. Adapted from [39].
Figure 2
Figure 2
AAV capsid engineering through directed evolution. Directed evolution involves (1) random mutagenesis, recombination, and/or DNA shuffling of AAV capsid genes from all AAV serotypes generate a large AAV capsid library with chimeric AAV capsids. (2) This capsid library is applied to (2a) in vitro or (2b) in vivo selection systems, and (3) AAV capsids that successfully overcome the selection criterion are identified.
Figure 3
Figure 3
Three AAV dual vector types. (1) Overlapping vectors have a homologous overlapping region between the two halves of the transgene of choice, which undergo homologous recombination for reconstitution of a full-length transcript of the transgene. (2) Trans-splicing vectors undergo splicing through their splice donor (SD) and splice acceptor (SA) sites at the ends of the transgene halves. (3) Hybrid vectors undergo splicing through the SD and SA sites, as well as recombination through a highly recombinogenic site from a exogenous gene, such as alkaline phosphatase (AP). Dashed lines show homologous recombination, dotted lines show splicing between SD and SA sites. Abbreviations: pA, polyadenylation tail; SD, splice donor; SA, splice acceptor; AP, alkaline phosphatase. Adapted from [76].
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References

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    1. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2231–2239. *Seminal Phase I/IIa RPE65-LCA study from University College, London with initial patient cohort results.

    1. Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19(10):979–990. *Seminal Phase I RPE65-LCA study from University of Pennsylvania, Scheie Eye Institute with initial patient cohort results.

    1. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2240–2248. *Seminal Phase I RPE65-LCA study from University of Pennsylvania, Children’s Hospital of Philadelphia with initial patient cohort results.

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Websites

    1. ClinicalTrials.gov Home Page. [Accessed 07 March 2015];U.S. National Institutes of Health. https://ClinicalTrials.gov.
    1. AGTC. [Accessed 08 March 2015]; http://www.agtc.com/products/achromatopsia.
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