Gene Therapy and Surgery for Retinal Diseases


The past several decades have shown major advancements in both gene augmentation and gene surgery techniques, many of which are applicable to treating human retinal diseases. New vectors, such as dual and triple AAVs, have allowed the safe and accurate delivery of genes into both the intravitreal and subretinal space. The advent of CRISPR/Cas9, which advanced the field of gene editing upon its discovery, and introduction of stem cell therapy to the scientific community have created opportunities to accurately and safely treat autosomal dominant diseases. Already uniquely immune privileged and easily accessible, the eye is now a more promising target than ever with advances in imaging and surgical technologies. Recent clinical trials have demonstrated both safety and efficacy of viral vector administration, and treatments are beginning to make their way into commercial medicine.

Key Concepts

  • The eye is suitable for gene therapy because it is immunologically privileged and easily accessed and observed.
  • AAV vectors are predominantly used to deliver gene packages because of their low immunogenicity, and the development of dual and triple AAV vectors can overcome their size limitation.
  • CRISPR/Cas9 is a simple and effective way to edit genes in vivo, and the development of high fidelity variants and nickase enzymes have greatly increased its safety and precision.
  • Stem cell therapy with induced pluripotent stem cells are a promising alternative to traditional in vivo gene therapy and editing.
  • Gene therapeutic agents can be administered to the eye via subretinal or intravitreal injection, the former of which is more invasive and the latter more immunogenic and less precise.
  • Multiple clinical trials for specific inherited retinal dystrophies are currently being conducted within the US.

Keywords: gene therapy; CRISPR/Cas9; dual AAV; triple AAV; clinical trials; ophthalmology; retina; inherited retinal diseases

Figure 1. For gene packages greater than 4.7 kb in size, the package may be split and stored in separate AAV vectors. When a cell is co‐infected by the two vectors, the split gene packages concatemerise.
Figure 2. After an endonuclease induces a double‐stranded break, the target site can be repaired via two pathways. Nonhomologous end joining (NHEJ) is an error‐prone process that simply ligates the two ends. Homology‐directed repair (HDR) is a more precise process that repairs the break with an exogenous template which is homologous upstream and downstream of the target site.
Figure 3. Therapeutic agents can be delivered to the eye either intravitreally or subretinally. Intravitreal injections, in which the agent is delivered into the vitreous cavity, are more common, simpler to perform and less invasive, but they are also less precise, hold a greater risk for immunological responses and are inefficient at transducing RPE and PR cells. Subretinal injections target the space between the RPE and PR cells.


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Further Reading

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Jiang, David J, Xu, Christine L, and Tsang, Stephen H(Dec 2018) Gene Therapy and Surgery for Retinal Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027221]