Gene and Cell Therapy for Inherited Retinal Dystrophies


Gene therapy and cell therapy are intersecting fields of biomedical research with the common aim of repairing the direct causes or consequences of genetic diseases by using genes and cells, respectively. Gene therapy is broadly defined as a set of strategies that modify the expression of an individual's genes for therapeutic benefit. It requires the administration of a specific deoxyribonucleic acid (DNA) (or ribonucleic acid (RNA)) into the patient's cells. Cell therapy on the other hand requires administration of a population of intact live cells to a patient whose cells have been lost due to injury or disease. These emerging strategies can also be applied in acquired diseases in order to re‐establish equilibrium and halt disease progression. In some cases, gene and cell therapy may be combined in order to obtain a therapeutic effect.

In addition to becoming emerging therapeutics in the clinic, these two fields of research continually generate tools, concepts and techniques for elucidating biological questions across multiple disciplines.

Key Concepts

  • The retina lines the back of the eye and comprises six different types of neuronal cells and their underlying retinal pigment epithelium (RPE).
  • Photoreceptors are the light‐sensitive first‐order neurons of the retina which capture the light stimulus and transform it into an electric signal.
  • Human iPSC have the same features of hESC in terms of their differentiation capacity.
  • Gene therapy is the use of genetic material as a drug to treat a chronic condition.

Keywords: cell therapy; gene therapy; human‐induced pluripotent stem cell; human embryonic stem cell; stem‐cell derived RPE; stem cell‐derived retinal progenitor; photoreceptor; viral vectors; genetics; retina

Figure 1. (a) Illustration of intraocular administration routes with respect to the retina. (b) Retinal structure and cell types in a normal retina. (c) Retinal degeneration and intervention by gene and cell therapy. (d) Gene replacement therapy into rod photoreceptors (PRs) is represented at a single cell level on the left and cell therapy (PR transplantation) after the loss of PRs is represented on the right.
Figure 2. (a) Gene replacement therapy in X‐linked retinoschisis (XLRS): An engineered AAV vector is used to deliver a healthy copy of the retinoschisis gene into rods (upper panel). AAV‐mediated gene replacement leads to long‐term rescue of retinal structure and function in the mouse model of XLRS (lower panel). Adapted from Dalkara et al., Sci Trans Med., 2013. © AAAS. (b) Effect of RdCVF on cone outer segment length in retinitis pigmentosa: An engineered AAV vector is used to deliver the gene encoding RdCVF broadly across retinal cells (MGCs, Cones, RPE…) (upper panel). AAV‐mediated RdCVF secretion leads to preservation of the cone outer segments and cone function in the rd10 model of retinitis pigmentosa. Adapted from Byrne et al. 2015 © American Society for Clinical Investigation. (c) Optogenetics activation of ON‐bipolar cells in retinitis pigmentosa: An engineered AAV vector is used to restore light responses in the rd1 mouse model of retinitis pigmentosa after complete PR degeneration (upper panel). Selective expression of Channelrhodopsin in the ON‐bipolar cells leads to restoration of ON and OFF responses in the retina and brain of treated mice (lower panel). Adapted with permission from Macé et al. 2015 © Nature Publishing Group.
Figure 3. Schematics of human‐induced pluripotent stem cells and its applications. Human iPSC can be generated from somatic cells by cell reprogramming, expanded in culture and differentiated into the desired cell type. The resulting cells can be used for transplantation, disease modelling and/or drug screening.
Figure 4. Schematic representation of structural changes during eye development and transcriptional regulation during PR differentiation. (a) The first morphological sign of the eye primordium occurs in the anterior region of the neural plate and is known as the eye field territory. Eye field acquisition is under the control of specific gradients of morphogens and growth factors. (b) Development expands the eye field to form the OV, where the presumptive neural retina (NR) comes in contact with the lens placode (LP). (c) Contact with the LP promotes the invagination of the OV to give rise to the optic cup (OC). At this stage, specific morphogens and growth factors allow the specification of the future RPE and the future NR respectively, the developing bilayered OC. (d) Retinal progenitors from the NR will be specified in different lineages along the retina such as PRs. BMP, bone morphogenetic protein; FGF, fibroblast growth factor; IGF, insulin‐like growth factor; SHH, Sonic Hedgehog; TGF b, transforming growth factor b. (e) Schematics of the transcription factors associated with each major stage of retinogenesis.


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Further Reading

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Trapani I, Banfi S, Simonelli F, et al (2015) Gene therapy of inherited retinal degenerations: prospects and challenges. Human Gene Therapy 26: 193–200. DOI: 10.1089/hum.2015.030.

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Garita‐Hernandez, Marcela, Goureau, Olivier, and Dalkara, Deniz(Aug 2016) Gene and Cell Therapy for Inherited Retinal Dystrophies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026565]