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., . © 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. © 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. © 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.


Assawachananont J, Mandai M, Okamoto S, et al (2014) Transplantation of embryonic and induced pluripotent stem cell‐derived 3D retinal sheets into retinal degenerative mice. Stem Cell Reports 2: 662–674. DOI: 10.1016/j.stemcr.2014.03.011.

Bainbridge JWB, Smith AJ, Barker SS, et al (2008) Effect of gene therapy on visual function in Leber's congenital amaurosis. New England Journal of Medicine 358: 2231–2239. DOI: 10.1056/NEJMoa0802268.

Bainbridge JWB, Mehat MS, Sundaram V, et al (2015) Long‐term effect of gene therapy on Leber's Congenital Amaurosis. New England Journal of Medicine 150504083137004. DOI: 10.1056/NEJMoa1414221.

Banin E, Obolensky A, Idelson M, et al (2006) Retinal incorporation and differentiation of neural precursors derived from human embryonic stem cells. Stem Cells 24: 246–257. DOI: 10.1634/stemcells.2005-0009.

Bennett J, Ashtari M, Wellman J, et al (2012) AAV2 gene therapy readministration in three adults with congenital blindness. Science Translational Medicine 4: 120ra15.

Boye SE, Boye SL, Lewin AS and Hauswirth WW (2013) A comprehensive review of retinal gene therapy. Molecular Therapy 21: 509–519. DOI: 10.1038/mt.2012.280.

Busskamp V and Roska B (2011) Optogenetic approaches to restoring visual function in retinitis pigmentosa. Current Opinion in Neurobiology 21: 942–946. DOI: 10.1016/j.conb.2011.06.001.

Byrne LC, Dalkara D, Luna G, et al (2015) Viral‐mediated RdCVF and RdCVFL expression protects cone and rod photoreceptors in retinal degeneration. Journal of Clinical Investigation 125: 105–116. DOI: 10.1172/JCI65654.

Cideciyan AV, Aleman TS, Boye SL, et al (2008) Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proceedings of the National Academy of Sciences of the United States of America 105: 15112–15117. DOI: 10.1073/pnas.0807027105.

Cideciyan AV, Jacobson SG, Beltran WA, et al (2013) Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proceedings of the National Academy of Sciences of the United States of America 110: E517–E525. DOI: 10.1073/pnas.1218933110.

Dalkara D, Kolstad KD, Guerin KI, et al (2011) AAV mediated GDNF secretion from retinal glia slows down retinal degeneration in a rat model of retinitis pigmentosa. Molecular Therapy 19: 1602–1608. DOI: 10.1038/mt.2011.62.

Dalkara D, Byrne LLC, Klimczak RR, et al (2013) In vivo‐directed evolution of a new adeno‐associated virus for therapeutic outer retinal gene delivery from the vitreous. Science Translational Medicine 5: 189ra76. DOI: 10.1126/scitranslmed.3005708.

Dalkara D and Sahel J‐A (2014) Gene therapy for inherited retinal degenerations. Comptes Rendus Biologies 337 (3): 185–192. DOI: 10.1016/j.crvi.2014.01.002.

Dalkara D, Goureau O, Marazova K and Sahel J‐A (2016) Let there be light: gene and cell therapy for blindness. Human Gene Therapy 27: 134–147. DOI: 10.1089/hum.2015.147.

Decembrini S, Koch U, Radtke F, et al (2014) Derivation of traceable and transplantable photoreceptors from mouse embryonic stem cells. Stem Cell Reports 2: 853–865. DOI: 10.1016/j.stemcr.2014.04.010.

Eberle D, Schubert S, Postel K, et al (2011) Increased integration of transplanted CD73‐positive photoreceptor precursors into adult mouse retina. Investigative Ophthalmology and Visual Science 52: 6462–6471. DOI: 10.1167/iovs.11-7399.

Eiraku M, Takata N, Ishibashi H, et al (2011) Self‐organizing optic‐cup morphogenesis in three‐dimensional culture. Nature 472: 51–56. DOI: 10.1038/nature09941.

Farrar GJ, Millington‐Ward S, Chadderton N, et al (2012) Gene‐based therapies for dominantly inherited retinopathies. Gene Therapy 19: 137–144. DOI: 10.1038/gt.2011.172.

Gagliardi G and Goureau O (2016) Replacing degenerated photoreceptors in macular degeneration and retinitis pigmentosa. Stem cells and Eye Disease. World Scientific Publishing Co. In press.

Garita‐Hernández M, Diaz‐Corrales F, Lukovic D, et al (2013) Hypoxia increases the yield of photoreceptors differentiating from mouse embryonic stem cells and improves the modeling of retinogenesis in vitro. Stem Cells 31: 966–978. DOI: 10.1002/stem.1339.

Gonzalez‐Cordero A, West EL, Pearson RA, et al (2013) Photoreceptor precursors derived from three‐dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina. Nature Biotechnology 31: 741–747. DOI: 10.1038/nbt.2643.

González F, Boué S and Izpisúa Belmonte JC (2011) Methods for making induced pluripotent stem cells: reprogramming à la carte. Nature Reviews. Genetics 12: 231–242. DOI: 10.1038/nrg2937.

Hambright D, Park K‐Y, Brooks M, et al (2012) Long‐term survival and differentiation of retinal neurons derived from human embryonic stem cell lines in un‐immunosuppressed mouse retina. Molecular Vision 18: 920–936.

Harvey AR, Hellström M and Rodger J (2009) Gene therapy and transplantation in the retinofugal pathway. Progress in Brain Research 175: 151–161. DOI: 10.1016/S0079-6123(09)17510-6.

Hastie E and Samulski RJ (2015) AAV at 50: a golden anniversary of discovery, research, and gene therapy success, a personal perspective. Human Gene Therapy 150326045720006. DOI: 10.1089/hum.2015.025.

Hirami Y, Osakada F, Takahashi K, et al (2009) Generation of retinal cells from mouse and human induced pluripotent stem cells. Neuroscience Letters 458: 126–131. DOI: 10.1016/j.neulet.2009.04.035.

Ikeda H (2005) Generation of Rx+/Pax6+ neural retinal precursors from embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America 102: 11331–11336.

Jacobson SG, Cideciyan AV, Ratnakaram R, et al (2012) Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Archives of Ophthalmology 130: 9–24. DOI: 10.1001/archophthalmol.2011.298.

Jacobson SG, Cideciyan AV, Roman AJ, et al (2015) Improvement and decline in vision with gene therapy in childhood blindness. New England Journal of Medicine 150503141523009. DOI: 10.1056/NEJMoa1412965.

Kaewkhaw R, Kaya KD, Brooks M, et al (2015) Transcriptome dynamics of developing photoreceptors in three‐dimensional retina cultures recapitulates temporal sequence of human cone and rod differentiation revealing cell surface markers and gene networks. Stem Cells 33 (12): 3504–3518. DOI: 10.1002/stem.2122.

Khabou H and Dalkara D (2015) Developments in gene delivery vectors for ocular gene therapy. Médecine Sciences: M/S 31: 529–537. DOI: 10.1051/medsci/20153105015.

Koch SF, Tsai Y‐T, Duong JK, et al (2015) Halting progressive neurodegeneration in advanced retinitis pigmentosa. Journal of Clinical Investigation. DOI: 10.1172/JCI82462.

Koso H, Minami C, Tabata Y, et al (2009) CD73, a novel cell surface antigen that characterizes retinal photoreceptor precursor cells. Investigative Ophthalmology and Visual Science 50: 5411–5418. DOI: 10.1167/iovs.08-3246.

Kotterman MA, Yin L, Strazzeri JM, et al (2014) Antibody neutralization poses a barrier to intravitreal adeno‐associated viral vector gene delivery to non‐human primates. Gene Therapy 22 (2): 116–126. DOI: 10.1038/gt.2014.115.

Kuwahara A, Ozone C, Nakano T, et al (2015) Generation of a ciliary margin‐like stem cell niche from self‐organizing human retinal tissue. Nature Communications 6: 1–15. DOI: 10.1038/ncomms7286.

Lakowski J, Gonzalez‐Cordero A, West EL, et al (2015) Transplantation of photoreceptor precursors isolated via a cell surface biomarker panel from embryonic stem cell‐derived self‐forming retina. Stem Cells 33: 2469–2482. DOI: 10.1002/stem.2051.

Lamba DA, Karl MO, Ware CB and Reh TA (2006) Efficient generation of retinal progenitor cells from human embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America 103: 12769–12774. DOI: 10.1073/pnas.0601990103.

Lamba DA, Gust J and Reh TA (2009) Transplantation of human embryonic stem cell‐derived photoreceptors restores some visual function in crx‐deficient mice. Cell Stem Cell 4: 73–79. DOI: 10.1016/j.stem.2008.10.015.

Leach LL and Clegg DO (2015) Concise review: making stem cells retinal: methods for deriving retinal pigment epithelium and implications for patients with ocular disease. Stem Cells 33: 2363–2373. DOI: 10.1002/stem.2010.

Léveillard T and Sahel J‐A (2010) Rod‐derived cone viability factor for treating blinding diseases: from clinic to redox signaling. Science Translational Medicine 2: 26ps16. DOI: 10.1126/scitranslmed.3000866.

Li Q, Miller R, Han P‐Y, et al (2008) Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential. Molecular Vision 14: 1760–1769.

Macé E, Caplette R, Marre O, et al (2015) Targeting channelrhodopsin‐2 to ON‐bipolar cells with vitreally administered AAV Restores ON and OFF visual responses in blind mice. Molecular Therapy 23: 7–16. DOI: 10.1038/mt.2014.154.

MacLaren RE, Pearson RA, MacNeil A, et al (2006) Retinal repair by transplantation of photoreceptor precursors. Nature 444: 203–207. DOI: 10.1038/nature05161.

Maguire AM, Simonelli F, Pierce EA, et al (2008) Safety and efficacy of gene transfer for Leber's congenital amaurosis. New England Journal of Medicine 358: 2240–2248. DOI: 10.1056/NEJMoa0802315.

Maguire AM, High KA, Auricchio A, et al (2009) Age‐dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose‐escalation trial. Lancet 374: 1597–1605. DOI: 10.1016/S0140-6736(09)61836-5.

Mellough CB, Sernagor E, Moreno‐Gimeno I, et al (2012) Efficient stage‐specific differentiation of human pluripotent stem cells toward retinal photoreceptor cells. Stem Cells 30: 673–686. DOI: 10.1002/stem.1037.

Meyer JS, Shearer RL, Capowski EE, et al (2009) Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proceedings of the National Academy of Sciences of the United States of America 106: 16698–16703.

Nakano T, Ando S, Takata N, et al (2012) Self‐formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10: 771–785. DOI: 10.1016/j.stem.2012.05.009.

Ohlemacher SK, Sridhar A, Xiao Y, et al (2016) Stepwise differentiation of retinal ganglion cells from human pluripotent stem cells enables analysis of glaucomatous neurodegeneration. Stem Cells. DOI: 10.1002/stem.2356.

Osakada F, Ikeda H, Mandai M, et al (2008) Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nature Biotechnology 26: 215–224.

Pearson RA, Barber AC, Rizzi M, et al (2012) Restoration of vision after transplantation of photoreceptors. Nature 485: 99–103. DOI: 10.1038/nature10997.

Reichman S, Terray A, Slembrouck A, et al (2014) From confluent human iPS cells to self‐forming neural retina and retinal pigmented epithelium. Proceedings of the National Academy of Sciences of the United States of America 111: 8518–8523. DOI: 10.1073/pnas.1324212111.

Reichman S and Goureau O (2014) Production of Retinal Cells from Confluent Human iPS Cells. Methods Mol Biol. DOI: 10.1007/7651_2014_143.

Rossmiller B, Mao H and Lewin AS (2012) Gene therapy in animal models of autosomal dominant retinitis pigmentosa. Molecular Vision 18: 2479–2496.

Sahel J‐A and Roska B (2013) Gene therapy for blindness. Annual Review of Neuroscience 36: 467–488. DOI: 10.1146/annurev-neuro-062012-170304.

Sander JD and Joung JK (2014) CRISPR‐Cas systems for editing, regulating and targeting genomes. Nature Biotechnology 32: 347–355. DOI: 10.1038/nbt.2842.

Santos‐Ferreira T, Postel K, Stutzki H, et al (2015) Daylight vision repair by cell transplantation. Stem Cells 33: 79–90. DOI: 10.1002/stem.1824.

Strauss O (2005) The retinal pigment epithelium in visual function. Physiological Reviews 85: 845–881. DOI: 10.1152/physrev.00021.2004.

Takahashi K, Tanabe K, Ohnuki M, et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861–872. DOI: 10.1016/j.cell.2007.11.019, S0092‐8674(07)01471‐7 [pii].

Tanaka T, Yokoi T, Tamalu F, et al (2015) Generation of retinal ganglion cells with functional axons from human induced pluripotent stem cells. Scientific Reports 5: 8344. DOI: 10.1038/srep08344.

Trapani I, Puppo A and Auricchio A (2014) Vector platforms for gene therapy of inherited retinopathies. Progress in Retinal and Eye Research 43: 108–128. DOI: 10.1016/j.preteyeres.2014.08.001.

Tucker BA, Park I‐HH, Qi SD, et al (2011) Transplantation of adult mouse iPS cell‐derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS One 6: e18992. DOI: 10.1371/journal.pone.0018992PONE-D-10-03834 [pii].

Vugler A, Carr AJ, Lawrence J, et al (2008) Elucidating the phenomenon of HESC‐derived RPE: anatomy of cell genesis, expansion and retinal transplantation. Experimental Neurology 214: 347–361. DOI: 10.1016/j.expneurol.2008.09.007, S0014‐4886(08)00358‐0 [pii].

Wang X, Xiong K, Lin C, et al (2015) New medium used in the differentiation of human pluripotent stem cells to retinal cells is comparable to fetal human eye tissue. Biomaterials 53: 40–49. DOI: 10.1016/j.biomaterials.2015.02.065.

Wright AF, Chakarova CF, Abd El‐Aziz MM and Bhattacharya SS (2010) Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nature Reviews. Genetics 11: 273–284. DOI: 10.1038/nrg2717.

Zhong X, Gutierrez C, Xue T, et al (2014) Generation of three‐dimensional retinal tissue with functional photoreceptors from human iPSCs. Nature Communications 5: 4047. DOI: 10.1038/ncomms5047.

Further Reading

Baehr W and Frederick J (2006) Inherited Retinal Diseases: Vertebrate Animal Models (In: eLS). Chichester: John Wiley & Sons, Ltd. DOI: 10.1038/npg.els.0004066.

Francis PJ (2010) Genetics of Retinal Disease (In: eLS). Chichester: John Wiley & Sons, Ltd. DOI: 10.1002/9780470015902.a0023109.

Giacalone JC, Wiley LA, Burnight ER, et al (2016) Concise review: patient‐specific stem cells to interrogate inherited eye disease. Stem Cells Translational Medicines 5: 132–140. DOI: 10.5966/sctm.2015-0206.

Hiler D, Chen X, Hazen J, et al (2015) Quantification of retinogenesis in 3D cultures reveals epigenetic memory and higher efficiency in iPSCs derived from rod photoreceptors. Cell Stem Cell 17: 101–115. DOI: 10.1016/j.stem.2015.05.015.

Kostic C and Arsenijevic Y (2016) Animal modelling for inherited central vision loss. Journal of Pathology 238: 300–310. DOI: 10.1002/path.4641.

Lachke SA, Zhang X and Maas RL (2010) Photoreceptor Cell Development Regulation (In: eLS). Chichester: John Wiley & Sons, Ltd. DOI: 10.1002/9780470015902.a0000833.pub2.

Nazari H, Zhang L, Zhu D, et al (2015) Stem cell based therapies for age‐related macular degeneration: the promises and the challenges. Progress in Retinal and Eye Research 48: 1–39. DOI: 10.1016/j.preteyeres.2015.06.004.

Oshimura M, Kazuki Y, Iida Y and Uno N (2013) New Vectors for Gene Delivery: Human and Mouse Artificial Chromosomes (In: eLS). Chichester: John Wiley & Sons, Ltd. DOI: 10.1002/9780470015902.a0024474.

Philpott NJ (2007) Viral Vectors for Gene Therapy (In: eLS). Chichester: John Wiley & Sons, Ltd. DOI: 10.1002/9780470015902.a0020707.

Roosing S, Thiadens AAHJ, Hoyng CB, et al (2014) Causes and consequences of inherited cone disorders. Progress in Retinal and Eye Research 42: 1–26. DOI: 10.1016/j.preteyeres.2014.05.001.

Tomita H (2015) Channelrhodopsin: Potential Applications in Vision Restoration (In: eLS). Chichester: John Wiley & Sons, Ltd. DOI: 10.1002/9780470015902.a0021388.pub2.

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]