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      Transplantation of Photoreceptor and Total Neural Retina Preserves Cone Function in P23H Rhodopsin Transgenic Rat

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          Abstract

          Background

          Transplantation as a therapeutic strategy for inherited retinal degeneration has been historically viewed to restore vision as a method by replacing the lost retinal cells and attempting to reconstruct the neural circuitry with stem cells, progenitor cells and mature neural retinal cells.

          Methods and Findings

          We present evidence for an alternative strategy aimed at preventing the secondary loss of cones, the most crucial photoreceptors for vision, by transplanting normal photoreceptors cells into the eye of the P23H rat, a model of dominant retinitis pigmentosa. We carried out transplantation of photoreceptors or total neural retina in 3-month-old P23H rats and evaluated the function and cell counts 6 months after surgery. In both groups, cone loss was significantly reduced (10%) in the transplanted eyes where the cone outer segments were found to be considerably longer. This morphological effect correlated with maintenance of the visual function of cones as scored by photopic ERG recording, but more precisely with an increase in the photopic b-wave amplitudes by 100% and 78% for photoreceptor transplantation and whole retinal transplantation respectively.

          Conclusions

          We demonstrate here that the transplanted tissue prevents the loss of cone function, which is further translated into cone survival.

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          Most cited references36

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          Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice.

          Deepak Lamba, Juliane Gust, Thomas Reh (2009)
          Some of the most common causes of blindness involve the degeneration of photoreceptors in the neural retina; photoreceptor replacement therapy might restore some vision in these individuals. Embryonic stem cells (ESCs) could, in principle, provide a source of photoreceptors to repair the retina. We have previously shown that retinal progenitors can be efficiently derived from human ESCs. We now show that retinal cells derived from human ESCs will migrate into mouse retinas following intraocular injection, settle into the appropriate layers, and express markers for differentiated cells, including both rod and cone photoreceptor cells. After transplantation of the cells into the subretinal space of adult Crx(-/-) mice (a model of Leber's Congenital Amaurosis), the hESC-derived retinal cells differentiate into functional photoreceptors and restore light responses to the animals. These results demonstrate that hESCs can, in principle, be used for photoreceptor replacement therapies.
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            Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium.

            T Green, Heywood M. Petry, N Radtke … (2008)
            To demonstrate efficacy and safety of the implantation of neural retinal progenitor cell layers (sheets) with its retinal pigment epithelium (RPE) in retinitis pigmentosa (RP) and dry age-related macular degeneration (AMD) patients with 20/200 or worse vision in the surgery eye. Interventional nonrandomized clinical trial. Ten patients (six RP, four AMD) received retinal implants in one eye and were followed in a phase II trial conducted in a clinical practice setting. Early Treatment Diabetic Retinopathy Study (EDTRS) was the primary outcome measure. All implant recipients and nine of 10 tissue donors were deoxyribonucleic acids typed. Seven patients (three RP, four AMD) showed improved EDTRS visual acuity (VA) scores. Three of these patients (one RP, two AMD) showed improvement in both eyes to the same extent. Vision in one RP patient remained the same, while vision in two RP patients decreased. One RP patient has maintained an improvement in vision from 20/800 to 20/200 ETDRS for more than five years; at the six-year examination, it was still maintained at 20/320 while the nonsurgery eye had deteriorated to hand motion vision. This patient also showed a 22.72% increase in light sensitivity at five years compared to microperimetry results at two years; the other patients showed no improved sensitivity. Although no match was found between donors and recipients, no rejection of the implanted tissue was observed clinically. Seven (70%) of 10 patients showed improved VA. This outcome provides clinical evidence of the safety and beneficial effect of retinal implants and corroborates results in animal models of retinal degeneration.
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              Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa.

              William W. Hauswirth, K A Drenser, S-I Nishikawa … (1998)
              Ribozymes, catalytic RNA molecules that cleave a complementary mRNA sequence, have potential as therapeutics for dominantly inherited disease. Twelve percent of American patients with the blinding disease autosomal dominant retinitis pigmentosa (ADRP) carry a substitution of histidine for proline at codon 23 (P23H) in their rhodopsin gene, resulting in photoreceptor cell death from the synthesis of the abnormal gene product. Ribozymes can discriminate and catalyze the in vitro destruction of P23H mutant mRNAs from a transgenic rat model of ADRP. Here, we demonstrate that in vivo expression of either a hammerhead or hairpin ribozyme in this rat model considerably slows the rate of photoreceptor degeneration for at least three months. Catalytically inactive control ribozymes had less effect on the retinal degeneration. Intracellular production of ribozymes in photoreceptors was achieved by transduction with a recombinant adeno-associated virus (rAAV) incorporating a rod opsin promoter. Ribozyme-directed cleavage of mutant mRNAs, therefore, may be an effective therapy for ADRP and also may be applicable to other inherited diseases.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2010
                Publication date (Electronic): 19 October 2010
                Volume: 5
                Issue: 10
                Electronic Location Identifier: e13469
                Affiliations
                [1 ]INSERM, U968, Paris, France
                [2 ]Université Pierre et Marie Curie-Paris 6, UM80, Institut de la Vision, Paris, France
                [3 ]CNRS, UMR_7210, Paris, France
                [4 ]Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France
                [5 ]Institute of Ophthalmology, University College of London, London, United Kingdom
                [6 ]Fondation Ophtalmologique Adolphe de Rothschild, Paris, France
                University of Washington, United States of America
                Author notes

                Conceived and designed the experiments: YY SMS TL JAS. Performed the experiments: YY SMS MS. Analyzed the data: YY SMS TL JAS. Contributed reagents/materials/analysis tools: VF MS. Wrote the paper: YY SMS.

                Article
                Publisher ID: 10-PONE-RA-16304R2
                DOI: 10.1371/journal.pone.0013469
                PMC ID: 2957406
                PubMed ID: 20976047
                SO-VID: bc942c25-9478-44ad-8e63-b9647f4bdb60
                Copyright © Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 15 February 2010
                Date accepted : 27 July 2010
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Cell Biology
                Subject: Neuroscience/Neuronal Signaling Mechanisms
                Subject: Ophthalmology/Inherited Eye Disorders
                Subject: Ophthalmology/Retinal Disorders

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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