title: Rescue of the MERTK phagocytic defect in a human iPSC disease model using translational read-through inducing drugs.
abstract: Inherited retinal dystrophies are an important cause of blindness, for which currently there are no effective treatments. In order to study this heterogeneous group of diseases, adequate disease models are required in order to better understand pathology and to test potential therapies. Induced pluripotent stem cells offer a new way to recapitulate patient specific diseases in vitro, providing an almost limitless amount of material to study. We used fibroblast-derived induced pluripotent stem cells to generate retinal pigment epithelium (RPE) from an individual suffering from retinitis pigmentosa associated with biallelic variants in MERTK. MERTK has an essential role in phagocytosis, one of the major functions of the RPE. The MERTK deficiency in this individual results from a nonsense variant and so the MERTK-RPE cells were subsequently treated with two translational readthrough inducing drugs (G418 & PTC124) to investigate potential restoration of expression of the affected gene and production of a full-length protein. The data show that PTC124 was able to reinstate phagocytosis of labeled photoreceptor outer segments at a reduced, but significant level. These findings represent a confirmation of the usefulness of iPSC derived disease specific models in investigating the pathogenesis and screening potential treatments for these rare blinding disorders.
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.|NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1V 2PD, UK.|Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London, EC1V 2PD, UK.
authors.forename: Conor M
authors.identifier: 0000-0002-4320-2994
authors.initials: CM
authors.lastname: Ramsden
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Britta
authors.initials: B
authors.lastname: Nommiste
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Amelia
authors.initials: A
authors.lastname: R Lane
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Amanda-Jayne F
authors.identifier: 0000-0002-5469-0030
authors.initials: AF
authors.lastname: Carr
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.|Division of Optometry and Visual Sciences, City University London, Northampton Square, London, EC1V 0HB, UK.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Powner
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: J K Smart
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Li Li
authors.initials: LL
authors.lastname: Chen
authors.affiliation: NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1V 2PD, UK.|Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London, EC1V 2PD, UK.
authors.forename: Manickam N
authors.initials: MN
authors.lastname: Muthiah
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.|NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1V 2PD, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.|NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1V 2PD, UK.|UCSF School of Medicine, Koret Vision Center, 10 Koret Way, San Francisco, CA 94143, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.|NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1V 2PD, UK.|Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London, EC1V 2PD, UK.
authors.forename: Lyndon
authors.initials: L
authors.lastname: da Cruz
authors.affiliation: Department of Ocular Biology and Therapeutics (ORBIT), Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK. p.coffey@ucl.ac.uk.|NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1V 2PD, UK. p.coffey@ucl.ac.uk.|Center for Stem Cell Biology and Engineering, NRI, UC Santa Barbara, USA. p.coffey@ucl.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Coffey
mesh_terms: D000328:Adult; D005839:Gentamicins / Q000494:pharmacology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology*; D010441:Peptide Chain Elongation, Translational; D010587:Phagocytosis; D010786:Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000628:therapy*; D000076202:c-Mer Tyrosine Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D005839:Gentamicins; D010069:Oxadiazoles; C010680:antibiotic G 418; D000076202:c-Mer Tyrosine Kinase; C515878:ataluren