title: Functional rescue of REP1 following treatment with PTC124 and novel derivative PTC-414 in human choroideremia fibroblasts and the nonsense-mediated zebrafish model.
abstract: Choroideremia (CHM) is an X-linked chorioretinal dystrophy that is caused by mutations within a single gene, CHM Currently no effective treatment exists for these patients. Since over 30% of patients harbour nonsense mutations in CHM, nonsense suppression therapy using translational readthrough inducing drugs may provide functional rescue of REP1, thus attenuating progressive sight loss. Here, we employed two CHM model systems to systematically test the efficacy and safety of ataluren (PTC124) and its novel analog PTC-414: (1) the chmru848zebrafish, the only nonsense mutation animal model of CHM harbouring a TAA nonsense mutation, and (2) a primary human fibroblast cell line from a CHM patient harbouring a TAG nonsense mutation. PTC124 or PTC-414 treatment of chmru848embryos led to a ∼2.0-fold increase in survival, prevented the onset of retinal degeneration with reduced oxidative stress and apoptosis, increased rep1 protein by 23.1% (PTC124) and 17.2% (PTC-414) and restored biochemical function as confirmed through in vitro prenylation assays (98 ± 2% [PTC124] and 68 ± 5% [PTC-414]). In CHMY42X/yfibroblasts, there was a recovery of prenylation activity following treatment with either PTC124 (42 ± 5%) or PTC-414 (36 ± 11%), although an increase in REP1 protein was not detected in these cells, in contrast to the zebrafish model. This comprehensive study on the use of PTC124 and PTC-414 as successful nonsense suppression agents for the treatment of CHM highlights the translational potential of these drugs for inherited retinal disease.
authors.affiliation: UCL Institute of Ophthalmology, London EC1V 9EL, UK m.moosajee@ucl.ac.uk.|Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK.|Great Ormond Street Hospital, London WC1N 3JH, UK.
authors.forename: Mariya
authors.initials: M
authors.lastname: Moosajee
authors.affiliation: UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Dhani
authors.initials: D
authors.lastname: Tracey-White
authors.affiliation: UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Smart
authors.affiliation: PTC Therapeutic Inc, NJ, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Weetall
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier cedex 5, France.
authors.forename: Simona
authors.initials: S
authors.lastname: Torriano
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, Montpellier cedex 5, France.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Kalatzis
authors.affiliation: UCL Institute of Ophthalmology, London EC1V 9EL, UK.|Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK.
authors.forename: Lyndon
authors.initials: L
authors.lastname: da Cruz
authors.affiliation: UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Coffey
authors.affiliation: UCL Institute of Ophthalmology, London EC1V 9EL, UK.|Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: PTC Therapeutic Inc, NJ, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Welch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015794:Choroideremia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006801:Humans; D010069:Oxadiazoles / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects; D012160:Retina / Q000187:drug effects / Q000473:pathology; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015027:Zebrafish; D029961:Zebrafish Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; D018389:Codon, Nonsense; D010069:Oxadiazoles; D029961:Zebrafish Proteins; C525249:chm protein, zebrafish; C515878:ataluren