Research Article: Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity

Date Published: April 05, 2018

Publisher: Elsevier

Author(s): Christina Zarouchlioti, Beatriz Sanchez-Pintado, Nathaniel J. Hafford Tear, Pontus Klein, Petra Liskova, Kalyan Dulla, Ma’ayan Semo, Anthony A. Vugler, Kirithika Muthusamy, Lubica Dudakova, Hannah J. Levis, Pavlina Skalicka, Pirro Hysi, Michael E. Cheetham, Stephen J. Tuft, Peter Adamson, Alison J. Hardcastle, Alice E. Davidson.


Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (MBNL1 and MBNL2) to the foci and altered mRNA processing. Antisense oligonucleotide (ASO) treatment led to a significant reduction in the incidence of nuclear foci, MBNL1 recruitment to the foci, and downstream aberrant splicing events, suggesting functional rescue. This proof-of-concept study highlights the potential of a targeted ASO therapy to treat the accessible and tractable corneal tissue affected by this repeat expansion-mediated disease.

Partial Text

Fuchs endothelial corneal dystrophy (FECD [MIM: 613267]) is a common, degenerative, age-related condition that usually presents during the fifth to sixth decade. The disease primarily affects the posterior cornea with the hallmark being the formation of focal excrescences of Descemet membrane (DM) termed “guttae.” Isolated guttae are common in the elderly and a case definition for FECD usually requires that the guttae are confluent. When assessed with specular microscopy, the prevalence of guttae is higher in white (11.2% >55 years) than East Asian (5.5% >50 years) populations and higher in females (5.5%–11%) than males (1.5%–7%).1, 2 An estimate of the prevalence of confluent guttae in individuals of white or black ethnicity >50 years with assessment by slit-lamp biomicroscopy reported a figure of 4.5%.3 Confluent guttae can be associated with a loss of corneal endothelial cell density to a critical stage when the remaining endothelium is unable to maintain appropriate stromal dehydration leading to fluid accumulation, painful epithelial bullae, and progressive corneal clouding reducing visual acuity.4, 5, 6 Early-stage disease is typically managed with topical hypertonic saline to reduce symptoms, such as corneal swelling, but surgical intervention is currently the only treatment option available to individuals with advanced disease to restore bilateral vision and prevent blindness.6 Full or partial keratoplasty are invasive procedures that rely upon specialist facilities and the availability of healthy donor material, of which there is a global shortage.7 These issues, coupled with the global aging population, highlight the need for alternative and effective treatment strategies.

ASOs have recently emerged as a powerful therapeutic option for disease intervention, including those caused by trinucleotide repeat expansions.10, 39, 40, 41, 42 Here we show that a non-coding CTG trinucleotide repeat expansion in TCF4 (CTG18.1) confers greater than 76-fold risk for FECD in a large white British and Czech cohort. We demonstrate that primary CECs derived from FECD-affected subjects display the predicted hallmarks of primary and downstream repeat-expansion-associated pathology, and subsequently show that these changes are reversed by an ASO treatment specifically targeted at the CTG18.1 trinucleotide repeat expansion. An ASO-based treatment could therefore offer an innovative therapeutic approach that could benefit a substantial number of individuals affected by this common and sight-threatening condition.43




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