Suppressing Thyroid Hormone Signaling Preserves Cone Photoreceptors in Mouse Models of Retinal Degeneration

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This abstract was presented today at the 2014 Association for Research in Vision and Opthalmology (ARVO) meetings in Orlando, Florida by Xi-Qin Ding, Hongwei Ma, Arjun Thapa, Lynsie Morris, T M. Redmond and Wolfgang Baehr.

Full size poster available here.

Purpose: Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling which regulates cell proliferation, differentiation, and apoptosis plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models.

Methods: Rpe65-/- mice (a model of severe Leber congenital amaurosis or LCA) and Cpfl1mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling (with anti-thyroid treatment) reduces cone death. Further, Cngb3-/- mice (moderate achromatopsia) and Gucy2e-/- mice (moderate LCA) were used to determine whether stimulating TH signaling (with triiodothyronine (T3) treatment) deteriorates cones. The serum T3 levels were analyzed by ELISA. Cone and rod survival were evaluated by examining cone density and expression levels of cone specific proteins using immunohistochemical and biochemical approaches, and by examining morphological integrity of the retinas.

Results: Cone density increased about 6-fold in Rpe65-/- and cpfl1 mice following anti-thyroid treatment and decreased about 40% inCngb3-/- and Gucy2e-/- mice following T3 treatment. Anti-thyroid treatment did not affect rod survival, manifested as unchanged outer nuclear layer (ONL) thickness and the number of nuclei in ONL. However, T3 treatment significantly reduced ONL thickness and the number of nuclei in ONL in Cngb3-/- andGucy2e-/- mice.
Conclusions: With multiple retinal degeneration mouse models, we demonstrate that TH signaling regulates photoreceptor viability in degenerating retinas. Suppressing TH signaling protects cones whereas stimulating TH signaling has a negative effect on both cones and rods. The findings of this study provide new insights into cone preservation and therapeutic interventions.

Seminar: Genetics of Inherited Retinal Degenerations: Genetic Diagnostic Testing and Novel Disease Gene Discovery

 

Eric Pierce from the Massachusetts Eye and Ear Infirmary and Harvard Medical School Department of Ophthalmology will be delivering a talk on Genetics of Inherited Retinal Degenerations: Genetic Diagnostic Testing and Novel Disease Gene Discovery Monday, December 10th at 12:00pm in the John A. Moran Eye Center Auditorium.

Abstract:

Inherited retinal degenerations (IRDs) are important causes of vision loss. Over 200 different genetics types of IRDs have been identified to date. Despite the notable progress made in identifying the genetic causes for IRDs, the specific genetic cause remains elusive in half of IRD patients. Identifying the genetic cause of patients’ IRD has become especially important with the recent success of clinical trials of gene therapy for RPE65 Leber’s congenital amaurosis (LCA). We are using a two-tiered next- generation sequencing (NGS) approach for disease gene identification. In the first tier, we use selective exon capture and NGS for all known IRD disease genes perform diagnostic genetic testing. Using this approach, we identified disease-causing mutations in 54 of 117 (46%) families tested to date. In tier 2, we are using whole exome sequencing to search for new IRD disease genes in patients and families who do not have mutations in known IRD disease genes. This approach has already been fruitful, and lead to the identification of NMNAT1 as a novel LCA disease gene. Our exome sequencing studies have also shown that sequencing does not provide a genetic solution for many of families that we have analyzed to date, indicating that improved approaches are needed to identify novel disease genes in patients with IRDs.