Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration

Abstract

Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have implicated TH signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we demonstrated that antithyroid drug treatment and targeting iodothyronine deiodinases (DIOs) to suppress cellular tri-iodothyronine (T3) production or increase T3 degradation preserves cones. In this work, we investigated the effectiveness of inhibition of the TH receptor (TR). Two genes, THRA and THRB, encode TRs; THRB2 has been associated with cone viability. Using TR antagonists and Thrb2 deletion, we examined the effects of TR inhibition. Systemic and ocular treatment with the TR antagonists NH-3 and 1-850 increased cone density by 30-40% in the Rpe65 2/2 mouse model of Leber congenital amaurosis and reduced the number of TUNEL + cells. Cone survival was significantly improved in Rpe65 2/2 and Cpfl1 (a model of achromatopsia with Pde6c defect) mice with Thrb2 deletion. Ventral cone density in Cpfl1/Thrb2 2/2 and Rpe65 2/2 /Thrb2 2/2 mice was increased by 1-to 4-fold, compared with age-matched controls. Moreover, the expression levels of TR were significantly higher in the conedegeneration retinas, suggesting locally elevated TR signaling. This work shows that the effects of antithyroid treatment or targeting DIOs were likely mediated by TRs and that suppressing TR protects cones. Our findings support the view that inhibition of TR locally in the retina is a therapeutic strategy for retinal degeneration

Deficiency of type 2 iodo‐ thyronine deiodinase reduces necroptosis activity and oxidative stress responses in retinas of Leber congenital amaurosis model mice

“…The finding that suppressing TH signaling protects cones in mice with normal serum TH levels suggests that there is locally elevated TH signaling in degenerating cones/retinas, the degenerating cones become more sensitive to TH, or both. We have previously shown that the expression levels of TR and Dio2 were increased in Rpe65-deficient mice (10,32). The present work showed elevated expression of the TR target genes Pdk4 and Pck2 in Rpe65 2/2 /Nrl 2/2 mice and reversal of those elevations by Dio2 heterozygous deficiency or after antithyroid treatment, supporting elevated TR transcriptional activity.…”

“…In the retina, TH regulates retinal development and cone opsin expression (26)(27)(28) and is associated with cone photoreceptor viability (10,(29)(30)(31)(32). Using cone degeneration mouse models, including the LCA model, Rpe65 2/2 and Rpe65 deficiency on a cone-dominant background (Rpe65 2/2 /Nrl 2/2 ) mice, we have shown that suppression of TH signaling with antithyroid drug treatment (31) or by targeting the intracellular TH components iodothyronine deiodinases (10) and thyroid hormone receptor (TR) (32) protects cones. In contrast with those findings, stimulation of TH signaling via triiodothyronine (T3) treatment or inhibition of T3 degradation was shown to cause cone death (30,31).…”

Deficiency of thyroid hormone receptor protects retinal pigment epithelium and photoreceptors from cell death in a mouse model of age-related macular degeneration

“…2), and the functional role of these receptor subtypes [38,41]. Because THRB2 is expressed only in the cones in the retina [29,32,33], and Thrb2 deletion has been documented in cone protection against T3-induced cell death [10] and in mouse models of LCA and achromatopsia [16], we also included Thrb2 −/− mice in this study to learn more about Thrb2 deletion-associated protection in an NaIO 3 -induced mouse model of AMD. Deletion of Thrb2 protected RPE and cones, similar to that in mice with Thrb deletion.…”

“…TH signaling has also been linked to cone viability/cone degeneration. Stimulating TH signaling induces cone death [10,11], whereas suppressing TH signaling improves cone survival in mouse models of Leber's congenital amaurosis (LCA) and achromatopsia [11,12,15,16]. Of note, TH signaling has been implicated in the pathogenesis of AMD.…”

“…However, THRB2 is expressed only in cones in the retina [29,32,33]. THRB2 has been shown to mediate the regulation of TH in cone opsin expression [13,14,34] and cone viability [10,16]. We examined the NaIO 3 -induced cell damage/death of the RPE and photoreceptors in Thrα1 −/− , Thrb −/− (resulting in deletion of both Thrb1 and Thrb2), Thrb2 −/− , and wild-type (C57BL/6 J) mice.…”