Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.
Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65-/-mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.-Yang, F., Ma, H., Belcher, J., Butler, M. R., Redmond, T. M., Boye, S. L., Hauswirth, W. W., Ding, X.-Q. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Fan
F
Yang
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Hongwei
H
Ma
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Joshua
J
Belcher
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Michael R
MR
Butler
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, Bethesda, Maryland, USA.
T Michael
TM
Redmond
Department of Ophthalmology, University of Florida, Gainesville, Florida, USA; and.|Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.
Sanford L
SL
Boye
Department of Ophthalmology, University of Florida, Gainesville, Florida, USA; and.|Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.
William W
WW
Hauswirth
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; xi-qin-ding@ouhsc.edu.
Xi-Qin
XQ
Ding
D000818:Animals; D002478:Cells, Cultured; D007453:Iodide Peroxidase / Q000378:metabolism*; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013963:Thyroid Hormones / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism
D013963:Thyroid Hormones; D014284:Triiodothyronine; D007453:Iodide Peroxidase
cone degeneration; iopanoic acid; photoreceptor; thyroid hormone