Abstract
Leber congenital amaurosis (LCA) is a devastating pediatric retinal degenerative disease, accounting for 20% of blindness in children attending schools for the blind. Mutations in the RPE65 gene, which encodes the retinal pigment epithelium-specific isomerohydrolase RPE65, account for 16% of all LCA cases. Recent findings have linked cone photoreceptor viability to thyroid hormone (TH) signaling. TH signaling regulates cell proliferation, differentiation, and metabolism. At the cellular level, TH action is regulated by the two iodothyronine deiodinases, DIO2 and DIO3. DIO2 converts the prohormone thyroxine (T4) to the bioactive hormone triiodothyronine (T3), and DIO3 inactivates T3 and T4. The present work investigates the effects of overexpression of DIO3 to suppress TH signaling and thereby modulate cone death/survival. Subretinal delivery of AAV5-IRBP/GNAT2-hDIO3 induced robust expression of DIO3 in the mouse retina and significantly reduced the number of TUNEL-positive cells in the cone-dominant LCA model Rpe65 −/− /Nrl −/− mice. Our work shows that suppressing TH signaling by overexpression of DIO3 preserves cones, supporting that suppressing TH signaling locally in the retina may represent a treatment strategy for LCA management.
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Acknowledgments
We thank Dr. T. Michael Redmond (NEI/NIH) for the Rpe65 −/− mouse line and Dr. Anand Swaroop (NEI/NIH) for the Nrl −/− mouse line. We thank Dr. P. Reed Larsen (the Brigham and Women’s Hospital) for human DIO3 cDNA. We thank the Imaging Core Facility of the Department of Cell Biology at OUHSC for technical assistance.
This work was supported by grants from the National Eye Institute (P30EY021725, P30EY021721, R01EY019490, and R21EY024583); the Research to Prevent Blindness for an unrestricted grant to the University of Florida, Department of Ophthalmology; the Foundation Fighting Blindness; and the Knights Templar Eye Foundation.
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Yang, F., Ma, H., Boye, S.L., Hauswirth, W.W., Ding, XQ. (2018). Overexpression of Type 3 Iodothyronine Deiodinase Reduces Cone Death in the Leber Congenital Amaurosis Model Mice. In: Ash, J., Anderson, R., LaVail, M., Bowes Rickman, C., Hollyfield, J., Grimm, C. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 1074. Springer, Cham. https://doi.org/10.1007/978-3-319-75402-4_16
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DOI: https://doi.org/10.1007/978-3-319-75402-4_16
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