Severe ocular hypotony [too low intraocular pressure (IOP)] can lead to blindness via Phthisis bulbi (shrunken, non-functional eyes). Currently, there are no effective treatments for hypotony. We recently showed that pharmacologic or genetic inhibition of bicarbonate-regulated soluble adenylyl cyclase (sAC) elevates IOP in wild type mice as well as in a mouse model of ocular hypotony. We have identified inhibitors of sAC in a small molecule screen, and we propose to develop these sAC inhibitors into first-in-class therapeutics for treatment of ocular hypotony. Our small molecule screen also identified the first known pharmacological tools for increasing sAC activity, and we propose to test whether they define lead compounds for a new therapeutic strategy for lowering IOP to treat glaucoma.
The fluid inside the eye must be maintained at a consistent pressure; pressure that is too high is a fundamental characteristic of glaucoma, while pressure that is too low is called hypotony. If uncorrected, both conditions will cause blindness. Although hypotony is rare, there is no known treatment for it. We have identified a previously unappreciated regulator of pressure in the eye, and we have shown that inhibiting this regulator elevated pressure in a mouse with hypotony. In this grant application, we propose to develop inhibitors of this regulator into first-in-class therapeutics to treat hypotony and test whether activators can treat glaucoma.
|Kleinboelting, Silke; Ramos-Espiritu, Lavoisier; Buck, Hannes et al. (2016) Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site. J Biol Chem 291:9776-84|
|Ramos-Espiritu, Lavoisier; Kleinboelting, Silke; Navarrete, Felipe A et al. (2016) Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase. Nat Chem Biol 12:838-44|