The present disclosure relates generally to treating diseases and disorders resulting from defects in cilia formation, cilia maintenance and cilia function. More particularly, the present disclosure relates to methods for reducing eye pressure, methods for treating ciliopathies and methods for treating glaucoma by administering transient receptor potential cation channel subfamily V member 4 (TRVP4) agonists.
The primary cilium is an evolutionarily conserved subcellular structure that protrudes from many post-mitotic eukaryotic cells. In response to changes in the extracellular environment, primary cilia coordinate signaling cascades that control cell differentiation, growth and function. A highly specialized extension of the plasma membrane, the ciliary membrane is enriched with many signaling proteins, including Transient Receptor Potential (TRP) channels. Upon extracellular stimulation, TRP channels initiate signal transduction cascades by inducing Ca2+ flow. Phosphoinositides within the ciliary membrane are essential secondary messengers for ciliary function, potentially through modulation of the activities of TRP channels.
Transient receptor potential cation channel subfamily V member 4 (TRPV4) is a member of the OSM9-like transient receptor potential channel (OTRPC) subfamily that in humans is encoded by the TRPV4 gene. TRPV4 protein is a Ca2+-permeable, nonselective cation channel that is thought to be involved in the regulation of systemic osmotic pressure. TRPV4 also functions as a ciliary mechanosensory channel. Mutations in the TRPV4 gene have been associated with disorders including brachyolmia type 3, congenital distal spinal muscular atrophy, scapuloperoneal spinal muscular atrophy and subtype 2C of Charcot-Marie-Tooth disease. A number of TRPV4 agonists and antagonists have been identified including, for example, the antagonist Ruthenium Red, the agonist 4aPDD, the selective antagonist RN-1734, the agonist GSK1016790A and the antagonist HC-067047.
Defects in cilia formation or maintenance underlie a wide range of human diseases, including retinitis pigmentosa, renal cysts, polydactyly, and developmental delays, which are collectively called ciliopathies. It has been discovered that OCRL, an inositol polyphosphate 5-phosphatase implicated in Oculocerebrorenal syndrome of Lowe (Lowe syndrome), a rare X-linked recessive disorder that presents in males with bilateral cataracts and glaucoma, as well as renal failure, muscular hypotonia, and mental retardation, regulates cilia biogenesis. OCRL substrates include phosphatidylinositol-4,5-bisphophatase [PI(4,5)P2] and phosphatidylinositol-3,4,5-triphosphate [PI(3,4,5)P3]. Decreased 5-phosphatase activity is demonstrated in fibroblasts from Lowe patients, as well as a two- to threefold elevated ratio of PI(4,5)P2:PI(4)P.
Mechanosensation of pressure underlies a number of important human diseases including the development of hypertension and glaucoma. In the kidney epithelium, ciliary proteins polycystins (PC1/2) have been shown to be important for flow-dependent calcium flux. In the lining of the ventricles of the brain, cerebrospinal fluid is regulated by cilia. Similar to the kidney, the eye is an enclosed organ with sensitive homeostatic regulation of fluid production and egress. Defective sensation of pressure may result in imbalance of aqueous humor, resulting in elevated intraocular pressure. Low levels of eye pressure result in structural changes of the retina and poor vision, while elevated eye pressure may damage the optical nerve. Glaucoma is an optic neuropathy associated with elevated intraocular pressure and is a leading cause of irreversible blindness in the world.
Trabecular meshwork cells are responsible for the drainage of the majority of aqueous fluid. Dysfunction of the trabecular outflow leads to elevated intraocular pressure, which in susceptible individuals, results in the death of retinal ganglion cells that leads to irreversible vision loss. However, the molecular events whereby elevated pressure results in aberrant mechanosensory signaling that lead to visual loss are poorly understood. As disclosed herein, trabecular meshwork cells of the eye have primary cilia that are responsive to pressure changes.
Consistent with the central role of increased pressure in the pathology of glaucoma, the only proven treatment is lowering of pressure. Five classes of medications are available for treating glaucoma, which include beta blockers, alpha adrenergic agonists, carbonic anhydrase inhibitors, cholinergic agonists and prostaglandin analogs. Many patients become intolerant of the side effects of these medications. It is also recognized that these medications cease to lower pressure after a number of years. As patients become intolerant of medications and as the medications lose their effectiveness, surgical intervention is required to lower pressure.
Accordingly, there exists a need to develop alternative treatments for lowering eye pressure.