Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension

Abstract

In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow, and even an antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.

A tissue-engineered human trabecular meshwork hydrogel for advanced glaucoma disease modeling

“…Together, these data show that DEX increases f-actin fibers and α-SMA in HTM hydrogels, which is potently rescued by Y27632. This is consistent with the reported reduction of actomyosin contractile tone in HTM tissue following ROCK inhibition [22][23][24][25] . These changes in f-actin and α-SMA could have a direct impact on HTM cell contractility and interactions with their surrounding ECM, as well as HTM tissue stiffness and ultimately AH outflow resistance.…”

“…The contractility status of HTM cells and overall tissue influences AH outflow resistance and [21][22][23][24][25] .…”

“…First line POAG medications do not specifically target the diseased HTM; instead, they lower IOP by either increasing AH outflow bypassing the HTM altogether, or by decreasing AH production 19,20 . In the United States, only the recently approved Rhoassociated kinase (ROCK) inhibitor netarsudil 21 directly aims at the stiffened HTM to increase AH outflow via cell/tissue relaxation [22][23][24][25][26] . However, various adverse events at the ocular surface in some patients have been reported during the drug's brief window of availability [27][28][29] , raising concerns over its routine use.…”

Adipose‐derived stem cells integrate into trabecular meshwork with glaucoma treatment potential

“…Current pharmacological and surgical therapies seek to lower IOP by facilitating aqueous outflow and suppressing aqueous humor production 19 ; recently, two classes of compounds (Rho kinase inhibitors 20‐22 and nitric oxide agonists 23,24 have been developed to specifically target conventional outflow pathway tissues to reduce IOP. However, these strategies fail to directly target TM cellularity loss, hypothesized to be an important factor in the pathophysiology of the IOP elevation.…”

Aktuelle Forschungsbemühungen zur Neuroprotektion, Verlauf und Behandlung eines Glaukoms

“…Der Rho-Kinase-Inhibitor Netarsudil (Rhopressa ® , Aerie Pharmaceuticals), der Ende 2017 in den USA zugelassen wurde [34,35], stellt eine völlig neue Klasse von Glaukommedikamenten dar. Die Möglichkeit, den Kammerwasserausfluss durch Manipulation des Zytoskeletts vom TM und SK mit Rho-Kinase-Inhibitoren zu steigern, bietet einen neuen Mechanismus für die Senkung des IOD im Vergleich zu bestehenden Arzneimitteln [36,37]. Rho-Kinase-Inhibitoren wirken durch die Verringerung des Kontraktionszustands und der Starre der TM-Zellen, indem sie die Mikrotubulidynamik und Aktinfilamentflexibilität verbessern [38,39].…”