Glaucoma is one of the leading causes of irreversible blindness worldwide, affecting over 60 million people. It is usually caused due to raised intraocular pressure (IOP). Although several drug classes which lower IOP are available, they all cause local and systemic side effects, and improved treatments are greatly needed. The group of Prof. Steve Karlish developed new drugs derived from Digoxin, which selectively inhibit Na-K-ATPase, an ion pump that produces the eye fluids. These compounds effectively reduce ocular hypertension in various glaucoma animal models, and as such, offer a potential new therapeutic class for IOP-lowering medications.
Glaucoma is a common eye condition in which the optic nerve that connects the eye to the brain is damaged, usually due to raised IOP. Glaucoma can lead to irreversible blindness if it is not diagnosed and treated early, and it is a leading cause of blindness globally. Over 60 million people worldwide are estimated with glaucoma, 10% of them will lose sight in one eye.1
Since raised IOP has been implicated as the major risk factor, the main goal of all glaucoma therapies is to reduce IOP sufficiently to prevent continuous irreversible retinal cell damage. Currently available drugs, given topically or systemically, include β-blockers, Prostaglandin analogs, α2 adrenergic receptor agonists, Cholinergic agonists, and Carbonic anhydrase inhibitors. However, all the existing medications have local and systemic side effects, from eye burning to breathing difficulties. Moreover, over 50% of the patients require more than one drug, and a substantial portion of the patients are refractory despite maximally tolerated antiglaucoma medications (topical and/or systemic).
The fact that glaucoma remains a leading cause of blindness, despite the availability of 5 different classes of IOP-lowering topical medications, suggests a great need for improved treatment options.
Prof. Steve Karlish and his team developed novel selective inhibitors of the Na-K-ATPase pump, which is critical for the production of eye fluids.2
The Na-K-ATPase consists of α and β subunits. Each subunit has several isoforms, differentially expressed in a tissue-specific fashion. The α2 isoform is the predominant isoform in the epithelium in the eye. The Karlish group has developed topically-applied inhibitors that are selective for the α2 isoform of Na-K-ATPase. These novel α2-selective inhibitors, derivatives of Digoxin and Digitoxin, show an increased selectivity for α2 over α1, up to about 8-fold, making them twice more selective than Digoxin. These novel inhibitors can penetrate the intact eye and effectively reduce IOP with negligible systemic toxicity, as demonstrated in rabbits and monkeys in vivo model systems. Moreover, the derivative DcB produced a 25–30% larger reduction in basal IOP than Latanoprost, the current first-line antiglaucoma drug. Furthermore, DcB/ Latanoprost combination reduced IOP for considerably longer than DcB or Latanoprost alone (Fig. 1). Overall, this technology offers an effective reduction in ocular hypertension, the primary risk factor in glaucoma.
Fig. 1 – The effect of DcB and Latanoprost, separately and combined, on basal IOP in rabbits. RE: (A) DcB, 1mM; (B) Latanoprost, 0.005%; (C) 1 mM DcB + Latanoprost. 0.005%. Left eye (LE): PBS, control. Within each figure, the inserted symbol Δ indicates the absolute difference in IOP (in mmHg) between time IOP t = 0 and the average of IOP between 3 and 8 h ± SEM. The P values refer to the difference between DcB versus Latanoprost (A) or DcB/Latanoprost versus Latanoprost (C). Points represent averages IOP/IOP t = 0 from five rabbits ± SEM.
- A treatment for glaucoma and other ocular hypertension-associated diseases
- α2-selective inhibitors with negligible systemic toxicity compared to Digoxin
- DcB reduces IOP to a greater extent and for a longer time as compared to common antiglaucoma drugs
- Can be used as a monotherapy or in combination with existing antiglaucoma drugs
- The new agents can be synthesized in a simple process
The Karlish lab synthesized new Digoxin derivates with improved selectivity to the α2 isoform of the Na-K-ATPase. They characterized the Ki values for inhibition of different isoforms of the Na,K-ATPase activity by all derivates in vitro. The toxicity and efficacy of the optimal derivate were assessed in two in vivo models: normotensive rabbits and spontaneous ocular hypertensive monkeys.
1. Allison K, Patel D, Alabi O. Epidemiology of Glaucoma: The Past, Present, and Predictions for the Future. Cureus. Published online November 24, 2020. doi:10.7759/cureus.11686
2. Katz A, Tal DM, Heller D, et al. Digoxin derivatives with selectivity for the α2β3 isoform of Na,K-ATPase potently reduce intraocular pressure. Proc Natl Acad Sci. 2015;112(44):13723-13728. doi:10.1073/pnas.1514569112