**5. Therapeutics for glaucoma**

#### **5.1 Current FDA-approved therapeutics**

At baseline, the goal of current glaucoma treatments is to decrease IOP, which is presently the only identified modifiable risk factor. There are a variety of medications that modify IOP by either decreasing production or increasing the outflow of aqueous humor. Factors such as patient compliance, costs, drug penetration, variations in drug metabolism and bioavailability, and even other factors such as systemic diseases, diet, alcohol, etc., all play a role in medical management. Additionally, glaucoma patients require long-term treatment to keep pressures low. Years of treatment can exacerbate ocular surface disease and cause chronic conjunctival inflammation, which may threaten the efficacy of future surgical procedures (such as trabeculectomy). IOP fluctuation can worsen disease progression, seen in the advanced glaucoma interventional study [81].

#### *5.1.1 Modulation of aqueous production*

Drugs that decrease the production of aqueous, such as beta blockers and carbonic anhydrase inhibitors, have been the mainstay in glaucoma treatment for years. However, these drugs can have systemic adverse side effects such as bradycardia, impotence, exacerbation of asthma, and also may demonstrate tachyphylaxis over time. The beta blockers, such as timolol, modulate aqueous inflow. The beta-1 receptor increases production of aqueous, and the beta blockers inhibit the production of cyclic AMP by this receptor which reduces aqueous production [13]. Carbonic anhydrase inhibitors, such as brinzolamide, decrease the production of aqueous via suppression of aqueous ducts [13], but can produce a renal metabolic acidosis as they inhibit acid secretion in the proximal tubule of the kidney as well [13]. Other drugs, such as brimonidine, modulate the production of aqueous via the alpha-2 receptor. Adverse effects to this drug can include a delayed hypersensitivity reaction and, due to their ability to cross the blood–brain barrier, they are contraindicated in children under two [13].

### *5.1.2 Modulation of aqueous humor outflow*

Parasympathomimetic drugs, such as pilocarpine, have been used to decrease outflow. They cause contraction of the longitudinal ciliary muscles, which increases aqueous humor outflow. However, due to its three-to-four times daily dosing paradigm, myopic shift, and risk of retinal detachment, along with decreased patient compliance, it is no longer a first-line treatment [13]. Presently, prostaglandin analogs, such as latanoprost (Xalatan), have become the mainstay first-line treatment. They function by increasing outflow via modulation of uveoscleral pores, opening them as a secondary outflow mechanism that decreases outflow resistance. Most recently, Rho kinase inhibitors, such as Rhopressa, inhibit actin/myosin contraction of these muscles and improve trabecular meshwork outflow by decreasing the episcleral venous pressure. In the acute setting, hyperosmotic agents such as glycerol and mannitol can be used to lower the IOP, given intravenously, increasing the tonicity of the plasma and drawing aqueous out of the eye [13].

#### *5.1.3 Sustained-release devices*

To combat challenges of drug delivery, different models of sustained release implants have been developed. One intracameral implant called Durysta is an FDAapproved device that delivers bimatoprost into the anterior chamber over a period of four months [82]. Unfortunately, complications of Durysta use include chronic inflammation and corneal endothelial cell loss.

Other sustained-release implants in development include intracanalicular devices, subconjunctival injections, and collagen shields [83]. Examples include latanoprost micro-dose delivery with Optejet (Microprost, Eyenovia), latanoprost delivery via an intracanalicular insert (OTX-TIC, Ocular Therapeutix), and latanoprost or travoprost delivery via a punctal plug (L-evolute and T-evolute, Mati Therapeutics). The latter includes two travoprost delivery platforms, ENV515 (Envisia Therapeutics) and iDose (Glaukos) [83–85]. iDose is a titanium implant that releases a unique formulation of travoprost into the anterior chamber [84]. It releases micro-amounts of the drug over a year and eliminates the barrier of the cornea. It is composed of three parts that titrates travoprost release [84, 86]. It was reported in a randomized, double-blind phase II trial, iDose achieved a 30% reduction in IOP at 12 months, lowering the average number of glaucoma medications per patient compared to the control group of 0.5% timolol, demonstrating noninferiority with minimal adverse effects [84]. At each stage of development of these FDA-approved therapeutics, multiple pre-clinical models were used to demonstrate safety and efficacy, making their inclusion in the drug pipeline invaluable.

#### **5.2 Therapeutics in development**

Treatments that mitigate risk factors other than IOP are an identified gap in treatment modalities [46]. These are especially needed for populations that do not respond to current IOP-lowering medications, when a lowered IOP is insufficient to halt visual field loss, and in normotensive glaucoma cases. A particular need exists for the identification of neuroprotective molecules that act directly on the optic nerve and RGC axons. Although several therapies are being evaluated in multiple laboratories across the world, there remains no FDA-approved neuroprotective option for glaucoma patients. In line with this treatment strategy, Kimura *et al*. disclosed treatment trials exploring the delivery of ciliary neurotrophic factor into the eye via modified human cells that secrete it. They postulate this mechanism has potential for neuroprotective effects in the treatment of normotensive glaucoma [46]. In addition,

#### *An Overview of Glaucoma: Bidirectional Translation between Humans and Pre-Clinical… DOI: http://dx.doi.org/10.5772/intechopen.97145*

on the progressive end of molecular modifying, it may be possible to use stem cell therapy with CRISPR-Cas 9 technology to neutralize mutations causing glaucoma phenotypes. This capability is currently being explored [15], but will take thoughtful risk/benefit analysis.

Approaching treatment from a different angle, a unique tool to modulate IOP is being explored. The Mercury Multi-Pressure Dial (Equinox) is a pair of pressurized goggles that create a pressure vacuum around the eye, which decreases pressure from gravity and increases ocular blood flow [87]. They operate on the principal that glaucoma is likely a dual-pressure disease due to the balance between IOP and intracranial pressure (ICP) [87]. Thus, the inventors of this device postulate that glaucoma is a result of high IOP and low ICP. By applying a moderate negative pressure in the front of the eye with their goggles, the pressure inside the eye is reduced and the ICP is restored to a physiological level [87]. Moreover, it serves as a point to demonstrate that one direction glaucoma treatment might be headed is 24/7 modulation of pressure where sensors monitor pressure on-the-go, allowing physicians access to IOP data without requiring an office visit and creating a practical opportunity for a telemedicine consultation.

Experimental models of glaucoma are crucial to understanding the mechanism of disease and designing novel treatments. Assessing their axonal degeneration in optic nerve cross sections has proven beneficial in this pursuit. Specifically, the BXD genetic reference panel will be used to detect and study spontaneous models of glaucoma. This will be invaluable to the scientific community, especially in an effort to develop novel treatment options. While the development of these novel modalities takes time, animal models can be used to explore the benefit of existing drugs, a method known as drug repositioning or repurposing [67]. Neuroprotection is one particular facet of interest, and it is postulated available drug modalities for diseases of the central nervous system such as Alzheimer's or Parkinson's might also exhibit neuroprotection in glaucoma patients [88]. Examples of these trials include memantine, valproic acid, edaravone, and niacin (vitamin B3). Unfortunately, memantine was ruled ineffective in 2018 [89]. Valproic acid was demonstrated to be neuroprotective in rodent models of normotensive glaucoma, and one study from India showed improvement of advanced glaucoma cases [90, 91]. Edaravone was also shown to decrease RGC death in mouse models of normotensive glaucoma [92]. Lastly, oral niacin was demonstrated to be protective in mouse models [93]. There is also interest in the potential of dairy products being neuroprotective due to their levels of spermidine, which is a compound that has demonstrated neuroprotection in mouse models [67]. Additionally, using rodent models, Chintalapudi *et al*. have demonstrated IOP-lowering effects of pregabalin, which inhibits calcium channels containing the CACNA2D1 subunit. It is mainly used for neuropathic pain but was developed initially as an antiepileptic [74, 94]. Animal models have clearly demonstrated their necessity in testing for current and future pharmacological treatments.
