Therapeutic Drugs and Devices for Tackling Ocular Hypertension and Glaucoma, and Need for Neuroprotection and Cytoprotective Therapies

Abstract

Damage to the optic nerve and the death of associated retinal ganglion cells (RGCs) by elevated intraocular pressure (IOP), also known as glaucoma, is responsible for visual impairment and blindness in millions of people worldwide. The ocular hypertension (OHT) and the deleterious mechanical forces it exerts at the back of the eye, at the level of the optic nerve head/optic disc and lamina cribosa, is the only modifiable risk factor associated with glaucoma that can be treated. The elevated IOP occurs due to the inability of accumulated aqueous humor (AQH) to egress from the anterior chamber of the eye due to occlusion of the major outflow pathway, the trabecular meshwork (TM) and Schlemm's canal (SC). Several different classes of pharmaceutical agents, surgical techniques and implantable devices have been developed to lower and control IOP. First-line drugs to promote AQH outflow via the uveoscleral outflow pathway include FP-receptor prostaglandin (PG) agonists (e.g., latanoprost, travoprost and tafluprost) and a novel non-PG EP2-receptor agonist (omidenepag isopropyl, Eybelis^®). TM/SC outflow enhancing drugs are also effective ocular hypotensive agents (e.g., rho kinase inhibitors like ripasudil and netarsudil; and latanoprostene bunod, a conjugate of a nitric oxide donor and latanoprost). One of the most effective anterior chamber AQH microshunt devices is the Preserflo^® microshunt which can lower IOP down to 10-13 mmHg. Other IOP-lowering drugs and devices on the horizon will be also discussed. Additionally, since elevated IOP is only one of many risk factors for development of glaucomatous optic neuropathy, a treatise of the role of inflammatory neurodegeneration of the optic nerve and retinal ganglion cells and appropriate neuroprotective strategies to mitigate this disease will also be reviewed and discussed.

Keywords: aqueous humor; drug discovery; glaucoma; intraocular pressur; neurodegenaration; neuroprotection; pharmacology.

FIGURE 1

Outline of the basic overall anatomy of the human eye illustrating some of the key features discussed in the text. (A). In (B), the key elements of the AQH synthetic machinery (ciliary procesess), and AQH outflow via the trabecular meshwork (TM conventional outflow) and via the uveoscleral pathway from the anterior chamber are shown. Note: none of the elements shown are to scale.

FIGURE 2

A pictorial view of the eye structures (A) with special reference to retinal architecture showing the various types of cells and their relative positions (B).

FIGURE 3

This figure depicts the effects of ANC fluid pressure (IOP) being radiated out to all parts of the eyeball. In OHT the elevated IOP (A) grossly and deleteriously affects the weak areas of the posterior globe at the level of the ONH/LC. The normal structural integrity of the LC and ONH area yields a small optic cup to optic disc ratio (B). When the LC/ONH tissues are damaged due to mechanical stress-induced remodeling, the LC area becomes excavated and the optic cup enlarges leading to a significantly increased cup to disc ratio (C). Additionally, the RGC axons are reduced and the retinal vasculature becomes displaced and causes potential ischemic conditions in the retina.

FIGURE 4

The detailed anatomical location and distribution of ocular blood vessels (A), and the interplay between the resident cells in the retina and blood-borne immune cells infiltrating into the retina (B) under GON conditions are shown. The activated microglia and astrocytes elaborate various injurious cytokines and up-regulate TLRs resulting in inflammatory neurodegeneration.

FIGURE 5

This figure shows the ANC and the location of the TM and SC relative to the cornea, iris and the ciliary body (A), and the more detailed juxtaposed cellular features of the TM and the SC in relation to the AQH flow (B).

FIGURE 6

The interplay between the biomechanical fluid pressure-induced stress from the ANC due to elevated IOP, the etiological elements (e.g., reduced axonal transport and ischemia), and the final pathological features and end-points observed in POAG and other forms of glaucoma at the retinal/LC/ONH and brain levels are depicted here.

FIGURE 7

The correlation between increasing IOP and RGC loss/optic nerve damage (A), and the ability of IOP-lowering drug treatment to slow down the GON/glaucoma progression (B) are shown in here.

FIGURE 8

The relationship between OHT, GON, RGC and RGC axonal loss, RNFL thinning and visual impairment over time is pictorially shown here. The insets depict the optic disc and the visual field as the GON progresses.

FIGURE 9

The chemical structures of some key pharmaceutical agents used to treat POAG are depicted. Many of the drugs have been approved by world health authorities for managing POAG.

FIGURE 10

Chemical structures of some of the emerging ocular hypotensive agents are shown. The diversity of the chemical classes of compounds working through receptors, channels and enzymes is readily apparent.

FIGURE 11

The technique of trabeculectomy to allow the excess AQH to leave the ANC to reduce IOP is shown in relation to other ANC ocular tissues (A), and how a patient’s eye looks after the surgery and the position of the bleb/flap (B).

FIGURE 12

This montage depicts the various sustained ocular hypotensive drug delivery techniques/technologies (A), and the various MIGS (AQH shunts) available to remove excess AQH from the ANC of the eye to reduce IOP (B,C).

FIGURE 13

IOP reduction over 3 years in OHT/POAG patients after implantation of the PRESERFLO^® microshunt into the ANC to permit AQH egress to lower IOP is depicted.

FIGURE 14

A comparison between various AQH microshunts on their ability to lower IOP in OHT/POAG patients (A), and the need for number of ocular hypotensive medications needed to maintain the lowered IOP pre and post-MIG implantation (B) is shown.

FIGURE 15

Examples of testing funnels for screening potential ocular hypotensive drug candidates are shown (A,B). In (A), the overall “hits” discovery and characterization is depicted, whereas in (B), the types of stage-gates and the Go/No Go criteria to progress for selected in vitro and in vivo studies are shown. Potency/efficacy/safety parameters are listed as examples.

FIGURE 16

Examples of in vitro cell-based functional data for selected prostaglandins for their concentration-dependent mobilization of intracellular Ca²⁺ via the human cloned FP-receptor is shown (A). Ex-vivo data for two different classes of compounds enhancing outflow facility in porcine eye ANC segments over a period of time is displayed (B).

FIGURE 17

The ability of two different classes of compounds (S- and R-DOI, a 5-HT2 receptor agonist (A) and a non-peptidic bradykinin B2-receptor agonist [FR-190997] (B)) to lower IOP in conscious ocular hypertensive Cynomolgus monkey eyes is shown.

FIGURE 18

Examples of use of remote telemetric monitoring of IOP in conscious monkey eyes (A–C), in human eyes with a contact lens-based device (D,E) and an intraocular lens-bearing device (F) are shown.