Presbyopia in the aging eye manifests as a difficulty in focusing on close objects. It is caused by hardening of the lens, which is in part the result of cross-linking in the extracellular matrix of that tissue, though other mechanisms are involved as well. Cross-links are hardy metabolic byproducts resulting from the normal operation of metabolism, capable of degrading the structural properties of tissue, particularly elasticity, by linking proteins together and restricting their motion. Cross-linking is likely of great importance in skin aging and cardiovascular aging. The primary age-related cross-links of the lens are not the same as those of other soft tissues in the body, however: disulphide bonds rather than glucosepane. So this research is interesting for all of us heading towards older age and dysfunctional vision, but only in the context of dysfunctional vision. As a first attempt, there is clearly some room for improvement in the degree to which the approach taken breaks cross-links, but, given this proof of principle, that further improvement should follow in the years ahead.
A new topical agent is coming closer than ever to improving the accommodative range for presbyopes. The agent, lipoic acid choline ester (UNR844, Novartis, formerly EV06), is a reducing agent that is purported to reduce the disulfide bonds that form between lens proteins, thus increasing the deformability of the crystalline lens. "This chemical was designed to improve the internal rheology of the cytosol within the lens fibers inside the lens capsule. It is safe, well-tolerated, and showed statistically significant near visual acuity improvement in clinical trials compared to placebo. The widespread use of this drug stands to radically alter the visual performance of humans within our lifetimes."
Presbyopia is not just a matter of lens compliance. It is caused by a few different events, each of which constitutes a potential treatment target: the crystalline lens enlarges over time (ectoderm), the ciliary body undergoes atrophic changes, the vitreous becomes less viscous, and the lens loses its flexibility. The hypothesis that drove the development of UNR844 addressed lens flexibility or the lack thereof in presbyopia. When lens proteins become oxidized over time, disulfide bonds form, rendering them less able to move relative to one another during the act of accommodation.
"The theory was that if we had a way to chemically reduce these disulfide bonds, the proteins would regain increased degrees of freedom and allow a greater range of deformation of the lens, translating into a greater dynamic range of accommodation." Lipoic acid is a naturally occurring antioxidant and reducing agent. To allow the reducing agent to achieve sufficient concentration within the eye, researchers developed a prodrug to improve the compound's penetration, allowing it to metabolize and convert to its active form (dihydrolipoic acid [DHLA]) once within the lens. DHLA reduces disulfide bonds between lens proteins and restores lens microfluidics. Proof of concept was confirmed in vitro with human cadaver lenses and in vivo in rabbit eyes, where in both trials the drug produced lens softening and an increase in lens deformability.
The Phase 1/2 clinical study evaluated safety and efficacy of EV06 ophthalmic solution 1.5% in improving distance corrected near visual acuity (DCNVA) in subjects with presbyopia. The prospective, randomized, double-masked, placebo-controlled study included 75 patients (45-55 years) with hyperopia, myopia, or emmetropia, and a diagnosis of presbyopia. At baseline, the study patients had DCNVA below 20/40 in each eye. The study drug was given for 91 days and patients were monitored during a 7-month follow-up period. Visual acuity improvements were most pronounced when subjects employed bilateral vision, with 84% achieving 20/40 bilateral vision or better versus 52% in the placebo group.