Advances in pharmacotherapy of cataracts

Abstract

Cataracts, the leading cause of vision impairment worldwide, arise from abnormal aggregation of lens proteins. According to the World Health Organization, cataracts cause more than 40% of blindness cases. As the population ages, the prevalence of cataracts will increase rapidly. Although cataract surgery is regarded as effective, it still suffers from complications and high cost, and could not meet the increasingly surgery demand. Therefore, pharmacological treatment for cataracts is a cheaper and more readily available option for patients, which is also a hot topic for years. Anti-cataract drug screening was previously mainly based on the specific pathogenic factors: oxidative stress, excess of quinoid substances, and aldose reductase (AR) activation. And several anti-cataract drugs have been applied in the clinic, while the effect is still unsatisfied. Makley and Zhao recently identified two kinds of novel pharmacological substances (25-hydroxycholesterol, lanosterol) that can reverse lens opacity by dissolving the aggregation of crystallin proteins, indicating that protein aggregation is not an endpoint and could be reversed with specific smallmolecule drugs, significantly boosting the development of the cataract pharmacopeia and being regarded as a new dawn for cataract treatment. Our team built a novel optimized platform and had screened several potential therapeutic agents from a collection of lanosterol derivatives. In this review, we would mainly focus on the advancement of cataract pharmacotherapy based on the targets for anti-cataract drugs.

Using genetics to investigate the association between lanosterol and cataract

“…Furthermore, lanosterol’s low solubility limits its clinical application. However, Xu et al found that lanosterol derivatives were able to effectively break down protein aggregations while avoiding the limitations surrounding lanosterol itself ( Xu et al, 2020 ). This suggests that lanosterol derivatives could form a viable cataract treatment, rather than lanosterol itself.…”

Inhibitory effect of lanosterol on cataractous lens of cynomolgus monkeys using a subconjunctival drug release system

“… 28 Moreover, the effect of lanosterol in binding α-crystallins and reversing their aggregation in vitro has been confirmed previously, 29 indicating that protein aggregation is not an endpoint and could be reversed with specific small-molecule drugs. 30 However, a recent study of in vitro rat lens along with a study of human lens protein solubilization showed that lanosterol failed in binding aggregated lens protein to dissolve cataracts. 31 Therefore, it is necessary to obtain more experimental evidence based on in vivo study.…”

Cataract: Advances in surgery and whether surgery remains the only treatment in future

“…A high-throughput platform in which human lens particles were removed from patients during routine cataract surgery and treated with candidate compounds has been established. 93 Based on the most recent one, 34 new synthetic lanosterol analogs were synthesized and evaluated, and lanosterol derivatives were demonstrated to reverse the lentic protein aggregation with better potency and efficacy. 94 Further evaluation of the lanosterol derivatives in lentoid bodies (LBs) and animal models, as well as detailed mechanistic studies, are in progress.…”