Abstract
Cataract, the leading cause of vision impairment worldwide, arises from abnormal aggregation of crystallin lens proteins. Presently, surgical removal is the only therapeutic approach. Recent findings have triggered renewed interest in development of non-surgical treatment alternatives. However, emerging treatments are yet to achieve full and consistent lens clearance. Here, the first ex vivo assay to screen for drug candidates that reduce human lenticular protein aggregation was developed. This assay allowed the identification of two leading compounds as facilitating the restoration of nearly-complete transparency of phacoemulsified cataractous preparation ex vivo. Mechanistic studies demonstrated that both compounds reduce cataract microparticle size and modify their amyloid-like features. In vivo studies confirmed that the lead compound, rosmarinic acid, delays cataract formation and reduces the severity of lens opacification in model rats. Thus, the ex vivo assay may provide an initial platform for broad screening of potential novel therapeutic agents towards pharmacological treatment of cataract.
Highlights
Been raised regarding the ability to achieve full transparency of the human lens in eyes with cataract
We have developed a novel ex vivo platform in which human lens particles removed from patients during routine cataract surgery were treated with one of several protein aggregation modulators
Treatment with rosmarinic acid deterred cataractogenesis in model rats, providing a proof of concept that modulation of protein aggregation can ameliorate cataract formation in vivo. These results provide conceptual and mechanistic insights into the development of novel therapeutic strategies for vision loss caused by cataract, and support the utility of the ex vivo platform for initial testing of the efficacy of potential cataract modulating agents
Summary
Been raised regarding the ability to achieve full transparency of the human lens in eyes with cataract. We postulated that targeting lenticular protein aggregates would reduce their load of precipitates and would affect their light-scattering properties, ameliorating cataract To address this hypothesis, we have developed a novel ex vivo platform in which human lens particles removed from patients during routine cataract surgery were treated with one of several protein aggregation modulators. Treatment with rosmarinic acid deterred cataractogenesis in model rats, providing a proof of concept that modulation of protein aggregation can ameliorate cataract formation in vivo These results provide conceptual and mechanistic insights into the development of novel therapeutic strategies for vision loss caused by cataract, and support the utility of the ex vivo platform for initial testing of the efficacy of potential cataract modulating agents
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