Zebrafish as a model to phenocopy and cure human cataracts

Cataracts are a leading cause of visual disability and blindness in both developed and developing countries. Age-related cataract is responsible for about 50% of world blindness, affecting about 18 million people, according to the World Health Organization. In India alone, cataract is responsible for 3.8 million new cases of blindness each year, whereas in Africa 36% of blindness is caused by cataract. The proportion of blindness in children due to cataract has a global average of 14% (about 200,000 children). Different cataracts can develop for a variety of reasons: advanced age, radiation (e.g. UV light), diabetes, hypertension, smoking, oxidative stress, genetic factors, steroid drugs and hormones, poor nutrition, severe dehydration, infectious diseases (e.g. cysticercosis, leprosy, onchocerciasis, toxoplasmosis). In most of these cases the final outcome is the denaturation of lens proteins. The set up of large-scale in vivo screens to validate compounds or to identify new anti-cataract drugs has hitherto been discouraged by experimental times, animal size and maintenance costs linked to the use of mammalian (rodent, canine) models. Moreover, mammalian systems are not easily manageable for in vivo time-lapse inspection of lens cell dynamics; in case of invasive approaches these models raise a series of critical ethical issues. We aim to overcome these limitations, by setting up an innovative platform for in vivo drug screening, based on the vertebrate model zebrafish (Danio rerio). This small fish (adult size: about 5 cm) has proved in recent years to be an excellent and cost-effective vertebrate system for high-throughput approaches, such as large-scale small molecule screenings. Several tools are available to easily reproduce human cataracts in zebrafish, such as chemical treatments, dietary regimes, gene knock-down strategies, as well as a series of accessible mutant fish lines displaying specific ocular disorders affecting the anterior segment of the eye. In this perspective, our group is currently analyzing two zebrafish mutant lines, bumper and helderziend, characterized by precocious lens degeneration, overtly evident at few days of embryonic development, which appear highly promising as a starting platform for our studies.