Cataracts cause blindness in tens of millions of people worldwide, and currently can be treated only with surgery. Cataracts form owing to aggregation of proteins in the lens of the human eye. This lens is made up of a complex crystalline protein array that gives it transparency and its refractive index. The major structural proteins of the lens are called crystallins, and mutations can cause crystallins to aggregate and form cataracts. The mechanisms underlying this aggregation of proteins in cataracts (and its absence in healthy lenses) are not well understood.

In a recent paper published in Nature (doi:10.1038/nature14650; published online 22 July 2015), Kang Zhang (University of San Diego, CA) and colleagues identified mutations in a gene, lanosterol synthase (LSS), in two families with congenital cataracts. Further experiments in cells and in animals showed that LSS regulates aggregation of cataract-forming proteins and identified a potential non-surgical treatment for cataracts.

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LSS synthesizes lanosterol, a molecule that is part of the cholesterol synthesis pathway. Lanosterol is enriched in the eye's lens and the mutations identified by Zhang and colleagues affect the ability of LSS to catalyze the formation of lanosterol. In cells expressing mutant crystallin proteins, existing protein aggregation was reduced by expression of wildtype LSS, but the mutant forms identified in the human families did not reduce aggregation. In vitro experiments showed that lanosterol itself could dissolve aggregated crystallin proteins. Encouraged by their in vitro results, the researchers tested lanosterol's efficacy in more clinically relevant models. They found that application of lanosterol increased the transparency of dissected cataractous lenses from rabbits, and it successfully decreased cataract severity in dogs.

These findings represent a significant advancement in our understanding of how cataract formation is prevented in healthy eyes. Perhaps more excitingly, they suggest a simple and noninvasive treatment for cataracts, although further research is required before this could be tried in humans. The study is also an excellent example of the power of genetics to inform biological understanding and development of new therapeutics. As one of the authors, Dr. Xin Jin (BGI-Shenzhen, Shenzhen, China), said in a press release, “This project is aimed to discover [casual] genes for congenital cataracts. Then we uncovered that [the] gene LSS [was] responsible for two affected families involved in the study. This is extremely exciting when we noticed that the discovery might lead to a novel and simple strategy for the prevention and treatment of cataracts. It encourages us to have more efforts from bench to bedside.”