Cholesterol-like Molecule Suggested As Possible Cataract Treatment

Patients with cataracts have clouding in their lenses that can blur and obstruct their field of vision. A controversial paper in Nature reports that a cholesterol-like molecule, lanosterol, can slow and possibly reverse the protein aggregation responsible for cataracts that form in people’s eyes. The molecule could provide the first nonsurgical therapy for cataracts, which is a major cause of blindness worldwide. But some cataract researchers don’t think the paper’s conclusions are justified by the data. Kang Zhang of the University of California, San Diego, and colleagues found lanosterol through their research on the genetics of cataracts. They were studying a family with three siblings who had a severe, congenital form of the disease. The researchers traced the genetic cause to a mutation in the gene that codes for the enzyme lanosterol synthase, which produces lanosterol, a cholesterol precursor. Meanwhile, Zhang’s group used computer modelling to study how lanosterol might interact with proteins in the lens of the eye, called crystallins. Cells in the lens are normally clear because they’re packed with crystallins that assemble into very ordered structures. If these proteins get damaged or start to unfold, they can clump and disrupt the ordered assemblies, leading to lens clouding, the defining characteristic of cataracts. The modelling suggested that lanosterol could bind to hydrophobic portions of crystallins and help break up clumps. To test this hypothesis, Zhang and colleagues added lanosterol to cells expressing crystallins with mutations known to cause the proteins to disorder and aggregate. The experiments showed that the molecule could reduce and even eliminate the crystallin clumps in cells. Then the researchers tested lanosterol on animals with cataracts. The results of these experiments are “absolutely compelling data that lanosterol interferes with and slows the aggregation of lens crystallin proteins,” says Jonathan A. King, a biologist at Massachusetts Institute of Technology, who studies crystallins. But some ophthalmology researchers aren’t convinced by the researchers’ data. Suraj P. Bhat of UCLA’s Jules Stein Eye Institute doesn’t think the study conclusively links lanosterol to the improvement of cataracts in dogs. For example, the researchers didn’t demonstrate that the compound reached the lens of the eye, and they didn’t confirm that lanosterol cleared protein clumps. Leo T. Chylack, emeritus professor of ophthalmology at Harvard Medical School, points out that the animal experiments did not have adequate controls and did not involve standard protocols used by many in the cataract field, including how to properly photograph eyes to grade the severity of cataracts. Zhang acknowledges that lanosterol’s abilities require further and more comprehensive testing. He calls the current study preliminary and says that his team’s goal was to demonstrate the compound’s potential.

Chemical & Engineering News, 27 July 2015 ;http://pubs.acs.org/cen/news ;