More than half of Americans over the age of 70 have cataracts caused by masses of collection of proteins in the lens of the eye. The only way to remove them is surgery, an option unavailable or unaffordable for many of the 20 million people worldwide who are blinded by the condition. Now a new study in mice suggests eye drops made with a natural steroid could reverse cataracts by teasing apart the protein clusters.
"This is a game changer in the treatment of cataracts," says Roy Quinlan, a molecular biologist at the University of Durham in the UK, who was not part of the study. " it takes decades for cataracts to get to this point, so if you can reverse that in a few drops into the eye over a couple of weeks, which is amazing. "
the proteins that make up the lens human are among the oldest in the body, forming about 4 weeks after fertilization. the majority are crystalline, a family of proteins that allow the eye to focus and keep a clear lens. Two of the most abundant crystalline , CRYAA and CRYAB are produced in response to stress or injury. They act as chaperones, identifying and binding to misfolded or damaged proteins in the lens, preventing aggregation. But over the years, such as damaged proteins accumulate in the lens, these chaperones become overwhelmed. The mutated proteins clump together and blocking the light and producing cloudiness revealing cataract.
To treat the disease without surgery, which is out of reach for many patients in developing nations, researchers studied the drug treatments. While strengthening the function and CRYAA CRYAB seems a good target, the development of a therapeutic has been difficult. Most drugs that act on proteins associated with the disease work by changing the way the protein functions, scientists can measure something by monitoring the enzyme activity of the protein. CRYAA, CRYAB and similar proteins are known as "undruggable" because their activity can not be measured, said Jason Gestwicki, a biochemist at the University of California (UC), San Francisco, and lead author of the new study, published in online today science .
Gestwicki team decided to use a technology called differential scanning fluorimetry, allowing scientists to measure the temperature at which a target protein begins to melt. They analyzed CRYAA and CRYAB and found that, in a type of hereditary cataract CRYAB takes a mutant form having a melting temperature much higher than the normal version. If we could find a molecule that bind to the mutant protein CRYAB and lower its return melting temperature than that of a healthy CRYAB, they speculated, CRYAB should function normally and prevent lumps damaged proteins in the lens . The researchers turned to a bank of 2450 molecules that had similar properties and CRYAA CRYAB. They added molecules mutant CRYAB, seeking a which stabilize their target. They are installed on the compound 29, a naturally occurring steroid in the blood, but not in the lens, which has no blood supply. Mice with cataracts and age-related hereditary received drops in his right eye while the left eye went untreated. After only a few weeks, the treated eye was visibly clearer, said Gestwicki, who led the work while at the University of Michigan. Cataract gravity is measured on a scale of zero to four, with four being the worst case. On average, the mice in the study had an improvement of one grade in serious cataracts after 4 weeks of treatment.
This is the second study this year to find that eye drops made from a class of steroids called sterols can successfully reverse cataracts. In July, the UC San Diego researchers reported that lanosterol, a steroid found in the human eye, inverted dogs cataracts.
"There is a me-too document in the sense that this new study also dealt with a sterol cataract," says Quinlan. "But they came to the same conclusion in completely different ways. This is how scientific excellence is done, and [it’s] something that should get philanthropists and pharma excited."
An essential difference between the two studies is how different steroids were administered. The dog study drug administered both by injection into the eye drops and eyes. The new study only used eye drops.
There is still a lot to discover before the two studies can move into clinical trials, Quinlan notes. The lens of the human eye is very different from those mice or dogs, and neither study explains how steroids work on cataract. "Mechanically, we do not really know what is going on here. It is a black box."
Understanding how the reverse cataract treatment is the next task of the team, a key step towards clinical trials which Gestwicki hopes to launch in the next year. ViewPoint Therapeutics, a biotechnology company he co-founded in San Francisco, California, holds the license for the technology and launch additional animal studies soon.
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