Newly identified chemical in eye drop could clear up cataracts

Newly identified chemical in eye drop could clear up cataracts

Identified as a "priority eye disease" by the World Health Organization, cataracts--caused when the lenses of the eyes lose their transparency--affect more than 20 million people worldwide. Although cataracts can be successfully removed with surgery, this approach is expensive, and most individuals blinded by severe cataracts in developing countries go untreated.

Reported in Science, the newly identified compound is the first that is soluble enough to potentially form the basis of a practical eye-drop medication for cataracts.

Cataracts are primarily a disease of aging. As is seen in neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, a hallmark of the condition is the misfolding and clumping together of crucial proteins. In the case of cataracts, the affected proteins are known as crystallins.

Crystallins are the major component of fiber cells, which form the eyes' lenses, and the unique properties of these cells make them particularly susceptible to damage. In order for our lenses to function well, this permanent, finite reservoir of crystallins must maintain both the transparency of fiber cells and their flexibility, as the eyes' muscles constantly stretch and relax the lens to allow us to focus on objects at different distances.

The crystallins accomplish these duties with the help of aptly named proteins known as chaperones, which act "kind of like antifreeze," author said, "keeping crystallins soluble in a delicate equilibrium that's in place for decades and decades."

This state-of-affairs is "delicate" because pathological, clumped-together configurations of crystallins are far more stable than properly folded, healthy forms, and fiber-cell chaperones must continually resist the strong tendency of crystallins to clump.

The research group used a method known as high-throughput differential scanning fluorimetry, or HT-DSF, in which proteins emit light when they reach their melting point.

Because the melting point of amyloids is higher than that of normal crystallins, the team focused on finding chemicals that that lowered the melting point of crystallin amyloids to the normal, healthy range.

The group began with 2,450 compounds, eventually zeroing in on 12 that are members of a chemical class known as sterols. One of these, known as lanosterol, was shown to reverse cataracts in a paper in Nature, but because lanosterol has limited solubility the group who published that study had to inject the compound into the eye for it to exert its effects.

Using lanosterol and other sterols as a clue, the group assembled and tested 32 additional sterols, and eventually settled on one, which they call "compound 29," as the most likely candidate that would be sufficiently soluble to be used in cataract-dissolving eye drops.

In laboratory dish tests, the team confirmed that compound 29 significantly stabilized crystallins and prevented them from forming amyloids. They also found that compound 29 dissolved amyloids that had already formed.

The team next tested compound 29 in an eye-drop formulation in mice carrying mutations that make them predisposed to cataracts. They found that the drops partially restored transparency to mouse lenses affected by cataracts, as measured by a slit-lamp test of the sort used by ophthalmologists to measure cataracts in humans.

Similar results were seen when compound 29 eye drops were applied in mice that naturally developed age-related cataracts, and also when the compound was applied to human lens tissue affected by cataracts that had been removed during surgery.

http://www.ucsf.edu/news/2015/11/176886/eye-drops-could-clear-cataracts-using-newly-identified-chemical
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