A newly identified compound is the first that is soluble enough to potentially form the basis of a practical eye-drop medication for cataracts. Credit: © BillionPhotos.com / Fotolia
Cataracts affect >20 million people worldwide. The affected proteins are crystallins, the major component of fiber cells, which form the eyes’ lenses, and they are susceptible to damage.”Shortly after you’re born, all the fiber cells in the eye lose the ability to make new proteins, or to discard old proteins,” said Gestwicki, who has continued his work on cataracts at UCSF, where he joined the faculty about two years ago. “So the crystallins you have in your eye as an adult are the same as those you’re born with.”
Thus your 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 this with chaperones, which act “kind of like antifreeze,” Gestwicki 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 team exploited a crucial difference between properly folded crystallins and their amyloid forms: put simply, amyloids are harder to melt.
METHOD: They used high-throughput differential scanning fluorimetry, or HT-DSF, in which proteins emit light when they reach their melting point. The team used HT-DSF to apply heat to amyloids while applying thousands of chemical compounds, focusing on chemicals that that lowered the melting point of crystallin amyloids to the normal, healthy range. 2,450 compounds were narrowed to 12 that are members of sterols. One of these, lanosterol, was shown to reverse cataracts in a June, 2015 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, Gestwicki’s team assembled and tested 32 additional sterols, and eventually settled on”compound 29,” as the most likely candidate that would be sufficiently soluble for cataract-dissolving eye drops.
In lab dish tests, compound 29 significantly stabilized crystallins and prevented them from forming amyloids and dissolved amyloids that had already formed. 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 in mice that naturally developed age-related cataracts, and human lens tissue affected by cataracts that had been removed during surgery.
Dogs are also prone to developing cataracts. Half of all dogs have cataracts by 9yo, and virtually all dogs develop them later in life. An effective eye-drop medication could potentially benefit about 70 million US pet dogs besides humans. https://www.ucsf.edu/news/2015/11/176886/eye-drops-could-clear-cataracts-using-newly-identified-chemical
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