Across the globe, cataracts are the leading cause of blindness, affecting more than 20 million people—most of whom can’t afford the surgery necessary to save their vision. However, we soon may have a simple, non-invasive solution in the form of eye drops.
As reported in Science, these eye drops are composed of a newly-identified chemical compound that helps restore vision on the protein level.
In fact, when it comes to cataracts, proteins in the eye known as crystallins are the cause of the problem. Similar to Alzheimer’s disease, cataracts form when these key proteins lose their shape necessary for proper function (known as misfolding) and begin to clump together.
These crystallin proteins are the major component of fiber cells—which form the lens of the eye. Much like lenses in glasses, the lenses in eyes are transparent, and help to focus light on the back of the eye so that we see clearly. If part of this structure breaks down, we lose at least part of the ability to see, and unfortunately crystallins are particularly vulnerable.
“Shortly after you’re born, all the fiber cells in the eye lose the ability to make new proteins, or to discard old proteins,” explained Jason Gestwicki, PhD, associate professor of pharmaceutical chemistry at UC San Francisco and co-senior author, in a statement. “So the crystallins you have in your eye as an adult are the same as those you’re born with.”
Crystallins must hold a certain shape to keep them transparent and flexible, but this shape is difficult to maintain. This is because the clumpy protein shape associated with cataracts is actually much more stable than the healthy shape—meaning that without aid, crystallins would almost constantly be in this dysfunctional shape.
Chaperones to the rescue
Luckily, another class of proteins known as chaperones help out, which “kind of like antifreeze,” said Gestwicki, “keeping crystallins soluble in a delicate equilibrium that’s in place for decades and decades.”
In order to find a way to bring misfolded crystallins back to correct shape, the researchers took an interesting attack. When a protein is in one shape or the other, it has different melting points—another indication of stability, as the melting point is the temperature at which a protein loses its 3D shape. A higher melting point is more stable—which in the case of crystallins isn’t a good thing, because the misfolded proteins are the more stable shape.
And so, using a method known as high-throughput differential scanning fluorimetry (HT-DSF)—in which proteins give off light when they reach their melting point—the team tested various compounds to see if any could change the high melting points of the misfolded proteins to the lower, less stable, melting temperature of healthy ones. This, in theory, would indicate the protein has changed back to the normal, functional shape.
The one compound to rule them all
After testing 2,450 compounds, the list was finally narrowed down to 12 candidates, all of which are from the chemical class known as sterols. These 12 sterols led to 32 other chemical compounds in the same family being examined—leading to the one, known as compound 29.
Compound 29 then went through a variety of tests. In laboratory dishes, 29 was found to significantly stabilize crystallins and kept them from shifting to the misshaped form. Then, it was discovered that 29 dissolved misfolded crystallins back to their proper shape.
From there, compound 29 was made into eye drop-form and used on mice. Some mice were genetically predisposed toward cataracts, while others developed them simply with age, but regardless, in those that had developed the disease, the drops partially restored lens transparency.
Lastly, the drops were applied to human lens tissue which had been removed during surgery to repair damage from cataracts—which showed partially restoration as well.
Gestwiki cautions that this does not mean compound 29 will work like it seems to here—only human clinical trials can determine that. However, if it does work, it promises to lift millions of people out of darkness—and pets too, as 70 million dogs are affected by cataracts. Even more tantalizing, though, is the fact that the misfolded crystallins bear a strong resemblance to the shape of the destructive proteins in other diseases.
“If you look at an electron micrograph at the protein aggregates that cause cataracts, you’d be hard-pressed to tell them apart from those that cause Alzheimer’s, Parkinson’s, or Huntington’s diseases,” Gestwicki said.
“By studying cataracts we’ve been able to benchmark our technologies and to show by proof-of-concept that these technologies could also be used in nervous system diseases, to lead us all the way from the first idea to a drug we can test in clinical trials.”
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Feature Image: Thinkstock
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