Researchers have identified a chemical that successfully restored transparency to mouse lenses and human lens tissue, paving the way for a cheaper, noninvasive treatment for a leading cause of blindness: cataracts.
Study coauthor Jason Gestwicki, PhD, associate professor of pharmaceutical chemistry at the University of California-San Francisco (UCSF), and colleagues recently published their findings in the journal Science.
Around 20.5 million Americans aged 40 and older have a cataract in one or both eyes – a condition characterized by clouding of the eye’s lens that can lead to blurred vision.
In the early stages, cataracts may be improved with magnifying lenses, new glasses, anti-glare sunglasses or brighter lighting. However, if such treatments fail, surgery is currently the only option.
Surgery for cataracts involves removing the cloudy lens and replacing it with an artificial one; around 6.1 million people with a cataract in the US have undergone surgery for the condition.
However, Gestwicki and colleagues note that – although highly successful – cataract surgery is costly, and many people with cataracts in developing countries often go untreated as a result.
But in this latest study, the team demonstrates the possibility of a cheaper, more practical alternative to treating cataracts: eye drops containing a chemical that dissolves crystallins – proteins that clump together and cloud the lens.
Crystallins are arranged in the lens in a certain way that allows light to pass through it, enabling us to see. As we get older, however, these proteins can clump together, preventing light from being able to pass through the lens.
The UCSF researchers note that these clumped-together crystallins – or amyloids, a reference given to all proteins that clump together – are much more stable than non-clumped forms, which makes them harder to “melt.”
For their study, the team used a process called high-throughput differential scanning fluorimetry (HT-DSF) – a method in which proteins give off light when their melting point is reached – to apply heat to both healthy crystallins and their amyloid forms, while also applying various chemical compounds.
The researchers began testing 2,450 compounds, gradually narrowing them down to 12 that helped reduce the melting point of crystallin amyloids to the normal range. The 12 compounds identified were part of a class of chemicals called sterols.
The team used these compounds to create and test another 32 sterols, and identified one – referred to as “compound 29” – that they believed could be added to eye drops to help dissolve amyloid crystallins.
Gestwicki and colleagues then tested compound 29 on crystallin amyloids in a laboratory dish. They found the compound not only prevented clumps from forming, but it also successfully dissolved the clumps that had already formed.
- More than half of all Americans either have a cataract or have had cataract surgery by the age of 80
- Smoking, alcohol use, diabetes and prolonged exposure to sunlight are all factors that can increase the risk for cataracts
- A cataract cannot spread from one eye to the other.
“Through these experiments, we are starting to understand the mechanism in detail. We know where compound 29 binds, and we are beginning to know exactly what it’s doing,” says Gestwicki.
Next, the researchers added compound 29 to eye drops and tested them in mice that possessed mutations that predisposed them to cataracts.
The team used a slit-lamp test to measure lens transparency in the mice – a test used to measure cataracts in humans – and found the eye drops partially restored transparency to the lenses of mice with cataracts.
What is more, on applying the eye drops to mice that developed age-related cataracts and cataract-affected human lens tissue that had been removed through surgery, they saw similar results.
The team stresses that the slit-lamp test does measure visual awareness, and as such, clinical trials are needed to determine whether compound 29 can improve vision in humans with cataracts.
The compound has already been licensed, and study co-leader Leah N. Makley, postdoctoral fellow in Gestwicki’s lab at UCSF, is in the process of formulating the compound so it is ready for human use.
If compound 29 is found to be a success, it may not only lead to new treatments for cataracts; it could also open the door to new treatments for other conditions involving amyloid proteins, such as Alzheimer’s disease.
“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.
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.”
Earlier this year, Medical News Today reported on another study that showed promise for the treatment of cataracts with eye drops. Published in Nature, researchers from the University of California-San Diego identified a compound called lanosterol – one of the compounds found in this latest study – that reduced crystallin clumping.