Identified by the World Health Organization (WHO) as a "priority eye disease," cataracts affect more than 20 million people and is the leading cause of blindness worldwide. The condition occurs when the lenses of the eyes lose their transparency causing blindness for the sufferer that only a surgical procedure can help reverse. Now a chemical that could potentially be used in eye drops has been identified by a team of scientists from three states.
Although cataract patients can be successfully treated with surgery to replace the affected lens, the procedure is expensive and most individuals in developing countries who have been blinded by severe cataracts go untreated. According to the National Institutes of Health (NIH), aid agencies assume a figure of 1,000 new blind people each year from cataract per million of the population.
Even in ideal conditions, corrective surgery risks include infection, retinal detachment, internal inflammation and swelling, glaucoma, hemorrhage as well as possible worsening of certain eye conditions such as diabetic retinopathy.
Cataracts are one of the prospective hazards of aging and, as worldwide life expectancy increases, health professionals naturally predict a rise in cases. The team from UC San Francisco (UCSF), the University of Michigan (U-M), and Washington University in St. Louis (WUSTL) have developed a solution that could mean things become a lot simpler in the future.
Cataracts occur because of the misfolding and clumping together of certain crucial proteins known as crystallins. These proteins are the major component of the "fiber cells" which form the lens of the eyes. According to Dr. Jason Gestwicki, co-senior author of a paper on the new research, it is the unique properties of these cells which make them particularly 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," he says. "So the crystallins you have in your eye as an adult are the same as those you're born with."
If our lenses are to keep working correctly, the crystallins must hang onto their youth by remaining both transparent and flexible as, over the years, the eye muscles stretch and relax to allow us to focus on different objects and distances. Unfortunately, because clumped-together configurations of crystallins — called amyloids —are far more stable than properly folded, healthy forms, the body needs a way to keep them apart. The process of keep things decent is the job of some special proteins — appropriately called chaperones — which prevent the unwanted clumps from forming. In another sense, says Gestwicki, they act "kind of like antifreeze, keeping crystallins soluble in a delicate equilibrium that's in place for decades and decades."
The new study, reported in Science, was led by Drs. Leah N. Makley and Kathryn McMenimen. Essentially, they knew there is a crucial difference between properly folded crystallins and their amyloid forms: amyloids are harder to eliminate because their melting point is higher.
The team decided to look for chemicals that lowered the melting point of crystallin amyloids to a normal, healthy range. They then applied thousands of chemical compounds to see if any would have the desired effect.
They began with 2,450 different compounds and eventually worked their way down to 12 — all of which make up part of a group of naturally occurring steroids known as sterols.
One of these — lanosterol — was already known to reverse cataracts but, because of its limited solubility, it had to be injected into the eye to work. The new compound is the first known to be soluble enough to be potentially used in a practical eye-drop medication.
After testing all the chemical candidates, Gestwicki's team eventually settled on one — which they call "compound 29" — as the most soluble and, therefore, the best suited to be developed as an eye-drop. The team discovered that compound 29 significantly stabilized crystallins and prevented them from forming amyloids and that it also dissolved any amyloids that had already formed. Testing the compound in an eye-drop formulation in mice carrying mutations that make them predisposed to cataracts, they found the drops partially restored transparency to mouse lenses affected by cataracts. Significantly, the team saw similar results when the compound was applied to human lens tissue affected by cataracts that had been removed during surgery although Gestwicki says the methods used in research are not a direct measure of visual acuity, and that only clinical trials in humans can establish the value of compound 29 as an effective cataract treatment.
Despite this, he is optimistic about developments. Dogs are also prone to developing cataracts — half of all dogs by nine years of age and virtually all later in life. Treatment could potentially benefit about 70 million affected pet dogs in the United States. In addition, says Gestwicki, the research could help in other fields of medicine. "If you look at an electron micrograph at the protein aggregates that cause cataracts," he says, "you'd be hard-pressed to tell them apart from those that cause Alzheimer's, Parkinson's, or Huntington's diseases. Chemicals like compound 29, he suggests "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."