Scientists have discovered a new chemical that could reverse cataracts, one of the leading causes of blindness. This new substance could be used in eye drops, greatly simplifying the treatment and making it accessible to the general population at a low price and without intrusive procedures. A cataract is a clouding of the lens in the eye leading to a decrease in vision. It can affect one or both eyes, generally evolves slowly, and causes about 50% of all the blindness cases in the world. Cataract removal can be performed at any stage and no longer requires ripening of the lens, however, it is still a surgical process and can be quite expensive, and of course, people are always reluctant to have eye surgery. This is where this new treatment enters the stage.
Jason Gestwicki, PhD, associate professor of pharmaceutical chemistry at UCSF and co-senior author of a paper on the new research explains: “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.” The newly identified compound is not the first one that can treat cataract, but it is the first one soluble enough that it can be incorporated in eye drops. 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,” 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. A similar process underlies other disorders related to aging, such as Alzheimer’s disease, but in each of these diseases the specific protein that clumps together and the place in the body that clumping occurs is different. In all cases, these clumped-together proteins are called amyloids.
In the new study, led by Leah N. Makley, PhD, and Kathryn McMenimen, PhD, the scientific team exploited a crucial difference between properly folded crystallins and their amyloid forms, put simply, amyloids are harder to melt.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. At the U-M Life Sciences Institute’s Center for Chemical Genomics, the team used HT-DSF to apply heat to amyloids while applying thousands of chemical compounds. 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 started with over 2000 chemicals that showed some potential, ultimately focusing on 12 that are members of a chemical class known as sterols. Sterols, also known as steroid alcohols, are a subgroup of the steroids and an important class of organic molecules. They occur naturally in plants and animals, with the most known sterol being, of course, cholesterol. Out of this dozen, they ultimately zoomed in on lanosterol.
Lanosterol was previously shown to clear out cataracts, but it had to be injected into the eye, so they assembled and tested 32 additional sterols, and eventually settled on one, which they call “compound 29.” Compound 29 can be used in drops, and can help not only in human cataracts, but also in that of dogs or other pets.The team next tested compound 29 in an eye-drop formulation in mice carrying mutations that make them predisposed to cataracts. In experiments conducted with Usha P. Andley, PhD, professor of ophthalmology and visual sciences at WUSTL School of Medicine, 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.
Gestwicki cautions that slit-lamp measures of lens transparency used in the research are not a direct measure of visual acuity, and that only clinical trials in humans can establish the value of compound 29 as a cataract treatment. He has licensed the compound from U-M, however, and Makley, a former graduate student and postdoctoral fellow in the Gestwicki laboratory, is founder and chief scientific officer of ViewPoint Therapeutics, a company that is actively developing compound 29 for human use. Dogs are also prone to developing cataracts. Half of all dogs have cataracts by nine years of age, and virtually all dogs develop them later in life. An effective eye-drop medication could potentially benefit about 70 million affected pet dogs in the United States.
In addition to compound 29’s potential for cataract treatment, the insights gained through the research could have broader applications, said Gestwicki, a member of UCSF’s Institute for Neurodegenerative Diseases whose main research interest is dementia and related disorders.”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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