A University of Arizona-led study on age-related macular degeneration likely will lead to a way to delay or prevent the disease, researchers say.

The study, led by co-principal investigator Brian S. McKay, associate professor of ophthalmology and vision science and cellular and molecular medicine at the UA College of Medicine-Tucson, found that patients who take levodopa, or l-dopa, a common treatment for Parkinson’s disease, appear far less likely to develop macular degeneration. And if they do develop the disease, it is significantly later in life.

L-dopa is a naturally occurring molecule that is made in pigmented human tissue, including the iris, and has a role in maintaining a healthy macula. A synthesized form of l-dopa is used to treat Parkinson’s and movement disorders.
“It is likely that this will lead to a way to prevent AMD, and it may also lead to treatment for macular degeneration in the future,” Dr. McKay said. “It may also help with other eye diseases characterized by retinal degeneration, such as retinitis pigmentosa.” The research was published online Nov. 4 in the American Journal of Medicine.

“Research points to this as a pathway to regulate and prevent this most common cause of blindness in adults,” said study co-principal investigator Murray Brilliant, PhD, director of the Marshfield Clinic Research Foundation Center for Human Genetics in Marshfield, Wisc. “Imagine telling patients we potentially have medication that will allow them to see and continue enjoying life, their family and perform everyday activities as they age. That is very powerful.”

Dr. Paul A. Sieving, director of the National Eye Institute, a branch of the National Institutes of Health, said the research “suggests an intriguing link between patients taking l-dopa and a lower incidence and delayed onset of AMD. Showing that l-dopa causes this protective effect will require further investigation, but if confirmed, could lead to new drugs or combination therapies for AMD that target dopa-responsive cells in the retina.”

Dr. McKay pursued this research after he discovered that the support tissue for the retina expressed a receptor for l-dopa, and that this signaling pathway fostered retinal survival. He and Dr. Brilliant, who previously was with the UA, hypothesized that those taking l-dopa may be protected from AMD.

To answer this question they analyzed the health records of 37,000 Marshfield Clinic patients to determine who had macular degeneration, who took l-dopa, or both. Dr. Brilliant found that patients who began taking l-dopa before they developed macular degeneration were diagnosed with the eye disease eight years later than those who had never taken l-dopa. They also noted that there were many fewer AMD patients in the group that were prescribed l-dopa.

The next phase of the research involved analysis of a much larger, insurance-industry database of medical records on 87 million patients. The same connection between l-dopa and macular degeneration held. Further, with this enormous dataset, they were able to show that l-dopa both prevented and delayed wet AMD, which is far less common than dry AMD but is responsible for about 90 percent of AMD-caused blindness.
A clinical trial to further validate these research findings will be the next step of the research.

Cataract-Staving Drop Identified
A chemical that could
potentially be used in eye drops to reverse cataracts has been identified by a team of scientists from UC San Francisco, the University of Michigan and Washington University in St. Louis.

Identified as a “priority eye disease” by the World Health Organization, cataracts affect more than 20 million people worldwide. Most individuals blinded by severe cataracts in developing countries go untreated.

Reported November 5, 2015 in Science, the newly identified compound is the first that is soluble enough to potentially form the basis of a practical eye-drop medication for cataracts.

As is seen in neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease, a hallmark of diseases of aging is the misfolding and clumping together of crucial proteins. In the case of cataracts, the affected proteins are known as crystallins.

Crystallins are the major component of fiber cells, which form the eyes’ lenses, and the unique properties of these cells make them particularly susceptible to damage, said Jason Gestwicki, PhD, an associate professor of pharmaceutical chemistry at UCSF and co-senior author of a paper on the new research.

“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 Dr. Gestwicki. “So the crystallins you have in your eye as an adult are the same as those you’re born with.”
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. The crystallins accomplish these duties with the help of aptly named proteins known as chaperones, which act “kind of like antifreeze,” Dr. 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 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 began with 2,450 compounds, eventually zeroing in on 12 that are members of a chemical class known as sterols. One of these, known as 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, Dr. Gestwicki and his group assembled and tested 32 additional sterols, and eventually settled on one, which they call “compound 29,” as the most likely candidate that would be sufficiently soluble to be used in cataract-dissolving eye drops.

In laboratory dish tests, the team confirmed that compound 29 significantly stabilized crystallins and prevented them from forming amyloids. They also found that compound 29 dissolved amyloids that had already formed. Through these experiments, said Dr. Gestwicki, “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.”

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.
Dr. 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 Dr. 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.

“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,” Dr. 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.”  REVIEW