EYE DROPS COULD CLEAR UP CATARACTS USING NEWLY IDENTIFIED CHEMICAL
A
chemical that could potentially be used in eye drops to reverse cataracts, the
leading cause of blindness, has been identified by a team of scientists from UC
San Francisco (UCSF), the University of Michigan (U-M), and Washington
University in St. Louis (WUSTL).
Identified as a
"priority eye disease" by the World Health Organization, cataracts --
caused when the lenses of the eyes lose their transparency -- affect more than
20 million people worldwide. Although cataracts can be successfully removed with
surgery, this approach is expensive, and 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.
Cataracts are
primarily a disease of aging. As is seen in neurodegenerative conditions such
as Alzheimer's disease and Parkinson's disease, a hallmark of the condition 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, associate professor of pharmaceutical chemistry at UCSF
and co-senior author of a paper on the new research, most of which was
undertaken in Gestwicki's laboratory at the U-M Life Sciences Institute.
"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."
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 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, 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
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.
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.
ViewPoint was formed
through the "incubator" program of the California Institute of Quantitative
Biosciences (QB3) at UCSF, and is located adjacent to the UCSF campus in QB3's
Janssen Labs.
McMenimen, also a
former graduate student in the Gestwicki laboratory, is now the Claire Boothe
Luce Assistant Professor of Chemistry at Mt. Holyoke College. The research was
supported by the National Institutes of Health, the American Foundation for
Pharmaceutical Education, and Research to Prevent Blindness.
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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