NOV 06, 2015 11:49 AM PST

Mystery Steroid Compound Melts Cataracts and Improves Vision

The World Health Organization estimates about 20 million people worldwide are afflicted with cataracts, a visual problem caused by protein aggregations in the eye lenses. Cataract surgery has long been the standard of treatment for the condition. However, vision restoration may soon be possible through non-invasive interventions, via eye drops containing a steroid compound that can directly disintegrate the cataracts.
A sterol-based eye-drop medication may soon replace cataract surgery.

Cataracts and neurodegenerative diseases, like Alzheimer and Parkinson’s, share a common molecular hallmark: the misfolding and clumping of proteins. In cataracts, the proteins are called crystallins and make up the major component of fiber cells in the eye lenses.
Several unique features about crystallins contribute to the pathology of cataracts. First, crystallins play a crucial role in visual acuity, aiding in the lenses’ flexibility and transparency. Secondly, though crucial for our vision, the crystallins are neither replenished nor removed in the aging process. This is because the fiber cells in the eye lenses cannot make new crystallin proteins long after birth. Thus, our precious crystallin stash is finite and permanent. To make the situation more precarious, crystallins have a natural affinity to clump together, forming pathological amyloids. Though noxious, the biological scale tips in favor of the amyloid clumps as these are more structurally stable than the healthy, clump-free form.
The two most abundant crystallins are CRYAA and CRYAB. These act as molecular chaperones, preventing damaged or misfolded proteins from clumping together. Jason Gestwicki, co-senior author of the research team, likened the chaperones as "kind of like antifreeze, keeping crystallins soluble in a delicate equilibrium that's in place for decades and decades."
But as we age, the chaperones eventually become overwhelmed with the accumulation of damaged proteins, and the clumping happens more frequently until it results in cataracts.
In an effort to treat cataracts non-invasively, researchers have tried to restore equilibrium by honing in on CRYAA and CRYAB. The research team found that the crystallin CRYAB possessed a much higher melting temperature than normal in a type of hereditary cataract condition. Exploiting this temperature difference, the team screened 2,450 compounds that have the potential to bind to CRYAB and lower its melting temperature back to the normal steady state.
The massive hunting expedition resulted in a sterol molecule that’s secretly veiled under the banal identification of “compound 29.” The research team found that compound 29 stabilized the CRYAB crystallin, thereby preventing amyloid formation. Furthermore, compound 29 melted the amyloid clumps that were already formed, reversing the pathological protein aggregates. Treatment of this compound in mice with both age-related and hereditary cataracts showed successful reversal of the cataracts. Within just 4 weeks of treatment, the mice showed a one-grade improvement in the cataract severity. This fast disappearing act is quite a feat considering that it takes decades for the amyloid clumps to form into cataracts.
Earlier this year, another steroid, lanosterol, was reported to dissolve amyloid clumps in dogs. However, compound 29 earns a unique merit because it has higher solubility than lanosterol, allowing the administration of the drug through eye drops instead of injections. This makes compound 29 a game-changer in the treatment of cataracts, as the potent drug could be easily self-administered at home.  And though cataract surgery has become a routine, the procedure is largely inaccessible for patients in underdeveloped countries. Having an effective commercialized drug for cataract could greatly reduce the prevalence of this condition worldwide.
The team cautions that the mechanism of how compound 29 works has to be further researched before clinical trials can begin. To this end, Gestwicki’s biotech company, ViewPoint Theraputics, holds the license to the compound and has begun additional animal studies. They aim to launch clinical trials in 2016.

Watch the video to learn more about cataract treatment through history. It’s sure to make you more appreciative of the future of our ophthalmological progress.

Source: Science
About the Author
Doctorate (PhD)
I am a human geneticist, passionate about telling stories to make science more engaging and approachable. Find more of my writing at the Hopkins BioMedical Odyssey blog and at
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