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Compound Found to Reverse Lens Clouding in Cataracts

Eye exam

U.S. Air Force doctor examining elderly patient in Honduras. (U.S. Southern Command)

6 November 2015. A biochemical and medical research team discovered a steroid that when given as eye drops to mice, reverses the accumulation of protein formations in cataracts. Researchers from the labs of protein chemistry professor Jason Gestwicki at University of Michigan and ophthalmology professor Usha Andley at Washington University in St. Louis published their findings in today’s issue of the journal Science (paid subscription required). Gestwicki and many of his colleagues since relocated to University of California in San Francisco.

Gestwicki and first author Leah Makley are co-founders of the biotechnology company Viewpoint Therapeutics in San Francisco that licensed the technology described in the paper from University of Michigan. Makley is Viewpoint’s chief scientist, while Gestwicki is on the board of directors and Andley serves as a scientific adviser to the start-up company.

Cataracts are considered the world’s leading cause of blindness, according to World Health Organization, resulting in blindness for some 20 million people worldwide, more than half of all people with total vision loss. Center for Disease Control and Prevention says in the U.S., more than 20 million people have cataracts in one or both eyes, with the number of Americans with cataracts expected to increase to 30 million by 2020.

Cataracts form on the eye lens when proteins known as crystallins misform and accumulate, causing the cloudiness and progressive loss of vision. For most of people’s lives, crystallins provide the lenses’ focusing power, and are helped along by two specific crystallin proteins — cryAA and cryAB — known as chaperones that keep crystallins soluble and prevent them from clumping together into formations called amyloids. As we age, however, chaperone proteins in some people become overwhelmed by the accumulation of amyloids from misformed crystallins, resulting in cataracts.

Surgery can remove lenses with cataracts, replaced with artificial lenses, and more than 6 million people in the U.S., says CDC, had this surgery, which can be performed as an outpatient procedure. But surgery is often not available in limited resource regions, leaving no practical treatments for millions of people afflicted with cataracts.

Gestwicki, Andley, and colleagues sought an alternative to surgery and began reviewing biocompatible compounds that can act on cataracts. The team used differential scanning fluorimetry, a screening technique to identify low-molecular weight compounds that bind to and stabilize proteins. The high-throughput screens measure the increase in fluorescence of a dye exposed as a protein unfolds in response to increasing heat, as they reach the point of melting.

In this case, the team looked for compounds that lower the melting point of crystallin amyloids to the range of normal crystallins, which the researchers tested as they heated amyloid samples. They screened more than 2,400 molecules similar to cryAA and cryAB, and found 12 candidates in a class of steroids known as steroid alcohols or sterols. Earlier this year, a U.S.-Chinese team found lanesterol, also a sterol, to prevent and reverse cataracts, in tests with dogs, but required injections as well as eye drops.

Further screens of the 12 candidates narrowed to a single sterol performing better than the others that the researchers call compound 29. The researchers first tested compound 29 on mouse lenses affected by cataracts, and then administered compound 29 as eye drops in aged mice with naturally developed cataracts. The results show compound 29 restored at least some transparency to the mouse lenses and living mice. Further lab tests on lenses with cataracts in human eyes returned similar results.

The authors caution that they measured the amount of cataract formation using a standard classification scale from slit-lamp microscope images. They did not directly measure visual acuity.

ViewPoint Therapeutics, founded by Gestwicki and Makley licensed compound 29, which they intend to develop into an eye drop therapy for cataracts in humans. Cataracts also form in dogs, often as a result of heredity or diabetes, and are common across a number of breeds. Thus, eye drops for cataracts could help more than just humans as they age.

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