Fight Aging!

Some types of cataract involve the formation of amyloid deposits in the lens of the eye made up of damaged crystallin. Researchers have made progress of late in finding sterols that clear this form of amyloid. This is of general interest as there are many types of amyloid that form in tissues in increasing amounts with advancing age, some of which are clearly linked to the pathology of specific age-related conditions. Progress towards effective means of clearance for any one amyloid might turn out to be the starting point for the development of a broader technology platform for therapies, so it is worth paying attention. Here is an update on the development of sterol compounds targeting crystallin amyloid:

In order for our lenses to function well, a 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, 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.

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, 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, the researchers 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, "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."

In addition to compound 29's potential for cataract treatment, the insights gained through the research could have broader applications. "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. 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."

Link: http://universityofcalifornia.edu/news/clearing-cataracts-eye-drops