“Whatever you may look like, marry a man your own age – as your beauty fades, so will his eyesight.”
The famous quote by American stand-up comedian, Phyllis Diller, does make us wonder as to how philosophical we need to get to accept our old age debilities. But science has constantly provided us with new solutions to make sure that age is just a number.
One of the recent scientific inventions by researchers at the University of California at San Francisco (UCSF), University of Michigan (U-M), and Washington University in St. Louis (WUSTL) is a chemical that can be potentially added to eye drops to reverse cataracts!
Our eye lens has a crystalline structure made up of water soluble proteins known as ‘Crystallins’ which form the major lens protein and also of transparent lens fibers. The crystallins aggregate and pack tightly within the fibres. Cataracts mainly occur during old age due to the misfolding and clumping together of these crystallin proteins. It is the most common cause of blindness worldwide and is associated with decrease in vision, halos around light, trouble with bright lights, and trouble seeing at night.
The eye stops synthesizing crystallins a little while post birth and these limited candidates have a difficult duty to perform in maintaining the transparency of the eye lens as well as their flexibility. Crystallins carry out these tasks with the help of anti-freeze proteins known as ‘Chaperones’ which maintain their solubility and resist their clumping.
Clumped crystallin structures are also called ‘amyloids’, similar to those observed in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Amyloids and have a higher melting point and hence are more stable than their flexible healthy counterparts.
The current study aimed at lowering the melting point of these amyloids to reverse cataracts and was led by Leah N. Makley, PhD, and Kathryn McMenimen, PhD at U-M under the supervision of Dr. Jason Gestwicki, associate professor of pharmaceutical chemistry at UCSF. (Prof. Gestwicki has moved to UCSF since the last 2 years but the current research was mainly carried out in his laboratory at U-M). They employed a technique known as high-throughput differential scanning fluorimetry, or HT-DSF, in which proteins emit light when they reach their melting point. They heated amyloids using HT-DSF while scanning a library of 2,450 compounds. These compounds were tested for their ability to lower the melting point of the amyloids to their melting point to the physiological range. Finally they were able to identify a chemical called ‘Compound 29’ a ‘sterol’ which was successful in stabilizing crystallins, deterring them from forming aggregating. It also dissolved pre-existing amyloids.
A similar research published in July 2015 by Ling Zhao from University of California (UC), San Diego, which not only identified the mutations leading to congenital cataracts but also showed that the compound Lanosterol dissolved cataracts in dogs. This research helped Gestwicki’s team narrow down their list of compounds and focus on sterols. Zhao’s study did have limitations wherein Lanosterol had low solubility and had to be injected into the eye. A previous post on the same can be read here.
Compound 29 was further tested for its efficacy in mouse models of hereditary cataract where a partial restoration of transparency was observed in their lenses. Compound 29 had the same effect when tested on mice which had naturally developed cataract and human lenses extracted after cataract surgeries. These experiments were carried out under the guidance of Usha P. Andley, PhD, professor of ophthalmology and visual sciences at WUSTL School of Medicine. “We are starting to understand the mechanism in detail. Gestwicki said, “We know where Compound 29 binds, and we are beginning to know exactly what its doing.”
Gestwicki has obtained a license for Compound 29 from U-M for human clinical trials and Leah Makely has founded a company called ‘ViewPoint Therapeutics’ which is focusing on its development for the trials. Gestwicki was also the winner of the prestigious UCSF Catalyst Award through which he obtained guidance and funding for ViewPoint.
An elated Gestwicki said “This is the first project I’ve taken this far from the laboratory to the clinic. I had some idea of the complexity and number of pieces involved in a drug discovery process but the Catalyst Awards allowed us to get quickly up to speed on the aspects of drug discovery that we were less familiar with, which was really valuable.”
Although cataract removal through surgery is common, it is still quite expensive in the developing nations where even healthcare is still unaffordable to many. This invention can not only help humans but also dogs which are prone to developing cataracts by the age of 9. It’s a landmark invention which goes way beyond the cataract field. 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.”
Original Source: UCSF.