Eye drops against cataracts

Researchers at the University of California at San Francisco, the University of Michigan and the University of Washington have identified a compound that, when used as part of eye drops, can eliminate the manifestations of cataracts.

The World Health Organization (WHO) has recognized cataract, which affects more than 20 million people worldwide, as a priority eye disease. With cataracts, progressive opacification of the eye crystal occurs, eventually leading to complete loss of vision. Despite the existence of effective surgical methods for the treatment of cataracts, in developing countries, the majority of patients who lose their eyesight do not have access to such interventions.

Cataract is mainly an age-related disease. As with neurodegenerative pathologies such as Alzheimer's disease and Parkinson's disease, cataracts are characterized by abnormal folding and aggregation of protein molecules. In the case of cataracts, crystallin proteins undergo pathological changes.

Crystallins are the main component of the fibrous cells that form the lens of the eye. Soon after a person is born, all fibrous cells lose the ability to synthesize new proteins and get rid of old ones, so the crystalline lens is not renewed throughout life. These unique features cause the predisposition of fibrous cells to irreversible damage.

For the normal functioning of the lens, this constant limited supply of crystallins must maintain not only the transparency, but also the elasticity of fibrous cells exposed to the muscles of the eye, constantly contracting and relaxing to ensure the focus of the gaze on objects at different distances.

This is achieved thanks to the participation of chaperone proteins, which have been supporting the solubility of crystallins for many decades. This equilibrium state is very fragile, since pathological aggregated forms of crystallins are much more stable than normally folded molecules. Therefore, chaperones of fibrous cells must constantly resist the pronounced tendency of crystallins to form aggregates. 

The authors, working under the guidance of Dr. Leah N. Makley and Dr. Kathryn McMenimen, devoted their research to the study of critical differences between normal crystallins and their amyloid (less soluble) forms. To do this, they applied a method known as high-throughput differential scanning fluorimetry, in which proteins emit a glow when they reach their melting point. 

The purpose of this work was to identify compounds whose presence reduces the melting point of amyloid forms of crystallins to normal values. First, the researchers tested 2,450 compounds, from which 12 of the most promising candidates were selected, all of them belonged to the sterol class. The ability of one of these compounds, known as lanosterol, to eliminate cataracts was demonstrated earlier in the work, the results of which were published in July this year in the journal Nature. However, due to the limited solubility of lanosterol, the authors of the work had to inject it into the eye tissue in the form of an injection.

Taking lanosterol and other sterols as a sample, the researchers synthesized and tested 32 additional compounds. The result of this was the identification of the most promising candidate, potentially capable of dissolving cataracts when used as part of eye drops. Today, this substance is known as "compound 29".

Experiments in test tubes have confirmed the ability of "compound 29" to provide pronounced stabilization of crystallins, prevent the formation of their amyloid forms, as well as dissolve already formed amyloids.

 

Five-week-old mice were instilled three times a week for six weeks into the right eye containing "compound 29" eye drops. An empty carrier solution was instilled into the left eye of the animals. At the end of the experiment, the condition of the animal lenses was assessed by biomicroscopy using a slit lamp, which demonstrated an increase in transparency. A white dotted line outlines the boundaries of the eyeball.

After that, the eye drops containing "compound 29" were tested on a line of mice with a mutation that causes a predisposition to cataracts. Examination of the eyes of animals using a slit lamp, similar to that used to assess the severity of cataracts in humans, showed that experimental drops provided partial restoration of transparency of the cataract-affected lens of animals.

Similar results were obtained when experimental eye drops were instilled in mice with naturally formed cataracts, as well as when "compound 29" was exposed to fragments of cataract-affected human lens tissue removed during surgical interventions.

The authors note that the assessment of the transparency of the lens using a slit lamp does not allow to directly assess the visual acuity and the effectiveness of "compound 29" as a means for the treatment of cataracts can only be determined during clinical trials. Currently, the license for "compound 29" belongs to one of the researchers who founded the company ViewPoint Therapeutics, working on the creation of a drug suitable for use in the clinic.

The authors believe that the scope of application of their results goes far beyond the treatment of cataracts. When examined under a microscope, the protein aggregates causing cataracts are practically indistinguishable from the protein aggregates causing Alzheimer's, Parkinson's and Huntington's diseases. Therefore, the researchers believe that the approach they have developed can be used to search for drugs potentially suitable for the treatment of neurodegenerative diseases.

Article by Leah N. Makley et al. Pharmacological chaperone for α-crystallin partially restores transparency in cataract models is published in the journal Science.Evgeniya Ryabtseva

Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the University of California, San Francisco:
Eye Drops Could Clear Up Cataracts Using Newly Identified Chemical.