Removing AGEs from the Lens of the Eye to Treat Presbyopia

A few different approaches have been proposed to clear advanced glycation endproducts (AGEs) from the lens of the eye, where they build up with age to make the lens stiffer. That stiffness results from cross-linking of extracellular matrix molecules by AGEs, restricting their ability to move relative to one another, and thus changing the structural properties of thetissue. That in turn leads to presbyopia as the muscles of the eye can no longer produce the desired changes to the lens needed to focus on near objects. Sadly, the most advanced program of cross-link breaking for the eye, a formulation of lipoic acid choline ester, failed in its phase IIb clinical trial after promising earlier results. We might hope that other, similar approaches to lens cross-linking have a larger effect size, such as the work of Lento Bio, and the project noted here.

Presbyopia is an age-related vision disorder that is a global public health problem. Up to 85% of people aged ≥40 years develop presbyopia. In 2015, 1.8 billion people globally had presbyopia. Of those with significant near vision disabilities due to uncorrected presbyopia, 94% live in developing countries. Presbyopia is undercorrected in many countries, with reading glasses available for only 6-45% of patients living in developing countries. The high prevalence of uncorrected presbyopia in these parts of the world is due to the lack of adequate diagnosis and affordable treatment.

The formation of advanced glycation end products (AGEs) is a non-enzymatic process known as the Maillard reaction. The accumulation of AGEs in the lens contributes to lens aging (leading to presbyopia and cataract formation). Non-enzymatic lens protein glycation induces the gradual accumulation of AGEs in aging lenses. AGE-reducing compounds may be effective at preventing and treating AGE-related processes.

Fructosyl-amino acid oxidase (FAOD) is active on both fructosyl lysine and fructosyl valine. As the crosslinks encountered in presbyopia are mainly non-disulfide bridges, and based on the positive results of deglycating enzymes in cataracts (another disease caused by glycation of lens proteins), we studied the ex vivo effects of topical FAOD treatment on the power of human lenses as a new potential non-invasive treatment for presbyopia.

This study demonstrated that topical FAOD treatment resulted in an increase in lens power, which is approximately equivalent to the correction obtained by most reading glasses. The best results were obtained for the newer lenses. Simultaneously, a decrease in lens opacity was observed, which improved lens quality. We also demonstrated that topical FAOD treatment results in a breakdown of AGEs, as evidenced by gel permeation chromatography and a marked reduction in autofluorescence. This study demonstrated the therapeutic potential of topical FAOD treatment in presbyopia.