In brief

Researchers found that restoring the function of ADAM10 sheddase enzyme prevents uncontrolled angiogenesis, making it a potential molecular target for treating diabetic retinopathy.

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Shedding light on diabetic blindness

9 Oct 2023

The discovery of an enzyme that prevents the formation of abnormal blood vessels may enable clinical strategies to manage diabetes-associated blindness.

Much of our vision can be attributed to the retina—a small, delicate layer of cells at the back of the eye which detects and processes visual information. People with diabetes, however, are prone to blurry eyesight as the intricate network of blood vessels that feed the retina become leaky, damaged and scarred due to chronically elevated blood glucose levels.

Diabetic retinopathy (DR) is an irreversible vision impairment that affects a third of patients with diabetes and is currently one of the leading causes of blindness in Singapore.

A treatment option known as anti-VEGF (vascular endothelial growth factors) therapy is often administered to slow the progression of DR, but not all patients benefit from it. “Close to 50 percent of the patients are refractory or develop resistance over time to the treatment,” said Jayantha Gunaratne, a Senior Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB). “This calls for an imminent need to exploit other alternative therapies.”

The vitreous, a clear, gel-like substance that fills the space between the eye’s lens and retina holds clues to current and future DR therapies, said Gunaratne. “VEGF was first discovered from DR vitreous previously, which led to the development of anti-VEGF therapy that has completely transformed clinical management of DR.”

Together with co-corresponding author, Xiaomeng Wang at Duke-NUS Medical School Singapore, Gunaratne and team collaborated with researchers from the Singapore Eye Research Institute and the Singapore National Eye Centre on a project to investigate differences in the vitreous profiles of DR patients and healthy individuals.

The researchers analysed vitreous samples using an advanced mass spectroscopy technique coupled with computational methods to determine the molecular compositions associated with DR. The team found that a sheddase enzyme called ADAM10 which helps in the formation of new blood vessels was defective in DR patients. They also observed that restoring ADAM10 function using a natural compound derived from green tea prevents uncontrolled blood vessel formation (angiogenesis) in a mouse model of DR. The first author of the work, Asfa Alli-Shaik, who drove the computational aspects noted that deep interrogation of proteome profiles allows uncovering molecular mechanisms to exploit novel therapies.

This exciting discovery can help steer future research on better DR treatments by targeting alternative pathways to those in anti-VEGF therapy.

Gunaratne is bracing for the challenges that lie ahead, given that restoring ADAM10 function clinically will be difficult to achieve using existing drug modalities. “This will first require the mechanistic elucidation of ADAM10 activation pathways,” said Gunaratne. Unfazed, the team has begun engaging with academic and industry stakeholders to begin translating their breakthrough findings into a new therapy for DR patients.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB).

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Alli-Shaik, A., Qiu, B., Lai, S.L., Cheung, N., Tan, G., et al. System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy. Theranostics 12 (15), 6682-6704 (2022). | article

About the Researcher

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Jayantha Gunaratne

Principal Investigator

Institute of Molecular and Cell Biology
Jayantha Gunaratne obtained his PhD degree from Tokyo Institute of Technology, Japan, in 2003 where he received training on gas and liquid chromatography, mass spectrometry and nuclear magnetic resonance technologies. In 2004, he joined the Scripps Institution, University of California San Diego, US, as a postgraduate research scholar. He moved to Singapore in 2007 and was a founder member of the Mass Spectrometry and Systems Biology Laboratory at A*STAR’s Institute of Molecular and Cell Biology (IMCB), pioneering the establishment of high-resolution advanced quantitative proteomics technology in Singapore. He is currently a Principal Investigator heading translational biomedical proteomics research at IMCB and an adjunct Associate Professor at Yong Loo Lin School of Medicine, National University of Singapore.

This article was made for A*STAR Research by Wildtype Media Group