Caption: The core scientific research team, (L-R) Associate Professor Wang Xiaomeng from the
Cardiovascular and Metabolic Disorders Programme and Centre for Vision Research at Duke-NUS
Medical School, Research Scientist Dr Asfa Alli Shaik and Senior Principal Investigator Dr Jayantha
Gunaratne from IMCB, investigated disease-modified protein profiles in the eye to discover novel
therapeutic targets for Diabetic Retinopathy, a condition which leads to blindness induced by prolonged
diabetes.
SINGAPORE - A local study discovered a novel therapeutic target named ADAM10
that could be used to treat patients with Diabetic Retinopathy (DR), a condition which
leads to blindness induced by prolonged diabetes. Abnormal blood vessel formation
in the eyes of diabetic patients is a common phenomenon for DR which could
ultimately result in vision loss. The study, published in the journal Theranostics,
demonstrated that by restoring the function of ADAM10, a major shedding protein, it
was possible in preclinical models to control the abnormal formation of blood vessels,
offering an attractive therapeutic target to treat DR.
A collaborative effort involving researchers and clinicians from A*STAR’s Institute of
Molecular and Cell Biology (IMCB), Duke-NUS Medical School, SingHealth,
Singapore Eye Research Institute (SERI) and Singapore National Eye Centre (SNEC),
the research team is exploring the potential of ADAM10 in various aspects of
angiogenesis and how it may be translated into beneficial solutions for patients.
Currently, DR affects about 103 million people worldwide1
. According to a study done
by the Centers for Disease Control and Prevention (CDC), DR is most common among
diabetic patients, with almost one in three developing the condition. It is the leading
cause of visual impairment and blindness in the working-age population globally2
. DR
usually presents without any symptoms in the early phase and is often diagnosed
when the disease has advanced, requiring immediate treatment intervention. The
current available form of treatment for DR is anti-VEGF (Vascular endothelial growth
factor) injections, however only around half of DR patients respond to the treatment.
The research team, led by Dr Jayantha Gunaratne, Senior Principal Investigator at
IMCB, conducted a comprehensive analysis of the eye fluid samples from a well-defined cohort of proliferative DR patients against the control cohort to deduce
impaired mechanistic aspects within the eye. The findings show that eye fluids from
DR patients displayed distinct protein patterns compared to the control cohort,
implying that the molecular composition of eye fluids is reflective of the health status
of the eye. By interrogating these altered profiles from DR patients, the team
discovered impaired protein shedding by ADAM10 as a prominent disease feature of
DR.
Working with the research team from Duke-NUS, these results were further validated
using well-established cell-line and preclinical models with eye diseases through
molecular, cell biological and functional assays to confirm the efficacy of the new target
ADAM10 in controlling abnormal growth of blood vessels in the eye. With ADAM10
regulating various functional processes including neural and vascular aspects, it
presents itself as an attractive therapeutic option for retinal angiogenic diseases.
This discovery provides key insights to the cause of DR and opens up a new path for
developing effective therapeutics for DR patients, including patients who do not
respond well to anti-VEGF treatments. Researchers also uncovered the involvement
of other unknown potential molecular players in DR and the importance of
understanding their mechanistic roles to effectively control or stop abnormal blood
vessel formation in the eyes of DR patients.
Professor Hong Wanjin, Executive Director at A*STAR’s IMCB, said, “Through our
collaborations with the local healthcare ecosystem, we have made significant progress
with the discovery of therapeutic target ADAM10 – This is a breakthrough for the
scientific community and will help advance the development of targeted therapeutics
leading to better healthcare outcomes.”
Dr Jayantha Gunaratne, Senior Principal Investigator at A*STAR’s IMCB and lead
author of the study, said, “This proteomics-centric discovery is a paradigm shift from
conventional to non-conventional drug target identification, focusing on protein
shedding activities of cell membrane proteins. It is a novel direction with immense
potential for investigating effective therapeutics for several other diseases as well.”
Professor Gemmy Cheung from the SingHealth Duke-NUS Ophthalmology and Visual
Sciences Academic Clinical Programme and Head and Senior Consultant, Medical
Retina Department at SNEC, said, “This collaboration between IMCB and SERI
provided our researchers and clinicians an immensely valuable platform to combine
our expertise towards the discovery of new treatments targeting DR. The combination
of eye fluid samples from patients and their clinical information provides our
researchers with a very powerful dataset from which the sophisticated analytical
methods was able to discover the new findings. We are confident that these
discoveries will lead to improved understanding and treatment of DR.”
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1 Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and
Meta-analysis, Ophthalmology, Volume 128, Issue 11, November 2021
2 International Diabetes Federation