New Therapeutic Target to Advance the Treatment of Diabetic Retinopathy

In a recent study, a new therapeutic target called ADAM10 was identified that could be used to treat diabetic retinopathy (DR), a disease that results in long-term diabetes-related blindness. The primary symptom of DR is abnormal blood vessel development in the eyes of diabetic patients, which could potentially lead to vision loss.

The study, which was published in the journal Theranostics, showed that it was able to limit the abnormal development of blood vessels in preclinical animals by restoring the activity of ADAM10, a significant shedding protein, providing an attractive therapeutic target to cure DR.

The research team is examining the potential of ADAM10 in various aspects of angiogenesis and how it may be translated into helpful solutions for patients as part of a collaborative effort with 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).

Currently, 103 million people worldwide are impacted by DR. Research by the Centers for Disease Control and Prevention (CDC) found that diabetic people are most likely to acquire DR—almost one in three of them. In the working-age population around the world, it is the main contributor to visual impairment and blindness.

Early on, DR typically exhibits no symptoms and is frequently only identified when the disease has progressed and requires rapid medical attention. Anti-VEGF (Vascular Endothelial Growth Factor) injections are the only currently approved method of treatment for DR, however only about half of patients benefit from it.

In order to determine impaired mechanistic aspects within the eye, the research team, under the direction of Dr. Jayantha Gunaratne, Senior Principal Investigator at IMCB, performed a thorough analysis of the eye fluid samples from a well-defined cohort of proliferative DR patients against the control cohort.

ADAM10 - An Appealing Therapeutic Option for Retinal Angiogenic Illnesses

The findings suggest that the molecular makeup of eye fluids is indicative of the state of the eye's health because eye fluids from DR patients showed unique protein patterns when compared to the control cohort. The scientists learned that defective protein shedding by ADAM10 is a key clinical characteristic of DR by analyzing these changed profiles from DR patients.

These findings were further validated in collaboration with the Duke-NUS research team using preclinical models of eye diseases and well-established cell lines in molecular, cell biological, and functional assays to confirm the effectiveness of the new target ADAM10 in regulating abnormal blood vessel growth in the eye. ADAM10 presents itself as an appealing therapeutic option for retinal angiogenic illnesses since it regulates a variety of physiological processes, including neuronal and vascular components.

This finding offers significant new information about the underlying causes of DR and paves the way for the development of potent medicines for DR patients, including those who do not respond well to anti-VEGF therapies. In order to properly manage or stop abnormal blood vessel development in the eyes of DR patients, researchers have discovered the participation of additional potential molecular players that are still unknown.

"Through our collaborations with the local health care 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 health care outcomes,” said Professor Hong Wanjin, Executive Director at A*STAR's IMCB.

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."

References: Asfa Alli-Shaik et al, System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy, Theranostics (2022): https://www.thno.org/v12p6682.htm