UF scientists eye novel drug candidate with marine origins to treat vision loss

Researchers from the University of Florida and Singapore are focused on a novel drug candidate with marine origins as a new method to prevent or treat vision loss.

Chen and Luesch
Qi-Yin Chen, Ph.D., a research assistant professor of medicinal chemistry, and Hendrik Luesch, Ph.D., a professor and chair of medicinal chemistry, examined whether Apratoxin S4, a novel molecule based on marine cyanobacteria, could be an effective therapy in restricting abnormal blood vessel formation in the eye.

According to the U.S. Centers for Disease Control and Prevention, 12 million Americans 40 years and older experience vision loss. Abnormal blood vessel formation is a defining feature of many eye diseases, including neovascular age-related macular degeneration, neovascular glaucoma and advanced diabetic retinopathy. A protein called vascular endothelial growth factor, or VEGF, has been identified as a key regulator of new blood vessel formations in controlling eye health and diseases.

“Therapies that inhibit VEGF have revolutionized the treatment of many retinal diseases, such as age-related macular degeneration and diabetic retinopathy, over the last decade,” said Tien Y. Wong, M.D., Ph.D., a professor and chair of ophthalmology at the Singapore National Eye Center and Singapore Eye Research Institute, or SERI. “Despite this progress, for some of these diseases, up to 30-40% of patients do not respond to treatment, may develop resistance over time or require long-term maintenance therapy.”

UF College of Pharmacy researchers teamed with collaborators at SERI and at A*STAR’s Institute of Molecular and Cell Biology in Singapore, or IMCB, to see whether Apratoxin S4, a novel molecule based on marine cyanobacteria, could be an effective therapy in restricting abnormal blood vessel formation in the eye, which may be a potential treatment for these retinal diseases in the future.

Apratoxin S4 originates from a family of molecules known as apratoxins, which are found in select areas of the world’s oceans. Years of medicinal chemistry refinements have yielded several potential cancer therapies from apratoxins, and scientists are beginning to explore the molecule’s potential in treating other health conditions, such as eye diseases.

The research team discovered in laboratory testing that Apratoxin S4 inhibited the development of abnormal blood vessels in the eye but left normal blood vessel formation untouched. They found multiple methods of delivering the therapy proved effective, including systemic drug delivery into the bloodstream or local drug delivery into the back of the eye. Finally, they determined Apratoxin S4 can be an effective therapy on its own, or work in combination with VEGF-inhibiting drugs to stop the growth of abnormal blood vessels.

“Apratoxin S4 could potentially address the resistance problem to standard-of-care VEGF therapy by inhibiting multiple new blood vessel forming pathways,” said Hendrik Luesch, Ph.D., a professor and chair of medicinal chemistry and the Debbie and Sylvia DeSantis Chair in Natural Products Drug Discovery and Development in the University of Florida’s College of Pharmacy.

“Our colleagues in Singapore showed in various models the efficacy and potency of the compound,” he said, “and it acts through a mechanism that is distinct, yet partially overlapping, with VEGF therapy. This is consistent with our original hypothesis based on years of studying the mechanism of action.”

Xiaomeng Wang, Ph.D., an associate professor at the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore and A*STAR’s IMCB, led the biological studies.

“Angiogenesis is a complex process involving coordinated interactions between different types of cells,” Wang said. “Pericyte-covered vessels are believed to be protected from anti-VEGF drugs. Apratoxin S4 has unique features in that it affects the signaling and function of retinal microvascular endothelial cells and pericytes, which is likely to be more effective than drugs targeting a single type of vascular cells.”

Professor Wanjin Hong, Ph.D., executive director of A*STAR’s IMCB, noted the growing need for treatment options for eye diseases.

“The burden of eye diseases around the world is expected to increase in the future, with the population being vulnerable at every stage of life,” he said. “Therefore, an urgent need exists to develop such novel approaches to addressing vision loss for those affected or at risk.”

Alfred Lewin, Ph.D., a professor of molecular genetics and microbiology in the UF College of Medicine, has devoted his career to studying age-related diseases of the retina. While Lewin was not involved in the study, he called the findings a “welcome alternative” to current treatments — which target a single signaling system.

“Some patients do not respond to the proteins that are the current front-line treatment for the spread of blood vessels,” Lewin said. “This study describes the use of a small molecule medicine that prevents the spread of blood vessels by a totally different mechanism than current treatments. The authors demonstrate that it can be delivered systemically, as well as by injection in the eye, and this is another advantage to the new treatment.”

UF’s Luesch said researchers increasingly are looking for answers to vexing questions in every corner of the globe, including under the sea.

“The biodiversity of organisms in the world’s oceans offers vast potential for discovering promising drug candidates from cyanobacteria and other sources,” he said. “The apratoxin family of molecules have produced another novel drug candidate that has the potential to treat eye diseases and improve the eyesight for many Americans struggling with vision loss.”

The worldwide commercial rights to the apratoxin family of molecules are exclusively licensed to Oceanyx Pharmaceuticals Inc., a novel drug discovery and development company that leverages marine biology-based, natural product research.

The study, “Apratoxin S4 inspired by a marine natural product, a new treatment option for ocular angiogenic diseases” was published in the journal Investigative Ophthalmology & Visual Science — an online journal published by the Association for Research in Vision and Ophthalmology. It was supported by the SERI-IMCB Programme In Retinal Angiogenic Diseases and Oceanyx Pharmaceuticals Inc.