NEI awards Scripps Research $10.2M grant to develop new treatments for vision disorders

A team led by a scientist from The Scripps Research Institute has been awarded a five-year, $10.2 million grant from the National Eye Institute (NEI) to develop a new type of treatment for diabetic retinopathy, macular degeneration, and other common vision disorders.

Martin Friedlander, a professor at Scripps Research and an ophthalmologist/retina specialist at Scripps Clinic, will collaborate on the project with molecular pathologist David Cheresh and biochemist Michael Sailor of the University of California (UC), San Diego.

The new treatment strategy targets a strand of regulatory "micro-RNA" in retinal cells that acts as an on-switch for new blood vessel growth. The inappropriate blooming of new blood vessels at the back of the eye, triggered by a decline in blood flow from aging, diabetes, or other conditions, is the leading cause of sight loss in adults. Diabetic retinopathy is estimated to affect a large proportion of diabetics, totaling more than 100 million people around the world. Millions of other, non-diabetic elderly people have a similar vessel-overgrowth condition known as wet, or neovascular, macular degeneration.

"We're very excited about this new direction our research has taken with microRNAs and induced pluripotent stem cells and continue to be extremely pleased by the strong support we receive from the National Eye Institute and other funding sources," Friedlander said. "Even with the advent of new therapies over the past few years, there is still a very large, unmet medical need in the area of retinal vascular and neurodegenerative diseases."

The project originated from a meeting two years ago between Friedlander and Cheresh. Cheresh and his team had found a small strand of gene-regulating RNA, a "micro-RNA" known as miR-132, that acts as an on-switch for the hyper-growth of new blood vessels (angiogenesis) in tumors. They had found that they could turn this angiogenesis switch off in both cell and mouse models by adding a solution of complementary micro-RNA, anti-miR-132, which latches onto miR-132 and blocks its biological activity.

Friedlander and Cheresh recognized that anti-miR-132 might also work against the abnormal blood vessel blooms that cause common retinal diseases. When Friedlander applied Cheresh's anti-miR-132s to his own lab's rodent models of pathological angiogenesis, he observed a dramatic effect in halting new blood vessel growth.

In adult eyes, angiogenesis usually occurs only in pathological conditions, so stopping it shouldn't harm normal processes. In contrast, recently introduced treatments for retinal vascular diseases affect more than just angiogenesis. The leading therapies block the action of VEGF-1, a growth factor upregulated by hypoxia, and inflammation associated with age-related macular degeneration and diabetic retinopathy. Blocking VEGF-1 does help stabilize abnormal blood vessels, but it also blocks VEGF-1's nourishing effects on normal blood vessels and retinal photoreceptors (e.g. rods and cones), leaving them more vulnerable to stress and degeneration. By contrast, the biological pathway activated by miR-132 in the eye appears to be much more tightly associated with angiogenesis.

"We're hoping that the blocking of miR-132 in the eye will have few or no significant side effects," Friedlander said.

During the grant period, Friedlander and Cheresh will be working closely with UC San Diego biochemistry professor Michael J. Sailor, an expert on nanotechnology-based drug delivery systems. Standard methods of delivering drugs to the back of the eye require frequent injections into the eye, which bring risks of damage and infection.

"We have some very exciting preliminary results suggesting that we can inject nano-particles that Mike's lab has designed, and these slowly release a steady dose of anti-miRs over several weeks to months, which could mean a lot fewer injections than with standard treatments," Friedlander said.

Under the new grant, Friedlander and his colleagues also will explore the activities of other miRs in human retinal vascular disorders, and the effects of blocking them.

The team expects to have one or more anti-miRs ready for clinical trials by the end of the five-year grant period. Regulus Therapeutics, a San Diego-based biotech company, and a leader in microRNA based drug design, will be a collaborator to assist with early-stage clinical development and modify anti-miRs to increase potency or extend their duration of action.