Dr. Kenneth Shindler tests the visual function of mice.
By Rebecca Salowe
Scheie Vision Annual Report 2018
Kenneth Shindler, MD, PhD, an Associate Professor of Ophthalmology and Neurology at the University of Pennsylvania, has spent his career studying methods to prevent damage to the optic nerve. A recent collaboration with Noveome Biotherapeutics has turned his research in a new and surprising direction. Together, these researchers showed that a biologic (i.e. naturally derived drug) called ST266 can prevent damage to the optic nerve and lessen vision loss, when intranasally delivered in mice.
Optic nerve disorders such as optic neuritis (inflammation) and traumatic optic neuropathy (acute injury following blunt head trauma) are notoriously difficult to treat. These disorders are not rare: approximately 50% of patients with multiple sclerosis have an episode of optic neuritis, and more than half of these patients experience permanent visual dysfunction, even after acute inflammation resolves. Traumatic optic neuropathy occurs in up to 5% of blunt head injuries, and is one of the leading ocular injuries sustained in military combat.
Dr. Shindler addresses the challenge of treating these patients: "Numerous therapies have been tried, and none have worked," he said. "People have advocated for high-dose steroids for traumatic optic neuropathy, but there is little evidence that they help patients. Optic nerve trauma results in permanent vision loss so there's a great need to prevent this loss of vision."
Over the past decade, as Dr. Shindler continued to study the mechanisms of optic nerve disorders, Noveome began to investigate a unique biologic called ST266, a solution containing secreted proteins produced by culturing a novel population of human amnion epithelial cells under proprietary conditions. This solution includes growth factors and cytokines that have anti-inflammatory and neuroprotective effects in human cells.
"Their initial reasoning for studying this biologic was wound healing," explained Dr. Shindler. "It was based on the observation that when surgeries are conducted in utero in human babies, the babies are born without a scar. The theory was that there was something about the amniotic fluid that the baby is bathed in that may promote wound healing."
Researchers at Noveome indeed found that ST266 was effective in topically treating wounds. They then experimented with administration of the biologic through the nose, hoping to surpass the blood-brain barrier and achieve delivery directly to the brain. "They found that the highest concentration of the proteins went to the eye and the optic nerve," said Dr. Shindler. Noveome contacted Dr. Shindler to inquire about testing ST266 in his animal model of optic nerve disease. "They said, 'We have this solution that reduces inflammation, prevents nerve cell damage, and goes to the eye and optic nerve. Can you test it in your models?'"
Still tentative, Dr. Shindler and colleagues agreed to proceed with a preclinical study in a mouse model with multiple sclerosis (simulating optic neuritis). "It was so unique that I thought it was worth trying," he recalled. As hoped, the biologic accumulated in rodent eyes and the optic nerve. More surprising, however, was its efficacy. ST266 reduced inflammation, prevented loss of retinal ganglion cells, and attenuated visual dysfunction in the mice. "We were surprised that it worked better than anything we've ever tested in these animals," Dr. Shindler said. These results, published in Scientific Reports in 2017, received substantial media attention.
Researchers remained unsure, however, if ST266 was effective in protecting the optic nerve simply because it reduced inflammation. Thus, in 2018, Dr. Shindler's laboratory published results of a second preclinical study on mice with optic crush injury, which simulates conditions in humans caused by head injury. Again, the biologic was administered non-invasively through nasal passages by Dr. Shindler. These mice also showed reduction of optic nerve inflammation, increased survival of retinal ganglion cells, and a trend towards improved visual function. These results, published in Investigative Ophthalmology & Visual Sciences, not only confirmed the previous study, but also showed that the biologic has neuroprotective properties beyond just reducing inflammation.
The success of the preclinical studies naturally leads to the question: is it possible that this biologic could be effective in humans? Dr. Shindler and colleagues are working with Noveome to begin a Phase I clinical trial to determine the safety of ST266 delivery via targeted intranasal delivery. The trial, which will take place at Penn, will be conducted in patients with ocular hypertension (who have normal retinas, but are being screened for glaucoma risk).
These results also suggest that intranasal administration could become an alternative option to deliver existing drugs to the retina. Currently, intravitreal injections are the primary method of drug delivery to the retina; though effective, this route of delivery is invasive and carries a small risk of adverse events. Additional studies are needed in humans, but it is possible that intranasal delivery may offer a safer, easier, and less invasive method to deliver therapies to the retina.
Ultimately, ST266 may hold promise for treating not only optic neuritis and traumatic optic neuropathy, but other diseases that affect the optic nerve, such as glaucoma. The biologic also could have benefits in targeting neurodegenerative conditions of the brain, such as Alzheimer's or Parkinson's Disease. Though no conclusions can be made in humans until the completion of clinical trials, researchers remain hopeful about the potential that this biologic may hold.