Clinical Trial Spotlight

For whom the cell tolls


For Whom the Cell Tolls

A treatment that targets toll-like receptors may halt progression to advanced dry AMD.


Much of the research into geographic atrophy, the advanced form of dry age-related macular degeneration, focuses on the effects of oxidative stress and complement-mediated pathways. However, a new clinical trial of a compound under investigation at the University of Kentucky Medical Center will instead look at the immune system and the role it may play in advanced dry AMD.

RNA-144101, an inhibitor of toll-like receptor 3 (TLR3), is the drug. The toll-like receptors are proteins that play an important role in immune response. Each has specific ligands; TLR3 binds to double-stranded RNA. RNA-144101 competes in this binding process.

In preclinical testing, the drug prevented the loss of cells from the retinal pigment epithelium in mice. Now it will be tested in humans in a phase 1 trial set to begin enrolling soon. Jayakrishna Ambati, MD, professor of physiology and professor and vice chair of the Department of Ophthalmology & Visual Sciences at the University of Kentucky, spoke with Retinal Physician about this trial.


Asked about the mechanism of action of RNA-144101, Dr. Ambati described the likely role of TLR3 in geographic atrophy. “TLR3 is expressed on the RPE,” Dr. Ambati said. “TLR3 activation is a potent innate immune response signaling mechanism that promotes RPE cell death. My lab has found increased levels of TLR3 agonists and of TLR3 activation in the RPE of patients with geographic atrophy. Therefore we have chosen to target this particular immune receptor.”

Given the role that the death of RPE cells plays in the progression of dry AMD to geographic atrophy, Dr. Ambati and his colleagues believe that TLR3 is critical in this process. If RPE apoptosis can be prevented, progression to geographic atrophy may be arrested. “Levels of TLR3 agonists and receptor activation are increased in the RPE of patients diagnosed with advanced, dry AMD compared to age-matched controls,” Dr. Ambati said.

One thing this trial will not examine is whether RNA-144101 can help prevent progression of dry AMD to the disease's exudative form. “We do not anticipate that this compound will be preventative in the progression of wet AMD,” Dr. Ambati said. However, preclinical data on the drug indicate that its effectiveness in halting the progression of geographic atrophy may be quite useful in preventing vision loss. The drug also appears safe; besides the aforementioned murine trial, other animal trials revealed no adverse effects under a battery of tests, including electroretinogram, electron microscopy and serial fundus photography. Furthermore, in vitro testing on human tissues showed no cytotoxicity.


The University of Kentucky trial will enroll 18 patients, and this enrollment is expected to begin later this year. Patients will participate in the study for a year. It will be a dose-escalation study, and like other phase 1 trials, the key end-point will be safety and tolerability.

Nevertheless, Dr. Ambati and his colleagues will be keeping an eye on other possible positive outcomes. “We will be conducting appropriate testing to detect a preliminary signature of efficacy,” Dr. Ambati said. “This would be suggested by stabilization or a decrease in the total aggregate area of RPE loss on fundus exam compared to pre-existing geographic atrophy progression data and the fellow eye. In addition to standard visual exam data, we will also be analyzing fundus autofluorescence imaging to assess RPE cell health.”

Because of the small size of the trial, the University of Kentucky will be the sole recruitment site. Provided the study meets its endpoints, larger, more inclusive studies of RNA-144101 will follow.

More information on the trial can be found online at: RP