A group of researchers from the University of California, Berkeley, is taking a new path of treatment development for eye diseases such as retinitis pigmentosa (RP), a blinding disease caused by photoreceptor degeneration. They think that reducing the noise generated by nerve cells in the eye, which can interfere with vision, should bring images more sharply into view, helping people with retinitis pigmentosa and other types of retinal degeneration, including age-related macular degeneration.
The research, done in the lab of Richard Kramer, PhD, professor in the department of molecular and cell biology was published on March 12th in Neuron in a paper titled, “Retinoic Acid Induces Hyperactivity, and Blocking Its Receptor Unmasks Light Responses and Augments Vision in Retinal Degeneration.”
“This isn’t a cure for these diseases, but a treatment that may help people see better. This won’t put back the photoreceptors that have died, but maybe give people an extra few years of useful vision with the ones that are left,” said Kramer. “It makes the retina work as well as it possibly can, given what it has to work with. You would maybe make low vision not quite so low.”
Light responses are initiated in photoreceptors, processed by interneurons, and synaptically transmitted to retinal ganglion cells (RGCs), which send information to the brain. Researchers have known for years that photoreceptor degeneration also triggers hyperactive firing of RGCs, obscuring light responses initiated by surviving photoreceptors.
Kramer and his team focused on the role of retinoic acid (RA), showing that signaling through its receptor (RAR), is the trigger for hyperactivity. They found that RA floods the retina, stimulating the retinal ganglion cells to make more retinoic acid receptors. It’s these receptors that make ganglion cells hyperactive, creating a constant buzz of activity that submerges the visual scene and prevents the brain from picking out the signal from noise.
“When we inhibit the receptor for retinoic acid, we reverse the process and shut off the hyperactivity. People who are losing their hearing often get tinnitus, or ringing in the ears, which only makes matters worse. Our findings suggest that retinoic acid is doing something similar in retinal degeneration—essentially causing ‘ringing in the eyes,'” Kramer said. “By inhibiting the retinoic acid receptor, we can decrease the noise and unmask the signal.”
Indeed, a genetically encoded reporter showed elevated RAR signaling in degenerated retinas from mouse RP models. Enhancing RAR signaling in healthy retinas mimics the pathophysiology of degenerating retinas.
The researchers sought out drugs known to block the receptor and showed that treated mice could see better, behaving much like mice with normal vision. They also tried gene therapy, inserting into ganglion cells a gene for a defective retinoic acid receptor. When expressed, the defective receptor bullied out the normal receptor in the cells and quieted their hyperactivity. Mice treated with gene therapy also behaved more like normal, sighted mice.
“There has been a lot of excitement about emerging technologies that address blinding diseases at the end stage, after all of the photoreceptors are lost, but the number of people who are candidates for such heroic measures is relatively small,” Kramer said. “There are many more people with impaired vision—people who have lost most, but not all, of their photoreceptors. They can’t drive anymore, perhaps they can’t read or recognize faces, all they have left is a blurry perception of the world. Our experiments introduce a new strategy for improving vision in these people.”
