Harnessing Inner Retinal Cells to Restore Vision in Advanced Disease

Photoreceptors are cells in the outer retina that provide vision, and once they’re gone due to an advanced retinal degenerative disease like retinitis pigmentosa (RP), a person’s eyesight is lost as well.

However, there is emerging research that could result in a treatment that empowers surviving ganglion cells, cells in the inner retina, to restore vision after photoreceptors are lost. FFB-funded scientists are making progress on an elegant strategy for restoring vision by using gene therapy to enable retinal ganglion cells to respond to light and perhaps provide useful vision for people with advanced retinal disease.

Ganglion cells are a good target for this approach, because they survive long after photoreceptors degenerate in RP and related diseases. Ganglion cells are the innermost cells of the retina and transmit electrical signals originating from photoreceptors and pass them through the optic nerve to the brain.

Dr. John Flannery, a Foundation-funded researcher from the University of California, Berkeley, recently restored some visual ability in mice with advanced RP by injecting a gene therapy that reached as many as 100,000 of their ganglion cells. The gene therapy worked by causing the production of a specially engineered protein called LiGluR, which enabled the ganglion cells to mimic the process of converting light to electrical signals — a process that normally occurs in photoreceptors. The electrical signals are sent back to the brain, where they are perceived as visual information.

The treatment restored pupillary reflexes and visual cortex responses to light in the mice. (The visual cortex is the part of the brain responsible for processing visual information.) The treated animals were also able to navigate a water maze and find an area with a lighted LED.

“This is an innovative approach to restoring vision in advanced disease, because Dr. Flannery is using the retina’s existing circuitry to respond to light,” says Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. “There are no external cells or devices to implant into the eye or the retina.”

The treatment involves the delivery of DNA to ganglion cells using an adeno-associated virus, a type of man-made therapeutic virus that is being used in a number of gene therapy studies, including clinical trials for Leber congenital amaurosis. The DNA causes the cells to produce the protein LiGluR, which helps the ganglion cells turn light into electrical signals.

The results of Dr. Flannery’s study were published online on May 24, 2011, in the journal Molecular Therapy.

Dr. Flannery is planning to study the approach in dogs and other large animals with more sophisticated visual systems to better understand the level of visual function that can be restored.

Another investigative team led by Dr. Alan Horsager at the University of Southern California was able to empower retinal bipolar cells — cells that reside between photoreceptors and ganglion cells — to respond to light in two different mouse models of retinal degeneration. His team enabled the bipolar cells to respond to light by treating them with a gene therapy that led to the production of a protein derived from algae called channelrhodospin-2 (ChR2). ChR2 enabled the bipolar cells to convert light into electrical signals which were sent back to the brain as visual information.

The results of Dr. Horsgaer’s study were published online on April 19, 2011 in the journal Molecular Therapy.

Dr. Flannery says that selecting which cells to treat will depend on the stage of the disease. While treating bipolar cells may restore more vision in the short run, ganglion cells survive longer and may thus provide a more viable long-term solution for people with advanced retinal degeneration.