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First patient with Degenerative Retinal Disease is cured by The Optogenetics Gene Therapy
A man who had been blind for 50 years allowed scientists to insert a tiny electrical probe into his eye.
The man’s eyesight had been destroyed and the photoreceptors, or light-gathering cells, at the back of his eye no longer worked. Those cells, known as rods and cones, are the basis of human vision. Without them, the world becomes gray and formless, though not completely black. The probe aimed for a different set of cells in the retina, the ganglion cells, which, along with the nearby bipolar cells, ferry visual information from the rods and cones to the brain.
No one knew whether those information-relaying cells still functioned when the rods and cones were out of service. As the scientists sent pulses of electricity to the ganglion cells, the man described seeing a small, faint candle flickering in the distance. That dim beacon was a sign that the ganglion cells could still send messages to the brain for translation into images.
That 1990s experiment and others like it sparked a new vision for researcher Zhuo-Hua Pan of Wayne State University in Detroit. He and his colleague Alexander Dizhoor wondered if, instead of tickling the cells with electricity, scientists could transform them to sense light and do what rods and cones no longer could.
The approach is part of a revolutionary new field called optogenetics. Optogeneticists use molecules from algae or other microorganisms that respond to light or create new molecules to do the same, and insert them into nerve cells that are normally impervious to light. By shining light of certain wavelengths on the molecules, researchers can control the activity of the nerve cells.
Optogenetics is a powerful tool for probing the inner workings of the brain. In mice, researchers have used optogenetics to study feeding behavior , map aggression circuits and even alter memories.
After years of work with animals, researchers are now poised to insert optogenetic molecules into the retinal cells of people. The aim is to restore vision in those whose rods and cones don’t work.
“It makes sense that the organ that is light sensitive would benefit from [optogenetics] first,” says José-Alain Sahel, director of the Vision Institute in Paris. He is involved in one of two efforts to bring optogenetics out of the lab and into the eye clinic.
Optogenetics is, at its heart, a gene therapy. Traditional gene therapy places a healthy copy of a mutated or damaged gene into the cells of a person with an inherited condition. The healthy copy is first packed into a virus. The virus delivers the gene to the “broken” cells and unloads its cargo. Once inside the cell, the gene produces functional copies of the proteins that the original mutations damaged, and the cell starts working again.
The inherited blindness called Leber congenital amaurosis, however, is the absolute best-case scenario for gene therapy, says neuroscientist Botond Roska. LCA patients eligible for gene therapy still have light-gathering rods and cones in their retinas but the cells don’t work properly because they have a mutation in a gene called RPE65 (one of a dozen gene mutations that can cause LCA). Introducing the normal version of the gene allows the rods and cones to function again. However, two studies published online this month in the New England Journal of Medicine suggest that even in patients who experience vision improvements after gene therapy for LCA, the photoreceptors continue to die and vision deteriorates over time. This could mean that, for long-term benefit, another approach is needed.
Most people with inherited blindness don’t even have the hope of temporary restoration. Mutations in any of more than 250 genes may lead to blindness, says John Flannery, a cell and molecular biologist at the University of California, Berkeley. Gene therapy is currently impractical or impossible for most of those diseases, he says.
Approximately 200,000 people in the United States have inherited retinal diseases that affect the rods and cones, according to estimates from the Foundation Fighting Blindness. Once those photoreceptors are gone, there’s no bringing them back, says Roska, of the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.
The optogenetics approach that Pan and others are studying circumvents the missing photoreceptors. That means it differs from traditional gene therapy in important ways: It doesn’t fix broken genes, so the therapy should work regardless of which of the 250 genes are causing problems. And instead of trying to resurrect dead or damaged photoreceptors, the scientists aim to transform relay cells into ersatz photoreceptors.
Pan and Dizhoor began kicking around the idea of making bipolar and ganglion cells light sensitive in 2000.The breakthrough came two years later when scientists discovered a light-responsive protein called channelrhodopsin in a single-celled algae called Chlamydomonas reinhardtii.
Channelrhodopsins form channels in a cell’s outer membrane. When certain wavelengths of light hit the protein, the channel opens and lets positively charged ions flow into the cell. That flow of energy is a nerve cell’s signal to talk to its neighbors and to the brain. Pan and Dizhoor immediately recognized its potential.
“We thought, ‘Wow! This is the molecule we’ve been waiting for,’ ” Pan says.
They lost little time packing a gene encoding a specific channelrhodopsin, ChR2, into a virus that could infect ganglion cells in blind mice. The researchers reported in Neuron in 2006 that the protein could make the cells light sensitive and send a message to the brain in response to blue light shone into the eyes of the mice.