Foundation Funding Two New Optogenetics Projects at UC Berkeley

August 05, 2013

The Foundation is bolstering its commitment to restoring vision for people with the most advanced retinal diseases by investing $800,000 in the development of two emerging optogenetic therapies at the University of California, Berkeley. The funding is in addition to nearly $1.5 million that the Foundation is already providing to the Institut de la Vision in Paris for advancement of itsoptogenetics treatment. The overarching goal of all three projects is to prepare the therapies for clinical trials.

Optogenetics involves the delivery of genes or chemicals to restore light sensitivity to a highly degenerated retina.  A major benefit of this approach is that it holds promise for restoring vision in people who have lost most or all of their photoreceptors — the cells that normally provide vision — to conditions like retinitis pigmentosa. It does so regardless of the genetic defect causing the disease.

“I’m very excited to tell people who have advanced vision loss, and whose gene mutation has not been identified, that we have a few promising options in development for restoring their vision,” says Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. “Our investment of more than $2 million in optogenetics reflects our commitment to people who are the most challenging to treat.”

Optogenetics works by providing light sensitivity to surviving retinal cells — for example, bipolar organglion cells — which normally don’t process light, to provide vision. Optogenetics has also been used to bring light sensitivity back to cones — photoreceptor cells that are responsible for central and color vision — that have gone into a dormant state but haven’t fully degenerated.

“We think all of these approaches are complementary,” says John Flannery, Ph.D., a UC Berkeley researcher and Foundation grant recipient who’s developing an optogenetic gene therapy for bipolar cells. “Each is optimized for patients with different stages of degeneration.”

Dr. Flannery says that many people with significant retinal degeneration have surviving bipolar cells. Given their adjacency to photoreceptors, he believes bipolar cells have the potential to provide meaningful vision when treated with an optogenetic therapy. Dr. Flannery will be testing the effectiveness of four different gene therapies, each of which delivers a different light-sensing protein to bipolar cells.

In addition to evaluating the various therapies in mouse models of retinal degeneration, he’ll be collaborating with William Beltran, V.M.D., Ph.D., of the University of Pennsylvania, to test them in canine models including those with cone-rod dystrophy.

“It isn’t easy to determine how much useful vision is being restored in mice, but we can run sophisticated visual tests for dogs,” says Dr. Flannery. “Dr. Beltran and his colleague Dr. Gus Aguirre have developed a maze, obstacle course and other visually guided behavior tests for canines. Those will be invaluable resources for measuring vision restoration.'

The other new optogenetics grant from the Foundation has been awarded to Richard Kramer, Ph.D., from UC Berkeley, to study variations of a synthetic compound called AAQ as an optogenetic treatment in ganglion cells. Previous studies showed that injections of AAQ restored vision in mice, but only in very bright light. Dr. Kramer will be engineering compounds to work in dimmer light. Because injections of AAQ have worked only temporarily, Dr. Kramer will be evaluating microspheres, small biodegradable particles, to provide sustained release of the compounds.

Previous research conducted by Dr. Flannery showed that ganglion cells were a good target for an optogenetic treatment, because they survive longer than most other cell types, including bipolar cells, in a degenerating retina. However, he believes that optogenetically-treated ganglion cells may not provide as much useful vision as bipolar cells.

“Treating ganglion cells may be the best approach for people with the most advanced disease, where a therapy directed at bipolar cells may work best for people with more moderate degeneration,” adds Dr. Flannery. “Through our studies, Dr. Kramer and I should get a better sense of which treatments will work best for different stages of disease.

The cone-directed optogenetic gene therapy being developed by Jose Sahel, M.D., Ph.D., of the Institut de la Vision, may be most suitable for people on the milder end of the disease spectrum — i.e., those individuals with some viable cones remaining.  And because cones normally provide vision, they hold potential for providing the most vision restoration of all the optogenetic options.

In addition to treating retinal disease, researchers are using this technique to control brain cells with light for potentially treating conditions such as obsessive-compulsive disorder, depression and Parkinson’s disease.