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Optogenetics, a new laboratory development, may be the key to a new therapy for retinitis pigmentosa.
By Lynda Charters
Reviewed by Luk H. Vandenberghe, PhD
Boston-A new laboratory development may be the key to a new therapy for retinitis pigmentosa (RP).
Luk H. Vandenberghe, PhD, discussed the progress in optogenetics.
“In most cases, RP results in the loss of photoreceptors due to a single gene defect,” said Dr. Vandenberghe, a lecturer in ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston.
“There are two main strategies to address RP, i.e., protective means and restorative means,” he said. “Ideally, we would like to be at the interface of the two.”
Optogenetic therapy for RP, according to Dr. Vandenberghe, is the re-sensitization of the retina to light by the introduction of a genetically encoded molecular light sensor that is coupled to the neural circuitry of the degenerated retina for functional restoration of light perception and ultimately vision.
The restorative methods that have been attempted previously that are currently in clinical trials involve retinal implants, cell replacement, and gene augmentation.
“All of these have advantages and disadvantages,” Dr. Vandenberghe said. “Using optogenetics, we are aiming to overcome some of the limitations of these strategies, such as the retinal coupling needed for implanted devices, grafting required for photoreceptor cell replacement, and a one gene/one drug regimen and a small window of intervention associated with gene augmentation.”
Three molecules-melanopsin, channelrhodopsin, and halorhodopsin-are studied to re-sensitize the retina to light.
“These have created a great deal of excitement in the field of neuroscience,” he said. “Upon the influx of light, a neuron that expresses one of these molecules is triggered.”
Channelrhodopsin, for example, is a channel protein that opens when light hits it and depolarizes the cell, Dr. Vandenberghe explained.
A few approaches can be used to place the molecules in the retina.
“The sensors can be placed either in retinal ganglion cells or deeper in the retina which would capture more of the endogenous retinal processing capacity and may restore a more natural form of vision,” he said. “The molecules can be placed in amacrine cells, bipolar cells, or remnant cone photoreceptors.”
While this endeavor may sound like science fiction, Dr. Vandenberghe said, “we have proof-of-concept data for at least four strategies in animal models, several of which can restore fairly complex vision.”
Optogenetics has a few limitations and hurdles to overcome that presently prevent application in a clinical setting. These include overcoming the host immune response, creation of possible undesirable forms of vision, the sensitivity and dynamic range of the molecules that require a great deal of light and are only active in about one or two orders of magnitudes compared with normal vision that can adapt to seven orders of magnitude, pupillary reflex, and nystagmus.
Dr. Vandenberghe pointed out that initially the therapy will be combined with a head-mounted display device that will activate the gene therapy in the retina. The patient or a computer will be able to modulate the increased sensitivities and adaptation to the surrounding light environment.
This technology is presently in the preclinical stage in primate and animal safety studies.
“We need four fairly developed fields to come together: retinal gene therapy, retinal circuitry, improved optogenetics, and engineering,” he concluded. •
Luk H. Vandenberghe, PhD
Dr. Vandenberghe is a co-founder of GenSight Biologics, which may develop the discussed therapy, and holds patents with GlaxoSmithKline and ReGenX Biosciences. This article was adapted from Dr. Vandenberghe’s presentation during Retina 2012 at the annual meeting of the American Academy of Ophthalmology.