Last updated: June 26, 2015
Genome Advance of the Month
Genomics holds promise of treatments for inherited blindness
By Bianca Patel
Scientific Program Analyst, NHGRI
Millions of people worldwide suffer from diseases of the retina that cause partial or complete blindness. Those with hereditary retinal degenerative disease suffer from a progressive loss of the light-sensing photoreceptor cells, caused by any of over 250 genetic mutations. The retina is the thin layer of tissue at the back of the eye that detects light and color. It contains photoreceptor cells, known as rods and cones, which are responsible for detecting light and converting it into electrical signals. The retina also contains nerves that relay the electrical signals to the brain, telling it what the photoreceptors are "seeing." These relay cells are known as bipolar cells and ganglion cells.
While there is no cure for retinal degenerative disease, there are several promising areas of research that aim to, at least, partially restore vision. May's Genome Advance of the Month focuses on two experimental therapeutic approaches - gene replacement therapy and optogenetics.
In gene replacement therapy, a normal copy of a gene is inserted into the cells of a person with a mutated and improperly functioning gene. Before insertion, the normal copy is packed inside a virus, and the virus transports the gene to the diseased cells. Once inside the cell, the gene begins to produce functional proteins - the molecules in the cell that carry out the structure, function and regulation of cell processes - and the cell is restored to normal activity.
This type of gene replacement therapy was used in a landmark 2012 study that partially restored vision in people with a form of childhood blindness called Leber congenital amaurosis (LCA). LCA is a rare, inherited condition, affecting about 1 in 80,000 people, and is one of the most common causes of blindness in children.
One type of LCA is caused by a mutation in the RPE65 gene. The protein made by this gene is an essential part of the visual cycle, as it helps produce vitamin A that allows the photoreceptors to function. REP65 gene mutations halt this production, and the patient's vision becomes progressively darker, as if the lights were slowly dimming.
Researchers set out to replace the mutated gene with a healthy gene and, hopefully, restore vision. Fifteen LCA patients received retinal injections of a virus that carried healthy RPE65 genes. Patients experienced improved eyesight and sensitivity to light within days to weeks of treatment. Today, RPE65 gene-replacement is the most notable example of successful gene therapy for retinal degenerative disorders.
A new study published this May in the New England Journal of Medicine followed up with three of the 15 patients who were treated with the investigational RPE65 therapy. Researchers found that visual benefits peaked between one and three years after the procedure, but then began to decrease. They also found that photoreceptors continued to degenerate steadily as they do in the natural course of the disease. The procedure seems to have boosted the visual cycle, but not by postponing the death of photoreceptor cells.
This study highlights the need to refine and optimize the gene therapy process. Researchers hypothesize that the amount of RPE65 protein (introduced by one round of gene therapy) was not enough to maintain improved vision, and that multiple treatments would help. Alternatively, gene therapy could be started at a younger age when there is less photoreceptor loss. Overall, the relative safety of RPE65 gene replacement studies in humans has opened the path for other gene therapy studies.
Gene replacement therapy is a conceptually straightforward and appealing strategy, but is limited by a number of factors. For one, the specific causative gene must be known, which is not usually the case. Additionally, gene replacement therapy is only feasible if the cell type expressing the gene is still alive; in many retinal degenerative disorders the photoreceptors are destroyed and vision restoration is impossible.
The shortcomings and challenges associated with gene therapy demonstrate a clear need for additional treatments for vision loss such as optogenetics. Optogenetic therapy takes gene therapy a step further by taking advantage of an important finding - that the inner retinal cell layers (basal and ganglion cells) and central visual pathways remain intact after photoreceptor degeneration. Optogenetic therapy uses a viral vector to insert light-sensing proteins into the surviving retinal cells, which are usually unable to sense light. The cells can then perform the job of the photoreceptors, and the visual pathway is restored.
However, optogenetic therapies face significant obstacles before they can be translated into clinical applications. One of the problems is finding the right optogenetic tool. Initial optogenetic testing has used proteins that require unnaturally high and potentially harmful light intensities to function. These proteins have the additional drawback of being foreign to the retina, meaning that they induce signaling that is alien to the cells and could cause immune rejection responses.
In another new study in the May issue of PLOS Biology, researchers report that they have created a molecularly engineered protein that is capable of restoring daylight vision in mice with retinal degenerative disease. Their protein, Opto-mGluR6, consists of two existing retinal proteins. One part comes from a light-sensing pigment, melanopsin, and the other part comes from a signaling molecule, metabotropic glutamate receptor 6 (mGluR6). Together, the two confer light sensitivity and the ability to amplify and mediate light responses. Since these two proteins are naturally present in the retina, this engineered protein is physiologically compatible with the retina and unlikely to be rejected by the immune system. Additionally, the melanopsin region of the protein is activated by moderate daylight, rather than the high levels of light required by other proteins in previous studies.
This approach brings optogenetic therapies closer to human trials and clinical application. Although gene therapy and optogenetics are still in their infancy, results from these studies are promising and have the potential to vastly improve vision in those with retinal degenerative diseases.
Read the Studies
- Jacobson SG, Cideciyan AV, Roman AJ, et al. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med, 372:1920-1926. 2015. [Full Text]
- van Wyk, M, Pielecka-Fortuna J, Lowel Sm Kleinlogel S. Restoring the ON Switch in Blind Retinas: Opto-mGluR6, a Next-Generation, Cell-Tailored Optogenetic Tool. PLOS Biology, 13(5). 2015. [Full Text]
Posted: June 26, 2015