In recent months, although our focus has been on the coronavirus outbreak, there has been a great deal of scientific progress in treating diseases that cause blindness.
Researchers at US-based Editas Medicine and Ireland-based Allergan have administered CRISPR for the first time to a person with a genetic disease. This landmark treatment uses the CRISPR approach for a specific mutation in a gene linked to childhood blindness. The mutation affects the functioning of the light-sensitive compartment of the eye, called the retina, and leads to the loss of light-sensitive cells.
According to the World Health Organization, at least 2.2 billion people worldwide have some form of visual impairment. In the United States, approximately 200,000 people suffer from inherited forms of retinal disease for which there is no cure. But things have started to change forever. Now we can see the light at the end of the tunnel.
I am a researcher in ophthalmology and visual sciences, and I am particularly interested in these advances because my laboratory is focusing on designing new and better gene therapy approaches to treat inherited forms of blindness.
The eye as a testing ground for CRISPR
Gene therapy involves inserting the correct copy of a gene into cells that have an error in that gene’s genetic sequence, restoring the normal function of the protein in the cell. The eye is an ideal organ for testing new therapeutic approaches, including CRISPR. This is because the eye is the most exposed part of our brain and is therefore easily accessible.
The second reason is that the retinal tissue in the eye is protected from the body’s defense mechanism, which would otherwise consider the injected material used in gene therapy to be foreign and would generate a defensive attack response. Such a response would destroy the benefits associated with the treatment.
In recent years, groundbreaking gene therapy studies have paved the way for the first Food and Drug Administration-approved gene therapy medication, LuxturnaTM, for a devastating childhood blindness disease, Leber’s congenital amaurosis type 2.
This form of Leber’s congenital amaurosis is caused by mutations in a gene that encodes a protein called RPE65. The protein participates in chemical reactions that are necessary to detect light. Mutations decrease or eliminate the function of RPE65, leading to our inability to detect light blindness.
The treatment method developed simultaneously by groups at the University of Pennsylvania and University College London and Moorefields Eye Hospital consisted of inserting a healthy copy of the mutated gene directly into the space between the retina and the retinal pigment epithelium, the tissue located behind the retina where chemical reactions occur. This gene helped the retinal pigment epithelial cell produce the missing protein that is dysfunctional in patients.
Although the treated eyes showed improved vision, measured by the patient’s ability to navigate an obstacle course at different light levels, it is not a permanent solution. This is due to the lack of technologies that can correct the mutated genetic code in the DNA of the patient’s cells.
A new technology to erase the mutation.
Lately, scientists have been developing a powerful new tool that is shifting biology and genetic engineering to the next phase. This innovative gene-editing technology, called CRISPR, allows researchers to directly edit the genetic code of cells in the eye and correct the mutation that causes the disease.
Children with Leber Type 10 congenital amaurosis experience progressive vision loss from one year of age. This specific form of Leber’s congenital amaurosis is caused by a change in DNA that affects the ability of the gene, called CEP290, to produce the complete protein. Loss of the CEP290 protein affects the survival and function of our light-sensitive cells, called photoreceptors.
One treatment strategy is to deliver the complete form of the CEP290 gene using a virus as the delivery vehicle. But the CEP290 gene is too large to be a virus load. So another approach was needed. One strategy was to fix the mutation using CRISPR.
Scientists at Editas Medicine first demonstrated the safety and proof of concept of the CRISPR strategy in cells taken from the patient’s skin biopsy and in non-human primate animals.
These studies led to the formulation of the first therapeutic clinical trial of the human CRISPR gene. This Phase 1 and Phase 2 trial will eventually evaluate the safety and efficacy of CRISPR therapy in 18 patients with Leber type 10 congenital amaurosis. Patients receive a dose of the therapy while under anesthesia when the retinal surgeon uses an endoscope, needle, and syringe to inject the CRISPR enzyme and nucleic acids into the back of the eye near the photoreceptors.
To make sure the experiment works and is safe for patients, the clinical trial has recruited people with late-stage disease and with no hope of regaining their vision. Doctors are also injecting CRISPR editing tools into one eye.
A new CEP290 gene therapy strategy
An ongoing project in my laboratory focuses on designing a gene therapy approach for the same CEP290 gene. Contrary to the CRISPR approach, which can only target one specific mutation at a time, my team is developing an approach that would work for all CEP290 mutations in Leber Type 10 congenital amaurosis.
This approach involves the use of shorter but functional forms of the CEP290 protein that can be administered to photoreceptors using viruses approved for clinical use.
Gene therapy involving CRISPR promises a permanent solution and a significantly reduced recovery period. A disadvantage of the CRISPR approach is the possibility of an off-target effect in which another region of the cell’s DNA is edited, which could cause undesirable side effects, such as cancer. However, new and improved strategies have made the probability very low.
Although the CRISPR study is for a specific mutation in CEP290, I think the use of CRISPR technology in the body is exciting and a huge leap. I know this treatment is in an early stage, but it shows clear promise. In my opinion, as well as in the minds of many other scientists, CRISPR-mediated therapeutic innovation is absolutely promising.
Joseph Giacomin
More ways to combat blindness
In another study just reported in the journal Science, German and Swiss scientists have developed revolutionary technology that allows mice and human retinas to detect infrared radiation. This ability could be useful for patients suffering from loss of photoreceptors and sight.
The researchers demonstrated this approach, inspired by the ability of snakes and bats to see heat, endowing mice and postmortem human retinas with a protein that activates in response to heat. Infrared light is light emitted by warm objects that is beyond the visible spectrum.
The heat heats up a specially designed gold particle that the researchers put into the retina. This particle binds to the protein and helps it convert the heat signal into electrical signals that are then sent to the brain.
In the future, more research is needed to adjust the capacity of infrared-sensitive proteins to different wavelengths of light, which will also improve the remaining vision.
This approach is still being tested in animals and retinal tissue in the laboratory. But all approaches suggest that it may be possible to restore, enhance, or provide patients with forms of vision used by other species.
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Hemant Khanna, associate professor of ophthalmology, University of Massachusetts School of Medicine
This article is republished from The Conversation under a Creative Commons license. Read the original article.
