Gene therapy has great potential in ophthalmology
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Most ophthalmologists are familiar and comfortable with the application of devices and drugs in their daily practice.
Devices such as a new IOL implant are approved by the FDA Center for Devices and Radiological Health, and we have a steady flow of new devices into the ophthalmology marketplace. Drugs, which represent the application of one or more molecules to prevent or treat disease, are regulated by the FDA Center for Drug Evaluation and Research, and again, we have new molecules approved to treat our patients every year.
Now we are entering a new era of disease therapy using biologics or biotherapeutics. A biologic is defined as a product that is produced by living organisms or contains a component of a living organism. There is a third division of the FDA that oversees and approves biologics, the FDA Center for Biologics Evaluation and Research. Gene therapy, cell therapy, secretomes, which are sets of proteins expressed by a living organism, and biotherapeutic protein products such as interferon, which is a signaling protein produced by cells and some bacteria, are all biologics. This is an area less well understood by many eye care practitioners, especially those like me who were trained in an era in which this category of therapy did not exist.
Biologics are attracting significant investment, and we have our first FDA-approved gene therapy, Luxturna (voretigene neparvovec) from Spark Therapeutics, for the treatment of a rare retinal dystrophy, Leber congenital amaurosis. We also have a promising new approach for the treatment of Fuchs’ corneal dystrophy, endothelial cell therapy from Aurion Biotech, entering FDA clinical trials later this year. Several secretomes are being evaluated, including one from Combangio/Kala for the treatment of persistent corneal epithelial defects. Biotherapeutic proteins including anti-VEGFs have already revolutionized the way we treat several retinal diseases. Biologics will be a critical component of our therapeutic arsenal in the decades ahead as we endeavor to preserve, restore and enhance vision. I needed to do a bit of education to better understand the exciting research and developments ongoing in biologics. For the more sophisticated reader, I apologize for the basics I am about to discuss, but many clinicians had their courses in cell biology 3 or more decades ago. So, back to the basics.
DNA resides in the cell nucleus, and it carries the genetic instruction for all cellular development, growth, reproduction and, key to us, function. RNA carries the messages from the DNA in the cell nucleus into the cytoplasm and tells the cytoplasm what proteins to manufacture. The ribosomes in the cytoplasm of a cell synthesize protein, and the mitochondria provide the required energy for the process. The biologic protein that is released is the entity that generates a positive or negative impact on a cell, organ or individual.
We as clinicians want to treat inherited dystrophies, diseases and degenerations. How might we do this is with gene therapy. In gene therapy, cell genetics are modified to produce a treatment effect. The accompanying cover story is focused on gene therapy for the retina. In the retina, one target to treat is the small number of devastating retinal dystrophies that include Leber congenital amaurosis, choroideremia, achromatopsia, Stargardt disease, and the more common retinitis pigmentosa and its many variants.
These retinal dystrophies are all caused by the negative impact of a congenital gene mutation that results in the generation of malevolent proteins. To treat these retinal dystrophies, we need to change the gene structure of a living patient’s nuclear DNA. We can now manufacture normal genes in the laboratory. Next, we need something to transport the normal gene into an individual’s cell nucleus. This seemingly impossible task can be accomplished by using a viral vector. Viruses can target DNA or RNA in a cell, and their usual impact is a negative one, hijacking a healthy cell and redirecting it to produce thousands more virus particles, which usually generate significant disease. However, scientists have learned how to use select viruses, primarily adeno-associated viruses and lentiviruses, as vectors to carry a benevolent gene replacement or addition into the nucleus of a living cell. This gene transplant can replace a bad gene or supplement a normal gene. Key targets today are the retinal dystrophies caused by a single gene mutation, as polygenetic diseases are beyond the scope of our present gene therapy technology.
The primary side effect, as one would expect, is inflammation. This inflammation, much like that associated with cell and organ transplantation, can be managed with immunosuppressive therapy. However, the impact of inflammation and the side effects of the drugs required to treat it are significant challenges in gene therapy.
Another category we would like to treat with gene therapy is retinal disease such as diabetic retinopathy and exudative age-related macular degeneration. How might this be possible? We know both retinal diseases respond positively to therapy with an anti-VEGF protein. What if we could vector a gene into one or another retinal cell that would cause that cell to manufacture a continuous output of anti-VEGF protein? Then, rather than repeated injections, a single therapeutic injection of a viral vector carrying the benevolent gene into the vitreous, subretinal or perhaps suprachoroidal space might generate a lifetime of anti-VEGF therapy. This exciting therapeutic approach is possible and attracting significant research and development capital.
The third category of vision loss is that caused by retinal degenerations such as dry AMD and its end-stage partner geographic atrophy. Here, the photoreceptor cells are dead and gone, so we cannot rehabilitate them with new or supplemental genes. How might we treat a retinal degeneration with gene therapy? In advanced AMD, even though the retinal pigment epithelium and photoreceptors are absent, other retinal cells such as the bipolar cells remain. Amazing and exciting to me, it appears that these surviving retinal bipolar cells can have their DNA modified to function like a photoreceptor and transmit neural pulses to the brain when irradiated with light.
In summary, there is a potential for gene therapy to play a positive role in the treatment of not only retinal dystrophies but also retinal diseases and retinal degenerations. Gene therapy can also be applied to other tissues of the eye, including the conjunctiva, cornea, trabecular meshwork and maybe even the ganglion cells and optic nerve. In the future, gene therapy, cell therapy, secretomes and biotherapeutic proteins will play a significant and virtuous role in the treatment of our patients.
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