Will gene augmentation and editing offer the fastest path to broad ocular disease treatment?
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Gene augmentation, editing offer fastest path to broad ocular disease treatment
In clinical ophthalmology, we are used to fixing problems on a physical or mechanical level.
This can be through an epiretinal membrane peel, a macular hole closure, laser surgery of any kind, cataract extraction, corneal transplant or even prescribing glasses. But underlying many common ophthalmic problems in ophthalmology are molecular defects or molecular pathways that are being targeted using gene therapy techniques.
The original test bed for gene therapy, with research reaching back 30 years now, was conceptually what you might expect — delivering the missing gene in patients with a defined genetic deficiency. That idea has now become reality with Luxturna (voretigene neparvovec, Spark Therapeutics), which was approved by the FDA in 2017. This gene therapy is for Leber congenital amaurosis or retinitis pigmentosa caused by RPE65 gene defects. Now the inherited retinal disease space is full of clinical trials for another gene-specific treatment, whether it be gene augmentation (or “reduce and replace” for dominant disease) for certain forms of retinitis pigmentosa, Leber congenital amaurosis or choroideremia, gene editing for one form of Leber congenital amaurosis, or oligonucleotide-based therapies for forms of retinitis pigmentosa and Leber congenital amaurosis. The genes include CEP290, CHM, CNGB3, NR2E3, RHO, RPGR and USH2A.
Treating patients with severe genetic defects, although elegant due to addressing the underlying problem, covers a narrow segment of ophthalmic problems. How is progress in that space going to get us to broadly applicable treatments? For example, there is the remarkable molecular confluence that wet age-related macular degeneration, proliferative diabetic retinopathy, diabetic macular edema and retinal vein occlusion-associated macular edema are all driven by the VEGF gene. Anti-VEGF antibodies, of course, have revolutionized the practice of retina and saved the vision of countless patients. Multiple companies are conducting clinical trials to use gene therapy to program the ocular tissue to produce its own anti-VEGF antibodies — a “biofactory” approach. And as many of these trials are in phase 2 and 3 right now, they are our best chance of getting a broadly applicable ocular gene therapy quickly. Clinical trials are never fast, but judging by the number of clinical trials ongoing at our institution and elsewhere, industry sponsors are betting on some near-term wins using this approach. Similarly, optogenetics is a vision restoration strategy that uses gene therapy to deliver an artificial light sensor to the inner retina, bypassing a loss of photoreceptors and retinal pigment epithelium. This may have broad applicability, and a next-generation version of the technology is first being tested in patients with retinitis pigmentosa.
There is another way that gene therapies might result in broad ocular disease treatment; our colleagues in other fields might be curing or treating systemic diseases that also show up in the eye. For example, a clinical trial has started to test how base editing, dubbed “CRISPR 2.0,” may be able to replace an antibody-based PCSK9 inhibitor used to treat hypercholesterolemia with a treatment based on genome editing. In the laboratory, these base editors have been shown to be active as well. Or what if genetic therapies put a dent in the burden of type 1 or type 2 diabetes? Genetic advances in systemic disease modification could help keep patients from developing the related ocular diseases in the first place.
- References:
- Khanani AM, et al. Eye (Lond). 2022;doi:10.1038/s41433-021-01842-1.
- Ledford H. CRISPR ‘cousin’ put to the test in landmark heart-disease trial. https://www.nature.com/articles/d41586-022-01951-1. Published July 15, 2022.
- Levy JM, et al. Nat Biomed Eng. 2020:doi:10.1038/s41551-019-0501-5.
- Russell S, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)31868-8.
Jason I. Comander, MD, PhD, is director of the Inherited Retinal Disorders service at Massachusetts Eye and Ear and Harvard Medical School.
Nonviral gene augmentation strategies may be safer, more efficient
Gene augmentation therapy consists of introducing a healthy copy of the defective gene to the target tissue to treat a disease. So far in ophthalmology, gene augmentation has typically involved introducing a viral vector to deliver a healthy gene, which is translated to replace the missing or abnormal nonfunctioning protein directed at treating monogenic recessive diseases, such as choroideremia, achromatopsia, or X-linked and autosomal recessive retinitis pigmentosa and Leber congenital amaurosis. The first FDA-approved product for RPE65-associated retinal degeneration, Luxturna (voretigene neparvovec, Spark Therapeutics), introduces the AAV2 viral vector carrying the RPE65 gene into the retinal pigment epithelium cells, where the crucial step in the visual cycle is restored.
More recently, gene addition therapy has emerged to treat more complex diseases, including dominant monogenic diseases. This method works by delivering a gene product whose function is to improve cellular homeostasis and function or to increase the expression of growth factors, cytokines or complement pathway modifiers. Examples of these include dry and exudative macular degeneration and autosomal dominant retinitis pigmentosa due to NR2E3 and RHO mutations and NR2E3-associated autosomal recessive retinitis pigmentosa.
This method, however, does not address the dominant conditions where the abnormal gene must be initially suppressed to silence the harmful cellular process. For example, an RNA-based gene suppression to downregulate and inactivate the abnormal gene would need to be performed first, followed by delivery of an AAV vector to deliver the functional replacement gene. Alternatively, gene editing via viral vector-based CRISPR-associated systems, which is able to cut and remove the target’s cell genome and add the functional gene with precision, is being explored to treat eye disorders, such as CEP290-associated Leber congenital amaurosis.
Unfortunately, the use of viruses even into a relatively immune-privileged and small organ such as the eye has several limitations. Post-delivery immune response leading to harmful inflammation even despite a course of oral steroids has been reported in current clinical trials. Expanding the vectors’ small carrying capacity, increasing the ability to reach the target cells, increasing transduction efficacy, preventing genome integration, ensuring long-term transgene expression and minimizing inflammatory reactions are the challenges faced by this approach. To mitigate these risks and limitations, various nonviral gene augmentation strategies are being developed, such as nucleic acid plasmid with a polymer, cationic lipids or nanoparticles, and gene editing, which one day may prove to be a safer and potentially more efficient and quicker path to broad ocular disease therapy.
- References:
- Banin E, et al. Mol Ther. 2015;doi:10.1038/mt.2015.114.
- Cabral T, et al. Curr Opin Ophthalmol. 2017;doi:10.1097/ICU.0000000000000359.
- Prado DA, et al. Curr Opin Ophthalmol. 2020;doi:10.1097/ICU.0000000000000660.
Ninel Z. Gregori, MD, is professor of clinical ophthalmology and chief of the ophthalmology section at Miami Veterans Affairs Medical Center.
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