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Knowledge in ocular genetics will be expanded to more common diseases
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Amazing progress is being made in our understanding of the genetic basis of a broad group of ocular disorders. The gene abnormalities in the rare but devastating Leber’s congenital amaurosis, Stargardt’s macular dystrophy and Usher’s syndrome are now elucidated.
Major tertiary university-based centers are investigating genetic therapy. The most promising current approach is to use a non-replicating virus as the vector to deliver replacement genes. This is invasive therapy, requiring vitrectomy and subretinal injections. In addition, the treatment must be done at an early enough age and stage of the disease so that there is vision to preserve.
While there is much to learn, and these invasive, expensive and ethically challenging treatments are best limited to a few focused centers, the possibility to cure a once blinding disease is extremely exciting. However, for me, the most exciting opportunity will be applying the learnings from this work to diseases with a higher prevalence in the population. I will share a few thoughts on that possibility gleaned from some reading. It is evident that genetic factors play a significant role in all common ocular diseases, including glaucoma, cataract, refractive error, age-related macular degeneration, and even diabetic retinopathy and macular edema.
While age and environment are the key factors in cataract progression, studies suggest that 50% of the variation in severity for nuclear cataract is genetic based. These genes primarily affect the protective glutathione pathway, which manages lenticular oxidative stress.
A growing number of genes are associated with glaucoma and may especially affect disease severity. Genetics may only affect glaucoma at the 20% level, but understanding which genetic profiles make the patient especially prone to progressive ganglion cell damage would be useful in setting pressure targets.
In the cornea, corneal thickness, keratoconus, Fuchs’ and other less common corneal dystrophies all appear to be significantly affected by genetics, along with some environmental factors and aging. While gene modification therapy is unlikely to be curative, understanding which patients are at risk for meaningful disease would be valuable.
Refractive error is the most common ocular disorder worldwide, affecting an estimated 2.3 billion individuals. Again, environment plays a role, but an individual’s genetic makeup is of greater importance. Might we treat myopia some day with gene therapy? I suspect “yes” will be the answer.
AMD, diabetic retinopathy, maculopathy and retinal vascular occlusion all are significantly affected, especially in severity, by genetics. One’s genetic makeup also appears to significantly affect response to therapy.
Finally, the prognosis for individuals with uveal melanoma is strongly influenced by chromosome 3 status. We now have a commercially available test that can help predict mortality rates for those with melanoma, which vary widely based on one’s genome. Therapy can then be customized and patients properly counseled.
In summary, knowledge is expanding rapidly in the field of ocular genetics. This knowledge will advance our ability to diagnose, treat and better define prognosis in nearly every ocular disorder. The research is expensive, but already clinically useful tests are becoming available and select treatments being applied. For the younger ophthalmologist, genetic testing and even gene modification therapy will be a significant part of the practice of ophthalmology.
For those interested in more detail, I found the following review article informative: Aboobakar IF, Allingham RR. Development in ocular genetics: 2013 annual review. Asia Pac J Ophthalmol. 2014;3(3):181-193.