By Tomasz Szeligowski
In the 19th century, Hermann von Helmholtz revolutionised ophthalmology with the direct ophthalmoscope - a device which gave ophthalmologists sight by allowing them to look inside the eye. Since this discovery, diagnosing retinal diseases has relied heavily on describing their abnormal appearance on examination. The emergence of genetic testing allowed us to understand that many conditions previously grouped together due to similar appearance were in fact caused by diverse gene mutations. Thus, patients could be stratified into increasingly precise diagnoses, each with unique features and possible treatments. This extended to both congenital eye diseases, and acquired conditions where many genetic risk factors contribute to the complex risk profile. But knowing the genetic causes of eye diseases is clearly not enough - after all, a patient who comes to see their ophthalmologist may not be interested in whether their condition is caused by mutations in retinoid isomerohydrolase or guanylyl cyclase 1. They come to have their sight restored, thus inspiring research in gene therapies.
The concept of manipulating human genes for medical purposes has, for a long time, existed in the realm of science fiction. Even when it started coming closer to reality, the problems associated with it, both in terms of creating efficient gene delivery systems and patient safety, cast doubt on how feasible it was as a treatment strategy. A true breakthrough came in 2017, when the FDA approved Luxturna - the first licensed gene therapy product in history. It was designed to treat a subtype of Leber congenital amaurosis - a family of inherited retinal conditions caused by a number of mutations, where impaired photoreceptor function leads to early loss of vision. Luxturna uses a viral vector - a genetically engineered virus which harbours a functional copy of the defective gene and has the ability to infect non-dividing retinal cells to induce production of the functional gene, and hence restore photoreceptor cell function. The virus is injected directly beneath the retina, allowing precise delivery to its target site. This milestone invention sparked renewed interest in gene therapies, and put ophthalmology at the forefront of gene therapy research. But why ophthalmology? And what can we expect in the future?
Delivering genes to human cells is a difficult task. It requires producing an effective vector which will deliver the genetic product to precisely targeted cells and maintain long-term gene expression, as well as avoiding anti-viral immune responses which can not only prevent the intervention from working, but also potentially trigger destructive inflammation in the target organ. The unique features of eyes make them the perfect candidate for gene therapies. First, they are one of the so-called “immune privilege sites” where immune responses are naturally dampened through a variety of mechanisms, as inflammation could result in clouding of the visual pathway. Another crucial feature is that the eye is simply easy to reach - it is one of the few organs we can look directly into, allowing precise delivery of vectors. Finally, its lack of lymphatic drainage limits the escape of vector viruses into the bloodstream where they might encounter the immune system, while the fact that retinal cells do not divide ensures long-term expression of introduced genes.
Where next? - Ophthalmology in the age of precision medicine
Although gene therapy is still in its infancy, it is a busy area of research. Its success will depend on parallel advances in two fields: gene therapies themselves and genetic testing. As mentioned before, eye conditions often have many possible mutations leading to similar presentations, making precise genetic diagnosis essential for identifying treatment targets. Once targets are identified, flexible and robust vectors will be necessary to allow efficient production of personalised vector constructs to match specific subgroups of patients. This in turn will be crucial in overcoming a great obstacle in gene therapies - their cost. Importantly, replacement of defective genes is only the beginning. There is growing interest in the use of advanced gene modification systems like CRISPR-Cas9 which allow direct repair of mutations at the nucleotide level. This system relies on a protein capable of cutting DNA at precise points, and an RNA construct which guides the cutting protein to its correct location. Thanks to this, the CRISPR-Cas9 system can be used in a variety of ways including inducing small deletions to inactivate abnormal genes, inserting DNA sequences, or even modification of individual nucleotides thanks to the addition of special DNA editing enzymes. Thus, these approaches require an even deeper understanding of the patient’s genetic make-up as they depend not only on the knowledge of the genes affected, but also the specific sequences of affected DNA regions.
An especially exciting new avenue for gene therapies will be the treatment of acquired conditions, for example, age-related macular degeneration (AMD) which is a leading cause of blindness in the developed world. The aetiology of AMD is extremely complex and large genetic studies identified many genes associated with its development, each contributing only a fraction of the overall risk. The most promising approach in gene therapy for AMD involves targeting the contributing physiological pathways, in particular the VEGF molecule responsible for formation of abnormal retinal blood vessels. Currently, VEGF is targeted with regular eye injections of anti-VEGF antibodies that inhibit its function, but this treatment is uncomfortable for patients, and associated with risks each injection. A clinical trial currently underway offers a solution to this problem by introducing the anti-VEGF antibody gene directly into the retina, thus allowing its prolonged expression. The available results already show great promise with stable visual function and a 96% reduction in the need for anti-VEGF injections. Increasing the availability of genetic testing may mean that in the future, AMD patients will be routinely tested for variants contributing to their disease, which may in turn inform which pathophysiological pathways could be targeted to stop the progression of their disease.
The future for gene therapies is bright, and ophthalmology will likely continue to lead the way in this field. However, developing treatments for previously untreatable conditions is not the only outcome; availability of gene therapies will undoubtedly widen general access to genetic testing. This change will improve diagnostic precision and as a result, truly launch ophthalmology into the era of personalised medicine.
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