BLOG: Entering the age of genomic medicine for the eye
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Genomic medicine encompasses a wide variety of interventional strategies.
The term “gene therapy” has commonly been used to refer to gene replacement, also known as gene augmentation or addition, as seen with the first approved gene therapy for RPE65 inherited retinal disease. But more recently, therapeutic strategies using gene editing, antisense oligonucleotide or RNA interference have entered clinical development.
Gene augmentation is commonly used to treat recessive monogenic disorders, often caused by the complete knockout of a gene function, thus inhibiting the production of the corresponding protein. Gene augmentation aims at supplementing the target cells with a normal copy of the gene in question in the hope of enabling the production of the missing protein and providing the absent function. This was exemplified by the clinical development and successful regulatory approval of Luxturna (voretigene neparvovec, Spark Therapeutics), a gene therapy for patients carrying variants of the RPE65 gene responsible for their inherited retinal disease.
However, not all retinal diseases are amenable to gene augmentation — for reasons that we will cover in a future blog — therefore, other therapeutic strategies have emerged. Gene editing has recently made a significant impact on both ocular and systemic pathologies. Gene editing aims at modifying a specific disease-causing genetic sequence using molecular scissors to mitigate the effects of the disease variant. A common example is the CRISPR-Cas9 approach, but others include zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). Recent reports on systemic and ocular indications using CRISPR-Cas9 have shown good safety and preliminary signs of efficacy in editing the human genome.
Another approach currently in clinical development is the use of antisense oligonucleotides (ASOs). Indeed, the adeno-associated virus (AAV), a viral vector commonly used for gene augmentation, has a limited gene carrying capacity, and it cannot deliver large genes implicated in common ophthalmic diseases. In this case, the use of gene editing and ASOs could bypass this challenge. While gene editing targets the mutated DNA, ASOs target the mutated messenger RNA to inhibit the production of the corresponding mutated protein that causes the disease. However, ASOs are mutation (variant) specific and not gene specific, so they may not be able to cover all the mutations present in the affected gene. Besides, this approach requires repeated dosing to maintain the therapeutic effect, which also means that the process can be reversed in case of undesired effects, unlike gene augmentation, which is largely irreversible.
Although other approaches are being developed to alter the genetics of disease, the three strategies outlined above are currently the most advanced in their respective clinical development. Gene therapy has had a long and, at times, tumultuous history in ophthalmology, but with the many different genetic modalities under investigation, we have now entered a time of “genomic medicine” for the eye.
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