By: Glenn Yiu, MD, PhD - Department of Ophthalmology & Vision Science, University of California, Davis, Sacramento, California
Ophthalmology Retina, Volume 2, Number 1, January 2018
What is Genome Editing?
Gene therapy has been the longstanding promise for not just treating, but providing a cure for retinal diseases. This is accomplished by using a delivery vector such as adeno- associated virus (AAV) to deliver a functional copy of a defective gene for inherited retinal degenerations, or to overexpress an antiangiogenic factor for neovascular con- ditions. One of the first ophthalmic applications of gene therapy was in patients with type 2 Leber congenital amaurosis, where subretinal delivery of an AAV expressing the RPE65 gene was successful in improving both sensi- tivity to light and functional vision.1 Similar strategies have also been used to deliver the ABCA4 gene to patients with Stargardt disease, or the CHM gene in X-linked choroideremia. However, these approaches require continuous production of the protein product, and the duration of viral-mediated gene expression is uncertain. For example, long-term follow-up of Leber congenital amaurosis patients who received the RPE65 gene showed possible loss of efficacy after 2 to 3 years.2
In contrast to traditional gene augmentation therapy, genome editing involves a direct modification to the DNA. Instead of overexpressing a functional protein to compen- sate for the mutated or defective gene product, genome editing using clustered regularly interspaced short palin- dromic repeat (CRISPR) systems repairs the actual disease- causing mutation in the genome. This technology is powerful for many reasons. Repairing mutations at the DNA level means that the repaired gene will be expressed and regulated physiologically, under the cell’s native pro- moter, rather than being overexpressed from an artificial promoter. The treatment effect is also theoretically per- manent, and the genetic modifications can propagate when the cell divides, even if the CRISPR system is no longer functional. Hence, genome editing represents a powerful and more refined gene therapy strategy with the potential to provide a true cure for retinal conditions.
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