There is a lot of optimism for the potential to treat inherited eye diseases with gene therapy. Around the world, scientists are exploring ways to fix the genetic errors that lead to gene-based diseases such as retinitis pigmentosa (RP) and Leber’s congenital amaurosis (LCA), editing or creating from scratch the genetic instructions that make sight possible.
Ruanne Vent-Schmidt, a PhD candidate in the Department of Ophthalmology and Visual Sciences at the University of British Columbia, recently spoke about the cutting edge of gene therapy research at the FFB’s Race to Restore Sight Speaker Series in Vancouver. “Gene therapy is a method to help correct abnormal instructions,” Ruanne explained. “For a missing instruction or a missing gene, gene therapy gives the cell a new, functional gene.” Ruanne also detailed a new gene editing tool: CRISPR (clustered regularly interspaced short palindromic repeats), an innovative approach that allows scientists to correct errors in genetic code, creating a new set of instructions for functional vision.
To illustrate the different kinds of gene therapies in development, Ruanne used a real-world comparison: “Think about the process of installing a refrigerator door. If the instructions to put on the door handle are missing, you would end up with no handle bar on the door, which would be a problem. One of the ways that gene therapy works is by delivering the original instructions to install the handle bar.” Ruanne expanded the analogy to show how CRISPR technology is being leveraged: “What if your original instructions asked you to put the fridge door handle bar on top of the fridge?” she asked. “You would first need to remove the faulty instructions and then replace them with new, correct instructions to put the handle on the door.”
CRISPR’s value lies in its ability to pinpoint mistakes and correct them, just as your word processor targets and corrects certain writing errors. It’s a level of precision that was not possible before the development of CRISPR. “It’s like editing a spelling mistake,” explained Ruanne, “and a new generation of researchers are working very hard to improve the technology for its use in vision research.”
Of course, in the context of gene therapy the process of editing genetic instructions is more complicated than installing a refrigerator door. Scientists are working to understand this complexity by asking: Which genes should be targeted? Which genes should be inserted to replace missing or faulty genes? How do we maximize the effectiveness of the inserted genes?
Thankfully, we learned a lot from the first gene therapy clinical trials that focused on replacing the missing instructions that lead to the eye disease LCA. Research published in 2008 detailed the use of inactive viruses as a mechanism to deliver new genetic instructions into DNA. These instructions consisted of a copy of the RPE65 gene, which filled-in for a missing gene by providing a light-sensing molecule to facilitate vision. Incredibly, participants showed improved vision only weeks after the RPE65 copy was inserted.
Unfortunately, some clinical trials reported that these positive results began to diminish and disappear between 6 months and 3 years after the initial treatment. But one of the trials continued to generate positive, encouraging results. This approach is being developed by Spark Therapeutics, and it provided researchers with the first signs that gene therapy has the potential to restore sight in a more permanent fashion, and that properly-designed viruses can serve as a safe and effective vehicle for delivering the necessary genes.
Researchers have identified 260 genes related to all forms of retinal disorders, a vast and complex instruction manual involved in the intricate work of telling the eye how to see. If an Ikea manual is a 140-character tweet, the retina’s genetic instructions are like a stack of hundreds if not thousands of textbooks, all linked in complex ways and modified by any number of environmental factors. Much of the work being undertaken in gene therapy labs today involves interpreting this monolithic stack to understand how it can be most effectively revised.
As Ruanne made clear in Vancouver, editing that complex manual by inserting new genes or replacing faulty ones is important work, but other approaches are being explored as well: “Remember the analogy of installing the handle bar on the fridge door?” she asked. “Well, let’s forget about the handle bar and install a motion sensor. It’s a new instruction that never came with the instruction manual, but it might work.” Just as an aftermarket motion sensor could be added to open your refrigerator door (even though it wasn’t part of the original plan), the photoreceptor cells in the retina that are responsible for receiving light could be given an instruction to boost their sensitivity. Or, those and other cells in the retina could be given genetic orders that prevent cell death from happening. The gradual death of photoreceptor cells leads to blindness in those living with RP. Or, alternatively, the cells could be instructed to make more nutrients, keeping the eye healthy and preventing the loss of sight.
“It’s like fighting the common cold,” explained Ruanne. “We can take a drug to get rid of the cough, regardless of its initial trigger.” Gene therapy offers this and other tantalizing possibilities, fueling our optimism that one day we will treat deteriorating vision just like a common virus. There is a lot of work required before something like this happens, and in science there are never any guarantees, but it is clear that at this point gene therapy is a strong contender in the race to restore sight.