Romesh Subramanian (Credit: Headshot supplied by author)
The eye has come to the forefront of gene and RNA therapeutics research for a simple reason – because we can see it! Unlike most parts of the central nervous system (CNS), using advanced imaging equipment, we can understand the changes that a drug may be producing to help patients even in the back of the eye, which is actually part of the CNS.
Drug administration is notably easier for the eye than for other organs. Interest in applying gene therapy approaches to ophthalmological diseases isn’t new – the first FDA approval for an ocular gene therapy was in 2017, but we are seeing a resurgence today.
At the same time, many blinding diseases remain out of reach of current approaches. A key challenge is that many of these diseases are genetically driven with numerous different mutations in a particular gene. Some medicines could in theory address a single mutation, but not retinal diseases with lots of causal mutations – because for each separate mutation there would need to be a different treatment.
This is one of the challenges RNA exon editing is designed to solve. Exon editing medicines have the potential to address hundreds of different mutations within a particular target with a single therapeutic agent, opening up new possibilities to treat conditions such as Stargardt disease – the most common inherited retinal disease and the category we’re studying in our lead program.
Before we delve deeper into Stargardt disease, let me explain a bit more about RNA exon editing, why it’s different from other approaches, and how it works.
By using RNA structure and biology, along with cutting-edge genomics, computational biology, and deep-sequencing technologies, our scientists have developed extremely sensitive and specific exon editors that replace whole exons in vivo, to rewrite RNA in patients with genetically defined diseases. This approach removes and replaces multiple whole exons simultaneously in a single reaction, without any DNA edits and without the use of any foreign enzymes. It therefore increases efficiency, decreases off-target effects, and is designed to treat diseases not addressed by today’s gene editing technologies.
Turning back to Stargardt disease, we’re looking at an inherited retinal disease that affects approximately one in 10,000 people worldwide and has no available treatments. It is caused by mutations in the ABCA4 gene that lead to progressive retinal degeneration and vision loss, typically beginning in childhood and young adulthood. Stargardt disease starts in the macula and slowly progresses to cover the entire macula, causing complete loss of central vision.
ABCA4 is a very large gene, about 7,000 bases, so gene therapy has not been able to solve the problem. Moreover, Stargardt disease is associated with over 1,000 mutations, meaning that if you were to use a DNA base editing technology, you’d need to make a different drug for every single mutation.
RNA exon editing, on the other hand, can cover patients with any kind of mutation in exons 1-22, so we can potentially address 70-80 percent of all people with Stargardt disease with a single medicine. Once we deliver one dose of an exon editor to the retina via a subretinal injection, preclinical animal data suggests it would stay in photoreceptor cells and continue to edit mutated exons and replace them with wild-type exons to restore normal protein production.
These are some of the key reasons why we’ve focused our lead program on Stargardt disease and other ABCA4 retinopathies. At the same time, we’re progressing a diversified pipeline of programs in additional retinal diseases, as well as neurological, neuromuscular, and other genetically defined conditions.
Our ultimate goal with RNA exon editing is to stop the progression of disease with a single dose. Stargardt disease robs people of the ability to drive, read, focus on the faces of loved ones, and more – stealing precious moments that most of us take for granted. The idea that we could give all of that back to improve quality of life for people with Stargardt disease and their care partners is what motivates my colleagues and me every day.
Looking ahead, our ambition to improve the lives of patients and their care partners expands to a wide array of other genetically defined diseases with significant unmet needs. The potential of RNA exon editing is vast. It holds the promise to address some of today’s most complex and devastating diseases and could exponentially expand the possibilities of RNA medicines for patients seeking breakthroughs. I’m excited to see where it takes us.
