Enter Exon Editing

Both as a scientist and entrepreneur, these are exciting times to be working in genetic and RNA therapeutics. The convergence of molecular biology, computational and machine learning tools, and increased mechanistic understanding of disease provide exciting opportunities to address genetic diseases that have long been out of reach of current approaches.

One key challenge in genetic disease lies in treating diseases that can be caused by multiple different mutations in a particular gene. In such cases, many current base editing approaches require a different treatment for each mutation, which is often not practical. A second key challenge lies in treating diseases in which the sheer size of the target gene limits the feasibility of traditional gene replacement.

To address these challenges, we need the ability to edit RNA at the kilobase scale. Enter RNA exon editing, which enables making changes to thousands of bases in a single reaction. Using an analogy to explain how this differs from other approaches, CRISPR-based editing has been likened to editing “words” or “sentences,” and base-editing is often compared to editing individual letters. Instead of changing a letter, or word or a line, RNA exon editing rewrites entire chapters – without any DNA edits and without the use of any foreign enzymes, which represent two potential limitations of CRISPR-based approaches. Because RNA exon editing can make such large-scale changes, it holds the potential to treat diseases not addressed by today’s gene editing technologies.

The origins of RNA exon editing technology lie in ascidians – also known as sea squirts. These are organisms that transform themselves from larvae to adults through a process mediated by the organism’s ability to rewrite its mRNA. This process, RNA trans-splicing, was discovered in the 1980s. Until recently, the technology did not exist to harness RNA trans-splicing for therapeutic purposes. But through deep understanding of RNA structure, cutting-edge genomics, high throughput molecular biology, computational biology, and next generation sequencing technologies, sensitive and specific exon editors are now being developed that replace whole exons in vivo, with the potential to rewrite RNA in patients with genetically defined diseases.

My company is pioneering a new class of RNA medicines with the first RNA exon editors. We are advancing multiple programs for difficult to treat conditions and recently announced FDA IND clearance for the first-ever RNA exon editing candidate – and the only clinical-stage therapeutic targeting the genetic cause of Stargardt disease. Stargardt disease is caused by mutations in the ABCA4 gene that lead to progressive retinal degeneration and vision loss, typically beginning in childhood and young adulthood. It is one of the most common forms of inherited blindness and a leading cause of blindness in children and young adults. 

Despite longstanding understanding of the genetic underpinnings, Stargardt disease remains out of reach of current gene therapy and gene editing approaches. ABCA4 is a very large gene containing nearly 7000 bases of coding sequence. Moreover, Stargardt disease is associated with over 1000 mutations, meaning that if one were to use a base editing approach, a different agent would be required for every single mutation. RNA exon editing, on the other hand, can cover patients with any kind of mutation in up to 22 exons at a time. This means potentially 70-75 percent of all people with Stargardt disease could be treated with a single medicine. 

Our goal is to stop the progression of Stargardt disease with a single dose. Once a dose of an RNA exon editor is delivered to the retina via a subretinal injection, non-human primate evidence from our labs (and others) suggests the treatment can continue to edit mutated exons and replace them with wild-type exons for years, and perhaps a person’s entire lifetime. 

Advancing our first RNA exon editing candidate into the clinic reminds us every day about the thousands of people with Stargardt’s disease hoping to maintain vision, see the faces of those they love, read their favorite books, and maintain independence. We are committed to making that possible.

At the same time, we are progressing a broad portfolio of programs in additional retinal diseases, as well as neurological, neuromuscular, and other genetically defined conditions – using RNA exon editing to treat diseases previously considered untreatable. 

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 significantly expand the possibilities of RNA medicines for patients seeking breakthroughs. I am excited to see where it takes us.