A Tremendously Big Deal

“For so many years, the editing field has been excited about the potential of RNA editing,” says Pete Beal, a biochemist at UC Davis who is leading one of RSRT’s RNA editing efforts. “Wave’s results are the first example of RNA editing for therapeutic purpose in humans. It’s a tremendously big deal for the whole RNA editing community.”

Wave revealed that the first two individuals dosed in their clinical trial for alpha-1 antitrypsin deficiency (AATD) had received the treatment with no serious adverse events and showed a therapeutic-level increase in the M-AAT protein that the patients otherwise lack. The protein increase began as early as day three and was observed through the duration of data analyzed thus far, representing almost two months after treatment.

Wave’s success is not only a major milestone in the treatment of AATD, a fairly common genetic condition which can cause lung and liver damage, but for the field of RNA editing. RNA editing has the potential to treat about a third of the mutations that cause Rett syndrome.

The Rett Syndrome Research Trust (RSRT) has invested $8.5 Million into this approach over the past decade.

RNA editing is one of a handful of promising new genomic techniques that has emerged over the past decade. In our cells, DNA is like the master copy of cellular instructions that is kept in a special, safe compartment called the nucleus. To make proteins based off of the DNA sequence, a cell copies a gene sequence into a related genetic material called messenger RNA (mRNA). The protein-making machinery of the cell outside the nucleus uses the mRNA as its “recipe” for making a protein.

Rett syndrome is a genetic disease caused by mutations in the gene MECP2, which codes for a protein that is crucial for brain function. RNA editing has the potential to edit RNA with disease-causing mutations such that it creates a healthy version of the MECP2 protein.

With the support of RSRT, Beal and collaborator company ProQR are working to edit mRNA to correct mutations that cause Rett syndrome by harnessing our cell’s natural mRNA-editing protein known as ADAR (Adenosine Deaminases Acting on RNA). Similar to the approach taken by Wave, they supply a guide RNA that acts as a GPS, directing ADAR to change an mRNA sequence at a targeted location. With his first round of funding awarded by RSRT in 2018, Beal conducted a novel, high-throughput screening system to find RNA guides that might work to correct Rett mutations. After identifying promising candidates, Beal used an approach known as rational design — using knowledge of the structure of the ADAR protein and protein-RNA interactions — to refine his guide RNAs and improve their editing efficiencies.

Since ADAR editing of MECP2 mRNA would target the underlying genetic defect that causes Rett syndrome, it offers a path toward restoring normal cell function without changing DNA.

“I’m optimistic that several of the most common mutations that cause Rett will be targetable using RNA editing,” says Beal. “There are three main reasons for my optimism. One, the ADAR enzyme that allows for RNA editing to take place already exists in our bodies. That helps to avoid the kinds of immune reactions that can occur with approaches like CRISPR and makes delivering the therapy considerably easier. Two, our group and others have made significant advances in the science of nucleic acids like the guide RNAs needed for RNA editing. And three, we know that these therapies can get to the central nervous system through intrathecal delivery. Two approved medications that use this type of delivery, including Spinraza for spinal muscular atrophy, are already out there, and at least 10 more are in trials.”

In addition to reduced immune risks, a benefit of RNA editing using non-viral delivery is that it leaves the door open for patients to use virally delivered medicines — which they can typically received only once in their lifetimes — at another point in time if desired. So, patients and their families don’t have to choose between using RNA editing therapeutics now and other genetic medicines down the road.

With the support of RSRT and in collaboration with Beal, biotech ProQR is currently testing guide RNAs for RNA editing in mice with MECP2 mutations — experiments that are critical to getting an RNA-editing treatment for Rett closer to the clinic. Beal meets regularly with RSRT’s RNA-Editing Consortium, who will come together for their annual in-person gathering in Boston in January 2025.

“The RNA-Editing Consortium that RSRT has put together has been really helpful and given us insight into different ways that we can improve the molecules that we are developing,” says Beal.

In addition to Beal, the RNA-Editing Consortium includes scientists at MIT and the University of Massachusetts Medical School. Shape Therapeutics, Wave Therapeutics, and Vico Therapeutics are also focused on harnessing RNA editing for Rett syndrome.

To learn more about our RNA Editing projects, click below!