Rett syndrome is caused by mutations in the gene MECP2, which codes for a protein that is crucial for brain function. The Rett Syndrome Research Trust (RSRT) is funding several cutting-edge approaches that target the genetic root cause of Rett syndrome. One of the most promising is RNA editing: changing RNA to create a healthy version of the MECP2 protein.
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. Pete Beal at UC Davis is leading one of RSRT’s efforts 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).
“A primary advantage of RNA editing over the kinds of genome editing we hear about a lot is that the editing enzyme is actually a human protein that already exists in our cells. So, we don’t need to worry about how to get the protein into the cells or triggering an immune reaction like we do with DNA editing,” says Beal. Another advantage of mRNA editing over conventional CRISPR-based DNA editing is that it’s reversible. If the treatment doesn’t work or if there are serious side effects, it can simply be discontinued like any typical drug.
Beal, a biochemist with expertise in RNA and proteins that interact with RNA, is expanding on his previous work on ADAR-based editing of MECP2. With a guide RNA that researchers supply, ADAR is directed to change an mRNA sequence at a targeted location. With his first round of funding awarded by RSRT in 2018, Beal investigated two approaches to creating guide RNAs that could edit Rett mutations. The first was a novel, high-throughput screening system to find RNA guides that might work. The second approach, done simultaneously, was a rational design approach — using knowledge of the structure of the protein and protein-RNA interaction to design guide RNAs. Both have yielded promising results.
“I started working on this project when Gail Mandel at Oregon Health and Science University reached out to me,” says Beal. “She was already funded by RSRT and wanted to work someone with biochemical expertise in RNA and RNA-editing proteins. Rett is a debilitating disease that primarily strikes girls and, honestly, I have two girls. So that really made me pay attention.”
Since ADAR editing of MECP2 mRNA targets the underlying genetic defects causing Rett it offers a path toward restoring normal cell function without changing DNA.
“There’s evidence that if the mutation is repaired and you get a functioning, full-length MECP2 protein again, the patients would really benefit. It was just very clear that we needed to get involved with this,” says Beal.
Beal is also motivated by his connection with Monica Coenraads, founder and CEO of RSRT.
“Monica influenced me, too,” he says. “She’s so inspiring as the mother of a patient who has taken it on herself to be on top of the science and keep pushing to help others.”
RSRT is funding Beal to take his success in earlier phases of the project to the next level and focus on experiments critical to get this towards an RNA-editing treatment for Rett closer to the clinic. The next phase of the project will use ADAR to edit cells from mice with MECP2 mutations in collaboration with the Mandel lab as part of RSRT’s RNA-Editing Consortium.
Other members of RSRT’s RNA-Editing Consortium have been developing mice that have a human version of mutated MECP2,” says Beal. “It’s going to be really useful which will be important to optimize the guide RNAs for therapeutic use in patients.”
The outcomes of the advanced stages of the project hold tremendous potential for advancing the landscape of curative Rett syndrome treatments and is a significant step in our mission to accelerate scientific advances that bring us closer to a cure.
In addition to Beal and Mandel, 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. Learn more about RNA editing for Rett here.