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Study Funded by the Rett Syndrome Research Trust Demonstrates First-Ever Symptom Improvement in a Mouse Model of Any Human Disease Using RNA Editing

TRUMBULL, CT – This week the Proceedings of the National Academy of Sciences published a paper online demonstrating that RNA editing can improve symptoms in a mouse model of Rett syndrome, a rare and severe neurological disorder. This is the first published study to demonstrate symptomatic improvement in a mouse model of any human disease by RNA editing, and the study provides an essential proof of concept for improving Rett syndrome symptoms using RNA editing.

The study was authored by Gail Mandel, PhD, and post-doctoral fellow John Sinnamon, PhD, of Oregon Health and Science University. During the span of a decade, the Rett Syndrome Research Trust (RSRT) has provided $3.2 million to the Mandel lab for this study and others related to the functioning of the MECP2 gene, which, when mutated, causes Rett syndrome.

“I am so proud to recognize Dr. Mandel, Dr. Sinnamon, and everyone in the Mandel lab for this important publication,” said RSRT CEO Monica Coenraads. “Our singular goal at RSRT is to accelerate a cure for Rett syndrome. Showing that RNA editing is a powerful strategy to achieve that goal means we are one step closer to fulfilling our mission.”

“We hope our proof-of-concept studies in mouse models of Rett syndrome will encourage studies by others to continue to advance the field rapidly toward a cure for Rett syndrome and other neurological diseases,” said Dr. Mandel. “In addition to the many other investigators before us who first discovered natural RNA editing and developed targeted RNA editing strategies, we owe particular thanks to Dr. Joshua Rosenthal of Marine Biological Laboratories in Woods Hole, Massachusetts, who introduced us to his Editase system that we adapted to repair MECP2 mutations.”

Rett syndrome is caused by mutations in MECP2, a gene located on the X chromosome. Rett syndrome affects 350,000 individuals worldwide, most of whom are female. The symptoms of Rett are devastating, including losing acquired skills such as walking, talking, and hand use, and symptoms such as scoliosis, extreme anxiety, tremors, seizures, hyperventilation, and digestive problems. Most people with Rett syndrome live into adulthood, requiring round-the-clock care.

RNA editing, one of six genetic-based curative strategies being pursued by RSRT, is a naturally occurring process in human cells. A group of enzymes called Adenosine Deaminase Acting on RNA (ADARs) changes the RNA base adenosine (A) to inosine (I), which is interpreted by the cell as guanosine (G). The editing of A-to-I(G) in RNA then causes coding changes in the resulting protein, altering protein function.

Using a newly developed mouse model of Rett syndrome containing a patient mutation, the authors injected into the bloodstream an adeno-associated virus (AAV) encoding an engineered ADAR enzyme, referred to as Editase, and a guide RNA, which acts like a GPS, that brings the enzyme to the correct spot in the mouse Mecp2 RNA. After injection of virus into young male Rett mice, they observed editing in multiple brain regions, with the highest amount of editing, 18%, in the brainstem. Looking at individual cells in the brainstem, about 20% of cells showed repair of MeCP2 protein, and the repaired protein was expressed to, on average, 70% of normal levels. Importantly, some cells even showed protein levels equal to those observed in wildtype cells, indicating that there is no inherent ceiling to the level of repair that is possible in vivo.

Many of the Rett-like behaviors involve multiple brain regions, or the specific neuronal circuits underlying the behavior are not well defined. However, the brainstem, which is the region with the highest level of MECP2 RNA editing, is known to be essential for the control of respiration, and respiratory dysfunction is a hallmark symptom of Rett syndrome patients that is repeated in Rett mice. Untreated mutant male mice and those injected with the Editase and a guide RNA that did not target Mecp2 messenger RNA showed an expected high number of apneas and irregular breathing patterns. However, the mutant male mice injected with a virus targeting Mecp2 RNA had the same number of apneas and breathing pattern as untreated normal mice.

Importantly, Dr. Mandel and her colleagues identified a limiting factor to maximizing editing of cells in the brain: expression of the guide RNA that targets the Editase enzyme to MECP2 RNA. While both the Editase and guide RNA were packaged in the same virus, the pattern of expression of these two essential components was inconsistent across different brain regions, with the brainstem showing the most cells showing expression of both enzyme and guide. This key finding is relevant for all guide-based therapies used in the brain, including DNA base editing, which typically uses the same viral component as this study to express guide RNAs. Improvements in the design of the virus will likely result in more cells exhibiting guide RNA expression and a correspondingly higher number of cells showing MeCP2 repair.

“Targeted RNA editing is another prime example of applying the knowledge gained from basic science research to develop therapeutic approaches for human disease. This study is the culmination of a multi-study project to test the feasibility of utilizing RNA editing to repair the mutations that cause Rett syndrome,” said Dr. Sinnamon. “We hope our work will continue to drive interest in RNA editing technology and the underlying biology, and ultimately result in a cure for diseases, including Rett syndrome. We are grateful to the Rett Syndrome Research Trust for recognizing the potential of our work and to the larger Rett syndrome community for their support.”

This study is the first demonstration of symptomatic improvement in a mouse model of human disease by RNA editing and provides an essential proof of concept for improving Rett syndrome symptoms using RNA. Potentially 45% of Rett syndrome mutations are repairable by RNA editing, including the common mutations R168X, R255X, R270X, and R294X. Now that it has been established that RNA can affect symptoms in models of Rett, future studies can focus on improving the efficiency of editing and of symptom rescue in models of these mutations.

Dr. Mandel and Dr. Sinnamon were the first researchers to pursue RNA editing for Rett after receiving funding through the organization’s MECP2 Consortium. Encouraging progress by the RSRT-funded Mandel lab catalyzed the launch in late 2019 of Vico Therapeutics. Dr. Mandel is a scientific co-founder of the company and a champion for the Rett syndrome program.

RSRT is a nonprofit organization with a highly personal and urgent mission: achieving a cure for Rett syndrome and related disorders caused by defects in the MECP2 gene. Since its founding in 2008, RSRT has awarded $64 million, more than any other Rett organization in the world, to leading scientists pursuing targeted research on Rett. RSRT funds and spearheads global scientific and clinical activities advancing the most promising curative approaches. To date, every biopharmaceutical company pursuing a cure for Rett syndrome is doing so because they leveraged discoveries and resources incubated with RSRT funding.