The International Rett Syndrome Foundation (IRSF) hosted its annual scientific meeting in Westminster, Colorado on June 18-19, 2024, as part of its ASCEND 2024 Rett Syndrome National Summit.
By Mackenzie Smith
PhD candidate at Loyola University Chicago in the lab of IRSF-funded researcher, Dr. Rocco Gogliotti
The IRSF Rett Syndrome Scientific Meeting is the only annual, global, and comprehensive research gathering focused exclusively on Rett syndrome. Bringing together scientists and clinicians studying Rett syndrome and related areas from around the world, the meeting’s topics of discussion ranged from the molecular basis for Rett syndrome to how patients respond to the treatments currently available. Attendees from academia and industry shared the latest research developments and discussed ways to best provide Rett patients with the care they deserve.
Day 1
Dr. Nupur Garg, IRSF VP of Research and one of the meeting organizers, offered some welcoming remarks before the talks began. There have been many developments in getting groundbreaking therapies to clinical trials over the past year; however, much work is left to be done to provide even more options for treatments that work for each unique individual. Dr. Garg celebrated that this is the greatest attendance ever seen at the IRSF Rett Syndrome Scientific Meeting, exemplifying how different stakeholders are committed to finding treatments and a cure for Rett syndrome.
Session I was titled “Molecular Clues” and kicked off by getting down to the very basics: how MECP2, the gene mutated in Rett syndrome, works in the body. While it is known that the MeCP2 protein interacts with DNA to regulate other genes, there are many unanswered questions as to how it does this and what about this process changes when there are mutations. Understanding these mechanisms can give us more hints about how to make up for MeCP2 loss in function to treat patients.
Dr. Richard Young shared some changing views on MeCP2 for his keynote presentation. While it was long believed that the most important role of MeCP2 was to silence genes, cutting-edge technology shows that it is also crucial to turning genes on. Dr. Harrison Gabel shifted gears to discuss the repressive role of MeCP2, and how it impacts different types of brain cells. Dr. Anne West discussed what we can learn about Rett syndrome from other disorders that share disruptions in regulating DNA, such as Rahman syndrome. Dr. Junyoung (Jun) Sonn then shared his findings that provide further evidence that MeCP2 has a gene-activating role as well, similar to what has been observed by the Young lab. This raises the possibility that drug treatments that help more genes get expressed could be useful in Rett syndrome. Finally, Dr. Zhaolan (Joe) Zhou shared why some genes are more likely to be disrupted when MeCP2 loses its normal function. Overall, the talks in this session show that we know more about the gene that causes Rett syndrome than ever before, and many offered possibilities on how we can use this knowledge to create treatment options.
Session I was followed by a series of 1-minute flash talks by each poster presenter before Dr. Ponni Subbiah took the stage. The first commercially available treatment for Rett syndrome, DAYBUE™ (trofinetide), has seen some success since its approval by the FDA in March 2023. Dr. Subbiah from Acadia Pharmaceuticals, presenting sponsor of the conference and makers of DAYBUE, shared with the scientific meeting attendees that the most common improvements seen so far include engagement with others along with improvements in hand use and eye gaze. Currently, over 1,300 patients have initiated this treatment.
After hearing about some real patient data, the attendees were ready to dive back into what researchers are learning in the laboratory. While the prior session focused on how MeCP2 works on DNA and affects other genes, the next topic of discussion was how Rett syndrome affects cells in the brain in the session on “Cellular Dynamics.” Dr. Qiang Chang gave the keynote address for Session II where he explained that the function of helper cells called astrocytes, which normally support neuron health, is disrupted with MeCP2 mutations. Dr. Cosmos (Yuqi) Wang followed by showing how MeCP2 helps to organize DNA structures within the cell’s nucleus. Steven Burger then transitioned to talking about the complexities of the “mosaic” MeCP2 expression found in girls with Rett syndrome, where some cells have fully functional MECP2 gene while others express the mutated copy of the gene. Each person has a unique skew of cells that do or don’t contain a mutation, and new methods have emerged to help study these cells at an individualized level. Dr. Zijie Xia continued the theme of using revolutionary methods to take a detailed look at which cell types are most affected by this disorder. Last in this session, Dr. Mirko Luoni presented data that has direct implications for gene therapy, as his work looks at the ideal levels of MeCP2 that should be present in the cells for them to work properly. All presenters were optimistic that there are ways to intervene and improve health at the level of individual cells to help patients.
During the final session of the day, “Neuronal Studies,” speakers tackled how and why brain cells send messages to each other differently in Rett syndrome. The keynote speaker, Dr. Joseph Dougherty, presented striking maps showing how the two halves of the brain connect and signal to each other, and how this may be different in many developmental disorders. Dr. Serena Dudek offered one explanation for why signaling may be different in the hippocampus which is important for memory and social behaviors. Her work suggests that some support structures around neurons in this part of the brain develop too quickly, keeping the neurons from having plasticity or being open to learning in the same way. Dr. Erica Levitt’s talk looked at the brainstem, which is more related to the breathing difficulties faced by patients. Like others in this session, Dr. Levitt’s work also supports the idea that disordered signals between neuron circuits may be to blame for sending mixed messages to the body and interrupting normal breathing. Dr. William Lowry then discussed how abnormal signaling may be related to DNA being damaged when MeCP2 loses function, which in turn makes cells lose their ability to remain dynamic and flexible in talking with each other. Finally, Dr. Tal Laviv also showed work suggesting that MeCP2 is involved in repairing damaged DNA. These sessions helped researchers understand why neurons can’t send each other messages in the same way when MeCP2 is mutated, and why this results in certain outcomes in Rett syndrome.
The excitement from hearing of so many groundbreaking results could be felt at that evening’s poster session, marking the end of an energizing day. Nearly 60 representatives from universities and companies from around the world presented their work on Rett syndrome, paving the way for many in-depth conversations and networking opportunities among attendees.
View the full 2024 IRSF Rett Syndrome Scientific Meeting Photo Album by CLICKING HERE.
Day 2
The first day offered some incredible insights into how MECP2 absence can cause abnormalities in the brain in Rett syndrome. The second day was then dedicated to translating this knowledge into ideas for new drugs or genetic therapies.
Many researchers are interested in getting more functional MeCP2 into cells to overcome the effects of mutations. Because girls with Rett syndrome have mosaic expression of normal and mutated copies of MeCP2, both Dr. Kyle Fink, keynote speaker of this “Therapeutic Approaches” session, and Dr. Shawn Liu talked about reactivating the silenced X-chromosome containing the functional copy of MeCP2, though using different approaches. Dr. Karen S. Ho then talked about a gold-based nanotherapeutic called CNM-Au8 that has previously been used in ALS and may protect against toxic factors in the brain to help neurons function. Dr. Amanda Vanderplow discussed how even the mutated copy of MeCP2 has some function and suggested that increasing its levels in the cell using a novel tool called antisense oligonucleotides can restore some functionality. Mackenzie Smith ended the session by suggesting that the drugs that help the neurotransmitter acetylcholine send messages may be repurposed for use in Rett syndrome, as they have seen success in other disorders. Her work also suggests that the mutation a patient has in MeCP2 may impact how well they respond to treatment, advocating for precision medicine and for researchers to consider this when designing clinical trials.
These talks were followed by real-world results from patients participating in ongoing gene therapy clinical trials. Dr. Elsa Rossignol and Dr. Colleen Buhrfiend presented interim results from Taysha Gene Therapies investigational TSHA-102 therapy and showed that the patients who have received it see improvements ranging from hand function to alertness and social interest. Dr. Bernhard Suter then shared preliminary safety results from the phase 1/2 study of Neurogene’s NGN-401. So far, there has been no clinical evidence indicative of MeCP2 overexpression, and only mild adverse events have been observed in patients. More data is expected later this year.
In the meeting’s final session, “Biomarkers & Behavior Studies, researchers discussed how to measure outcomes for the many exciting therapeutic options emerging for Rett syndrome. In his keynote talk, Dr. Jeffrey Neul showed that an electroencephalogram (EEG) can be used to make objective, non-invasive measurements of brain activity that correlate with symptom severity. Effective measures of symptom severity and improvement with treatments are also needed in animal studies, which are a crucial step in looking at safety and efficacy before introducing a drug to humans. Dr. Hui Li presented the many benefits that can be brought about by exercise in a mouse model of this disorder, even extending to social behavior. Dr. Stephen Shea’s work utilized a clever way to measure brain plasticity by seeing how a mouse model of Rett syndrome interacts with young mouse pups. Dr. Victor Faundez showed that MeCP2 levels correlate with levels of a protein named VGF, which plays a role in supporting brain health. This protein can be measured in Rett syndrome patients and used to track improvements in brain wellness in response to therapeutics. Dr. Kira Sheinerman showed that a class of molecules called microRNAs can similarly be used as biomarkers of disease progression and can be measured in blood samples, which is supported by real-world data from patients.
The last two talks of the session focused on approaches to assess clinical trial outcomes. Dr. Jenny Downs discussed the workings of an international workshop on designing the best outcome measures for Rett syndrome that took place in Nashville following the 2023 Scientific Meeting. Kriszha Sheehy then discussed the usefulness of at-home videos to measure patient well-being and progress in response to therapy. Presentations like this help show the crucial role that families and caregivers play in advancing research. Scientists are indebted to those close to Rett patients who offer so much of their time to help researchers understand what is meaningful for improving the quality of day-to-day life for patients and caregivers.
These talks offer a glimpse at the incredible advancements being made in understanding the biological basis of Rett syndrome, and the progress in learning how to treat it. IRSF is proud to host this gathering of Rett experts every year to help share knowledge and resources to propel cutting-edge research and the next wave of treatments.
Thank you to our Scientific Meeting organizers:
Vania Broccoli, Ph.D. (San Raffaele Hospital)
Stuart Cobb, Ph.D. (The University of Edinburgh)
Kathrin Meyer, Ph.D. (Alcyone Therapeutics)
Lucas Pozzo-Miller, Ph.D. (Michigan State University)
Thank you to our generous sponsors who made this event possible:
Acadia Pharmaceuticals
Neurogene | Taysha Gene Therapies
Anavex Life Sciences | DepYmed
Finally, thank you to everyone who attended, presented, and contributed to this exciting meeting. We hope that your time in Colorado sparked fresh ideas, dialogues, and inspiration to accelerate research and ultimately create a world without Rett syndrome.