RettSyndrome.org Webinar Describes 2019 Research Priorities

Rettsyndrome.org is dedicated to funding research in every stage of development and every aspect of Rett syndrome — that’s the main message from a recent webinar hosted by Steve Kaminsky, PhD, the organization’s chief science officer.

The webinar, along with other RettEd webcasts, can be found here.

The presentation, titled “RettEd: Rett Syndrome Research Outlook: 2019 & Beyond,” started with an overview of two main avenues of biological research into treatments for Rett syndrome. First, as the MECP2 gene was found to hold the mutation responsible for the disease 20 years ago, researchers are, of course, looking into ways of fixing the gene. Second, scientists are considering “downstream targets” to ease symptoms by mitigating the gene’s molecular effects.

“If we can fix the DNA, we may be able to fix the syndrome,” Kaminsky said. “If we can’t fix the DNA, then we know MECP2 has a lot of downstream effects on other molecular targets. … If we attack the downstream pathways, maybe we can correct the biology that’s gone wrong in Rett syndrome.”

In response to what he said had been a common request prior to the webinar, he quickly reviewed the status of six clinical trials — ongoing and planned — for Rett syndrome, which currently has no approved treatments.

Newron Pharmaceuticals recently completed its enrollment of a Phase 2/3 study (NCT02790034) in patients ages 4  and older assessing sarizotan, which has been shown to improve breathing in mouse models of the disease. The study’s estimated completion date is April this year.

Center for Rare Neurological Diseases researchers in Georgia are recruiting 12 patients for a Phase 2 trial (NCT02696044) investigating triheptanoin in females ages 2 and older with Rett. The investigational treatment, which scientists believe acts as a possible energy source for the brain, seemed to help relieve motor symptoms and metabolic profiles in mice. The trial is being conducted in collaboration with Ultragenyx Pharmaceutical and the Rett Syndrome Research Trust.

A Phase 2 trial (NCT03633058) evaluating ketamine — a treatment commonly known for its use as a general anesthetic — is recruiting 48 girls ages 6–12 at several U.S. locations. Researchers hope the therapy will be able to alleviate breathing issues and improve motor sensory skills. The trial is being sponsored by the Rett Syndrome Research Trust in collaboration with Vanderbilt University Medical Center.

The  U.S. Food and Drug Administration has approved a Phase 2 safety trial (NCT03758924) in Rett syndrome patients testing Anavex 2-73, an investigational oral therapy being developed by Anavex Life Sciences to potentially modify the course of Alzheimer’s disease. Sites across the U.S. are still being selected, and the trial is not yet recruiting. It is expected to begin in either this quarter or the second quarter of 2019. Anavex 2-73 is a small molecule that activates the sigma-1 receptor, which is known to modulate cellular processes relevant to neurodegeneration. In mouse models of Rett syndrome, the compound demonstrated significant motor sensory improvement.

The largest trial ever attempted for Rett syndrome patients is in the planning stages. The Phase 3 efficacy trial of trofinetide will enroll a minimum of 180 girls throughout the U.S. and last for one year. According to the company, Neuren, a previous Phase 2 trial (NCT02715115), showed “statistically significant and clinically meaningful improvements.”

Two other studies are planned: one testing Epidiolex, the cannabinoid approved last year to treat Dravet syndrome, and one testing a new gene therapy made by AveXis. Details of both trials are yet to be announced.

Kaminsky also detailed the projects that RettSyndrome.org is funding in 2019. These projects are spread across basic research in understanding the disease and possible targets for intervention, translational research to see if observations from basic research might translate into effective interventions, clinical research to test those interventions in patients, and neuro-habilitative research on cognitive and physical therapies that improve patient lives.

Four scientists conducting the basic research are being funded. They will be studying cellular and molecular interactions in disease models.

Zhaolan (Joe) Zhou, PhD, an associate professor of genetics at the University of Pennsylvania, will be exploring “mosaicism,” or how mutant cells interact with normal ones, causing differing levels of symptom severity in girls with the same Rett mutation.

Saad Hanaan, PhD, a research associate at the University College London, is a mentored fellow who will work to understand and create a mouse model of Rett syndrome that expresses a mutation in the GABAb receptor — a mutation believed to cause the disorder, independent of the previously identified MECP2 mutation. The model will be used to explore possible treatments.

“We at rettsyndrome.org feel it’s incredibly important to be funding young fellows, whether they’re clinical fellows or research fellows because we’re going to need to continue to build the bench of the next generation of clinical researchers and basic science researchers as we continue to solve the problems of Rett syndrome,” Kaminsky said.

In another funded project, Erica Levitt, PhD, an assistant professor at the University of Florida, will try to build upon the strengths of sarizotan. She hopes to use a more powerful treatment addressing the same pathway to improve breathing in mouse models of Rett syndrome.

“This might be the next compound in line to improve upon what sarizotan is doing,” Kaminsky said.

Previously a mentored fellow, now a full professor at the University of California San Diego, Alysson Muotri, PhD, will be studying the impact of interleukin 6 (IL-6), an inflammatory cytokine, on cells in the brain. IL-6 released by astrocytes causes inflammation that can damage brain tissue. Muotri plans to use “mini brains” in petri dishes (several cells from the central nervous system grown together) to see if tocilizumb, a treatment approved under the brand name Actemra for rheumatoid arthritis, caused by excessive inflammation in the joints, can decrease IL-6 activity and save neurons.

The group will fund one translational research project, by Antonino Cattaneo, PhD, a researcher at the Scuola Normale Supreriore in Italy. A protein that helps generate nerve cells, called nerve growth factor (NGF), is known to be deficient in Rett syndrome, but making up for the deficit currently requires painful injections. Cattaneo is testing a noninvasive approach called hNGFp, which can be delivered intranasally and may be 10 times more powerful than NGF injections in mouse models.

“If this is effective, it could be a new way to approach the nervous system in regards to Rett syndrome,” Kaminsky said.

Three researchers are taking on projects to improve clinical trials. The first, Sarika Peters, PhD, an assistant professor at Vanderbilt University Medical Center will be testing wearable devices that she hopes will collect accurate, objective measures of disease severity such as heart rate variability, skin conductance, and repetitive hand movements. The device would be integrated with a smartphone so data can be stored and compared with parent and clinician observations.

“The whole idea here, and this is very forward-looking, is ‘how can we do better research in clinical trials?’ ” Kaminsky said. “We can take some subjectivity out of those observations.”

Assistant professor Cary Fu, MD, is a clinical training fellow working with Jeffrey Neul MD, PhD, a professor at Vanderbilt University Medical Center, on an attempt to develop an algorithm to predict epilepsy in Rett patients.

Another clinical training fellow, Carrie Buchanan, MD, a pediatrician at the Greenwood Genetic Center in South Carolina, will be measuring biomarkers such as heart rate variability, inflammatory markers, and cortisol levels, which may help diagnose behavioral disorders such as anxiety in Rett syndrome.

The two researchers who received grants for neuro-habilitation research will be using telehealth initiatives to support patients. Jenny Downs, PhD, an associate professor at the University of Western Australia, is developing sets of exercises for increasing physical activity in Rett syndrome girls that she hopes can be implemented with Skype or other telehealth technologies. Her previous work, showing that enriched environments can change the course of Rett syndrome even without any biological treatments, has been “game-changing,” according to Kaminsky. If successful, she’ll develop online resources for parents regarding increasing physical activity.

Meir Lotan, PhD, an associate professor at Ariel University Israel, conducted a pilot study in Ireland showing that five Rett patients decreased their physical limitations with interventions guided by their caregivers. The exercise programs were designed and conducted with bimonthly professional supervision via Skype. The new study will include 40 participants ages 10–40, who will be supported with biweekly Skype sessions for four months.

Kaminsky stressed the importance of supporting research that spans every aspect of Rett syndrome, from genes and cellular interactions to organ development through individual and community experiences. He also emphasized the organization’s commitment to focusing not only on short-term initiatives such as clinical trials but also on long-term work that may not affect patients for another 10 years.

“There are therapies that are in test right now … if any of them have a positive effect, that’s going to be great. But that doesn’t mean that that’s the therapy for five years from now or 10 years from now because we’re going to improve upon those things,” he said.