Inside the Lab with Cerevance

Inside the Lab- with Cerevance

By Dr. Dominique Pichard, CSO, International Rett Syndrome Foundation (IRSF)

At the International Rett Syndrome Foundation (IRSF), much of the research we fund aims to create new therapeutic options. The option featured in this month’s Inside the Lab is one of the closest to becoming a reality. Indeed, Cerevance’s current research could advance this promising approach to clinical trials. Thank you very much for making this work possible through your financial support of our foundation.

Cerevance has developed a Rett syndrome drug that could advance to first-in-human clinical trials within a few years if effective in mice. The drug, CVN636, acts on an entirely new target for Rett syndrome treatment development: metabotropic glutamate receptor 7 (mGluR7). It may address the underlying pathology caused by the loss of MECP2 and improve outcomes for individuals with Rett syndrome overall.

New Target for Rett syndrome

Science has already established a compelling case for targeting mGluR7 as a potential Rett syndrome treatment. Many of the symptoms of Rett come from defects in communication between cells in the brain, and mGluR7 regulates cell-to-cell communication. mGluR7 responds specifically to high levels of glutamate, one of the primary chemical signals that nerve cells use to talk to each other.

“[mGluR7] is like a safety brake on a train,” says Cerevance CSO Mark Carlton, who directs the research on the mGluR7 drug, “When a train is going too fast [i.e., glutamate levels are too high], it pulls the brake, slows the train down, and stops the disaster, which in the brain is the cell dying.”

Unfortunately, mGluR7 isn’t fulfilling this function in Rett syndrome. Why? Research supported by IRSF in 2013 from Dr. Colleen Niswender’s lab at Vanderbilt University provides some answers. MECP2 mutations that cause Rett syndrome also reduce the amount of mGluR7 in cells. As a result, there isn’t enough mGluR7 to respond appropriately to the excessive levels of glutamate in individuals with Rett. Communication between cells breaks down, cells die, and Rett syndrome symptoms surface. Conversely, boosting the activity of the mGluR7 that is present in a mouse model of Rett syndrome restores brain cell functioning and improves Rett symptoms.

Developing a New Rett Syndrome Treatment

The Niswender lab’s results made mGluR7 a viable target for Rett syndrome treatment development. However, efforts to leverage mGluR7 for therapy face a significant challenge: specificity. mGluR7 looks like three other glutamate receptors, and existing compounds can’t tell these receptors apart. Because they trigger multiple glutamate receptors, these drugs could induce side effects. To address this specificity issue, Cerevance created a new compound that distinguishes mGluR7 from related glutamate receptors.

Cerevance’s mGluR7 drug is now ready for animal testing. Scientists will need to show that CVN636 treats Rett syndrome symptoms in mice to further its development. Thanks to our Foundation’s Kaminsky Scout Program and research funding, these experiments are now underway. Additionally, these resources connected Cerevance with Rett syndrome experts. These experts are now helping the company conduct the necessary studies, evaluate the data, and build momentum for the project.

[IRSF’s Scout Program] introduced us to other [Rett syndrome] experts,” Carlton says, “The CSO at the time, Steve Kaminsky, was pretty excited about the data that was coming out of that Scout Program, which really helped us create momentum internally to take forward this [project].”

Dr. Ana Abdala, a scientist at the University of Bristol, is one of the experts that IRSF introduced to Cerevance. Her lab regularly works with Rett mice. In fact, Abdala has studied Rett syndrome for more than ten years because of the relationships she’s formed with those affected by the disorder.

“I’ve gotten to know a lot of the families who are affected by Rett syndrome and formed friendships, Abdala explains, “[This] guided my choices of projects.”

Abdala leads the current work on Cerevance’s mGluR7 compound in Rett mice. With help from collaborators at the University of Bristol, Abdala will study how the drug impacts apnea, behavior, cognition, and memory in the Rett mouse. Through this work, researchers hope to show that Cerevance’s mGluR7 drug can treat mice with Rett.

Abdala’s assistance and IRSF’s support provide the best chance for Cerevance’s mGluR7 drug to reach clinical trials. If this compound does advance to clinical trials, it will achieve several exciting milestones. The drug would investigate mGluR7 as a therapeutic target in humans for the first time. It would add another compound to the list of Kaminsky Scout Program drugs to proceed to clinical trials. Most importantly, it would take us closer to approved treatment options for individuals living with Rett.