CWRU, Cleveland Clinic win $1.3 million grant to start Rett syndrome trial

The Plain Dealer, by Brie Zeltner
February 05, 2015, updated February 12, 2015

CLEVELAND, Ohio -- A team of researchers at Case Western Reserve University and the Cleveland Clinic will use a $1.3 million grant from the Rett Syndrome Research Trust to launch a clinical trial of a new treatment for the rare genetic disorder, which shares some symptoms with autism.

The Phase 2 clinical trial which may launch as early as this spring, will test the effectiveness of low-dose ketamine in treating the symptoms of Rett syndrome, which can include characteristic hand movements, breathing difficulties, difficulty walking, and loss of social interaction and communication.

In early research by Case neurosciences professor David Katz, mice genetically engineered to mimic the condition of Rett syndrome responded well to treatment with low doses of ketamine, showing improvements in brain activity and breathing. Katz, the co-principal investigator (PI) of the trial at Case, will be working with Dr. Daniel Sessler, the co-PI at the Clinic and chair of the Department of Outcomes Research there. Their research team will include Thomas Frazier, director of the Cleveland Clinic Center for Autism; Dr. Sumit Parikh, director of the Clinic's Neurogenetics, Metabolic & Mitochondrial Disease Program; and Edward Mascha, senior biostatistician in the Clinic's Department of Outcomes Research.

Rett syndrome, a developmental disorder that affects girls nearly exclusively, is caused by mutation in a gene called MECP2. The gene contains instructions for the creation of a protein which is critical for brain development, which causes many problems when it doesn't work properly. Rett syndrome is rare -- it affects only one in every 10,000 to 15,000 live female births, and is found in all racial and ethnic groups worldwide, according to the National Institute of Neurological Disorders and Stroke.

"The disease is treated with supportive measures that aren't very effective," said Katz. He has been studying Rett syndrome for more than 10 years, and first published his research on ketamine as a potential treatment in 2012. "Based on what we've seen with the mice, we're really hopeful that this is going to bring some benefit to these kids." Ketamine, which since the 1960's has been used as an anesthetic agent, has been classified as a Schedule III drug since 1999 because of its potential for abuse. In the 1970's and 1980's, it became a popular illicit drug due to its hallucinatory effects, and is still abused today.

"When people think of ketamine they still think of the 60's and 70's and its use as a recreational drug," said the Clinic's Thomas Frazier. "We're using very different doses." Ketamine is often still used as a sedative during dental procedures, Frazier said, and Katz has been compiling anecdotal evidence of children with Rett syndrome who have shown symptom improvement in the days following receiving ketamine at a dentist's office.

Low-dose ketamine is also being tested as a treatment for chronic pain, depression, obsessive-compulsive disorder, and some anxiety-related disorders. Frazier and Katz believe it's possible ketamine is working on a shared brain pathway that is not functioning well in all of these disorders, including Rett syndrome. "I do believe that we may be looking at the same mechanism which underlies the effectiveness of ketamine in depression," Katz said. "We're actually benefiting from all the activity around all those diseases and how you might use ketamine to treat a chronic disease."

Frazier believes ketamine may be acting on what neuroscientists call a "brain network"-- interconnected brain systems that work together to perform functions in a synchronized way. One of these, dubbed the "default mode network," is the one that's at work when the brain's on hold or not engaging in a specific task, and seems to be faulty in those with Rett syndrome.

"Ketamine may be able to enhance the functioning of that network," he said. In Rett syndrome and in autism in general we think that network isn't working very well -- that's why they have so much trouble picking up social cues spontaneously." The trial will enroll about 30 patients in a crossover design, meaning that each participant will be randomly assigned to sequence of treatments (placebo and different doses of ketamine) during the course of the trial -- a method that requires fewer participants and is helpful when studying rare disorders.

"We're all very excited about this because this is a devastating disease and there are no treatments currently available," Katz said. "It's a disease that's really crying out for effective treatments."