Researchers Propose Minocycline to Treat Fragile X

Study leader Iryna Ethell awarded FRAXA Breakthrough Award for 2008

A University of California Riverside team of scientists has found that an available drug called minocycline, used widely to treat acne and skin infections, might also be used to treat Fragile X. The study’s findings have already led to the approval of a FRAXA-funded clinical trial in Toronto, Canada, that will test minocycline in patients with Fragile X.

Neurons in the brain communicate with each other at specialized contact sites called synapses, with many of these synapses occurring on small mushroom-shaped structures called dendritic spines. During early development dendritic spines have immature finger-like shapes. But learning stabilizes the synapses and dendritic spines take on a mature mushroom shape, which make them more efficient. The brains of patients with Fragile X syndrome have an overabundance of immature dendritic spines.

In their report, the researchers, led by Iryna Ethell and Douglas Ethell, faculty members in UCR’s Division of Biomedical Sciences, describe how dendritic spine development in mice with Fragile X is delayed by enzymes called matrix metalloproteinases (MMPs), which are involved in normal brain development and physiological processes. They report that high levels of certain MMPs keep the synapses immature and inefficient. But minocycline, they found, reduces these MMP levels in the mice, allowing the synapses to mature and make more efficient contacts between neurons in the brain. The outcome: corrected brain abnormalities in dendritic spines, reduced anxiety and improved cognitive function.

Iryna Ethell, PhD, at University of California

Study results appear online, ahead of print, in the Journal of Medical Genetics. In their experiments, the Ethells found that young Fragile X mice treated with minocycline showed an increase of dendritic spine maturation in the hippocampus, a brain area that is critical for learning and memory. Besides less anxiety, minocycline-treated mice showed better exploration skills as compared to untreated mice.

The Ethells are enthusiastic about how their discovery already is leading to a clinical trial. “Clinical studies often quickly follow such basic science because once there is a solid understanding of how problems arise, it is much easier to come up with solutions,” said Iryna Ethell, an associate professor of biomedical sciences.

The study was funded by a grant from FRAXA. Dr. Michael Tranfaglia, FRAXA’s chief scientific officer, said of the UCR researchers, “This group has done something unique and incredibly valuable: They have identified an off-the-shelf treatment for Fragile X through their basic research. By bringing their unique perspective to Fragile X research, they have helped us to understand why neurons are malformed in this disorder, and more importantly, how we can treat it. “We were so impressed with their work that we just awarded Dr. Iryna Ethell the FRAXA Breakthrough Award for 2008. This is easily the most important scientific breakthrough in the Fragile X field in many years.”

According to Dr. Carlo Paribello, president of Fragile X Research Foundation of Canada and the director of the clinical trial (scheduled for early 2009) at Surrey Place Centre Fragile X Clinic in Toronto, Canada, the UCR-led study “will go a long way towards dispelling the idea that mental impairment cannot be treated.”

UCR’s Douglas Ethell, an assistant professor of biomedical sciences, noted that effective therapies for Fragile X syndrome are few and far between. “This is a good time for identifying highly effective therapeutic strategies that might work in Fragile X patients,” he said. “We are excited that our research has the potential to affect many lives.”

Minocycline belongs to a group of antibiotics that has been used in people for more than fifty years to treat Lyme disease, acne, and other skin infections. Minocycline may have beneficial effects in other disorders where higher-than-normal brain levels of MMP-9 are found. It is currently under study for treating rheumatoid arthritis, multiple

THE AUTHOR

After her son Andy was diagnosed with Fragile X, Katie, her husband Michael Tranfaglia, and a third parent founded FRAXA Research Foundation. She has served as FRAXA’s executive director since 1994. Katie has a BA in History from Harvard and an MA in Computer Science from UNC Chapel Hill. She worked as a software engineer and instructor in computer science before FRAXA.

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