This following article describes an experiment with a new drug compound used in the FXS mouse model and shows promise as a basis for future treatments for Fragile X syndrome (FXS) in the long-term. In humans, the PAK inhibitor, used in this experiment, would need to be given regularly and not just once to continue to be effective. In this experiment, tests were all done a short time after the injection and in that time frame the drug was able to reverse multiple abnormal features and characteristics of the FXS mouse. Many of these are the same features that mGluR5 blockers and arbaclofen reverse in young and adult mice. This drug still requires lots of work to develop it before it can be used in humans with FXS as a treatment, including chronic dosing experiments to make sure the improvements persist in the FXS mouse model over longer term treatment, preclinical toxicological work to make sure the drug is safe and does not cause undesired symptoms in the body, and early phase I trials to understand how to dose the drug in humans. It is exciting to have another possible future treatment for FXS and it is expected that good progress will be made towards treatment studies in humans with FXS over the upcoming years.
Commentary provided by a representative of the Scientific & Clinical Advisory Committee
Researchers Reverse Fragile X Syndrome Symptoms in Adult Mice
Picower Institute neuroscientists use single dose of experimental drug; could prove promising for treatment of autism symptoms.
Deborah Halber
Picower Institute for Learning and Memory
March 19, 2013
Neuroscientists at MIT’s Picower Institute for Learning and Memory report in the March 18 Proceedings of the National Academy of Sciences (PNAS) that they have reversed autism symptoms in adult mice with a single dose of an experimental drug.
The work from the laboratory of Nobel laureate Susumu Tonegawa, the Picower Professor in the Department of Biology and a principal investigator at the Picower Institute, points to potential targets for drugs that may one day improve autism symptoms such as hyperactivity, repetitive behaviors and seizures in humans by modifying molecular mechanisms underlying the disease.
“These findings suggest a possible novel therapeutic target for the treatment of Fragile X Syndrome (FXS) — the most common inherited form of autism and intellectual disability,” said Eric Klann, a professor of neural science at New York University.
Using genetically modified mice that exhibit FXS symptoms, the researchers targeted neurons’ dendritic spines, small protrusions that receive signals from other neurons and are key to effective neuron-to-neuron communication within the brain. The researchers focused on spines in the temporal cortex, a part of the brain implicated in autism in humans.
Humans with FXS and autism, and the mouse model with FXS symptoms, have abnormally high densities of dendritic spines, leading to deficits in learning, cognition and behavior.
Tonegawa is scientific co-founder of Afraxis, a California-based company developing drugs that target p21-activated kinase or PAK, a key regulator of dendritic spines. Calling the inhibitor drug FRAX486, Tonegawa and colleagues demonstrated that inhibiting PAK with a single dose of FRAX496 reduced cellular and behavioral abnormalities in mice that model FXS.
This work was supported by the National Institutes of Health, the RIKEN Brain Science Institute and the Simons Center for the Social Brain at MIT.