An older existing medication that targets a pathway thought to be involved in fragile X syndrome failed to reverse any behavioral characteristics in mouse models of the disease, and was found to further compromise social skills in the mice.
The therapy, rapamycin (also called sirolimus, brand name Rapamune), was first approved by the U.S. Food and Drug Administration in 1999 as a prescription medicine used to prevent rejection after a kidney transplant.
It works by inhibiting the mammalian target of rapamycin (mTOR), which is involved in cell growth and metabolism control in response to nutrients, growth factors, cellular energy, and stress.
Evidence suggests rapamycin has the potential to stop a tumor’s progression, has beneficial effects on neurodegeneration models, and can act as an anti-aging drug.
Some studies have indicated that in mice with fragile X, the mTOR molecular pathway is overactive.
Researchers treated fragile X mice with rapamycin to determine if the treatment could reverse behavioral problems associated with the disease.
The mice were given weekly behavioral tests for five weeks to evaluate their motor activity, anxiety, social demeanor, and sleep duration.
Fragile X mice had higher levels of a specific protein, p-S6, at the start of the study, which rapamycin managed to reduce. However, the treatment failed to reverse most of the behavioral phenotypes measured. And, it enhanced some of the abnormal behaviors, resulting in less sleep and increased deficits in social interaction.
In particular, rapamycin increased anxiety and decreased sleep duration in both fragile X and healthy mice (controls).
Mice have a tendency to socialize; they will spend more time with another mouse if given the opportunity to choose between a mouse and an object. In this study, treated animals did not choose the mouse over the object, which shows that rapamycin aggravated social disturbances in the treated mice.
Interestingly, scientists did not observe the previously reported mTOR pathway overactivation in the brain area under study, the neocortex, adding the possibility that mTOR may not be directly involved in the underlying molecular mechanisms behind fragile X syndrome.
A previous study had also reported that a six-month treatment with a drug similar to rapamycin did not improve symptoms of tuberous sclerosis complex (TSC), a rare genetic disease known to frequently co-occur with autism spectrum disorders, such as fragile X.
“These results suggest that targeting the mTOR pathway in [fragile X] is not a good treatment strategy and that other pathways should be considered,” researchers wrote.