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Tuberous Sclerosis Moves toward Drug Therapy, Offers Clues to Epilepsy and Autism

For release: Friday, October 24, 2008

Three recent studies show that the drug rapamycin reduces neurological symptoms in mouse models of tuberous sclerosis complex (TSC), a rare genetic disorder associated with epilepsy and autism.  Scientists say those results could pave the way for effective treatment – and not just for TSC.

"The work may have broader implications for treating epilepsy and autism in the general population," says Jane Fountain, Ph.D., of the National Institute of Neurological Disorders and Stroke, which funded all three studies. 

TSC is associated with benign tumors that can grow in nearly any tissue, including the skin, heart, kidneys, eyes or brain.  Up to 90 percent of people with TSC develop epilepsy and about half are intellectually impaired and/or have autism spectrum disorder.  In some cases, severe seizures or large tumors that compress vital brain areas may be fatal.  The brain in TSC patients is typically enlarged and contains cortical tubers – disorganized areas of the brain that are made up of cells with characteristics of both neurons and glia, the brain's support cells.  Scientists have long theorized that tubers are the cause of seizures and other symptoms.

Some TSC patients with epilepsy benefit from antiepileptic drugs, but others do not.  For individuals with autism and other cognitive disabilities, there are few options other than behavioral therapy. 

Scientists began to investigate treating TSC with rapamycin – an immunosuppressant drug that is used to prevent organ transplant rejection – based on the genetics of the disease.  About one quarter of TSC cases are caused by mutations in the TSC1 gene, and the remainder are caused by mutations in the TSC2 gene.  In 2002, researchers discovered that the products of the TSC genes have something in common with rapamcyin:  they act like an off-switch for the aptly named “protein mammalian target of rapamycin” (mTOR), a potent stimulator of cell division and growth.  In an emerging picture of TSC, mTOR became a runaway train – causing tumors and abnormal brain function – and rapamycin became the potential brake.

In a 2005 study, researchers tested rapamycin in five TSC patients with astrocytomas, a type of brain tumor made up of glia called astrocytes.  The tumors shrank in all five patients after a few months of oral rapamycin.  Another study showed that rapamycin shrank kidney tumors in TSC patients.

Neither study examined whether rapamycin could reduce the seizures and cognitive disabilities associated with TSC.  Also, the research did not conclusively link rapamycin's anti-tumor effects to mTOR.

The new mouse studies allowed researchers to probe both issues.  The studies tested rapamycin at a variety of different doses and schedules, and because there are still questions about how to best replicate TSC in mice, they used a variety of different mouse strains.  Some of the strains had TSC1 mutations, others had TSC2 mutations, and some strains had those mutations restricted to specific brain cells, either neurons or astrocytes.  The highlights:

  • Counter to the idea that tubers cause symptoms, all the mutant mice had the major neurological symptoms of TSC, but lacked tubers.
  • In all three studies, researchers tried treating the mice continuously with rapamycin, starting within days after birth.  This continuous treatment blocked mTOR activity, and reduced brain enlargement and mortality.  However, if rapamycin was stopped, the mice rapidly deteriorated.
  • One of the studies, in the Journal of Neuroscience,* showed that a derivative of rapamycin called RAD001 had similar effects.
  • A study in the Annals of Neurology** showed that rapamycin could prevent seizures when given to newborn mice and eliminate seizures when given to adult mice.  Again, the drug's benefits wore off when it was discontinued.
  • A study in Nature Medicine*** showed that acute treatment with rapamycin could improve learning and memory in adult mice.

Alcino Silva, Ph.D., a neurobiologist at UCLA who led the Nature Medicine study, says that rapamycin's effects on adult mice with TSC overturn long-held doubts about the ability to treat the disease in older patients.  "Many researchers believed that the cognitive deficits [in TSC] are caused by abnormal development and that they cannot be reversed later in life.  Our data suggest this is not the case," he says.

As an immunosuppressant, rapamycin impairs the body's ability to heal wounds and fight infections, so researchers say further clinical studies are necessary to determine whether it is safe for long-term use in people.

In collaboration with Petrus De Vries, M.D., Ph.D., of the University of Cambridge, Dr. Silva is investigating whether rapamycin can reduce neurological symptoms in childrenwith TSC.  Drs. Silva and De Vries met at a NINDS workshop on mTOR signaling held in January of this year in Bethesda, Maryland.

Researchers are also beginning to explore the role of mTOR in epilepsy and autism.

"We still don't understand how epileptic seizures develop in TSC," says Michael Wong, M.D., Ph.D., the lead scientist of the Annals study and a neurologist at Washington University in St. Louis.  "We're looking at how different abnormalities of neurons and astrocytes might play a role."  Those studies could reveal key mechanisms of epilepsy in the general population, he says.

Meanwhile, researchers continue to find connections between autism and mTOR.  A 2005 study showed that up to 17 percent of children with autism and macrocephaly (head enlargement) have underlying mutations in Pten – a gene that regulates mTOR.

The Tuberous Sclerosis Alliance and Autism Speaks provided additional support for the research described here.

NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services.  The NIH — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research. It investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

-By Daniel Stimson, Ph.D.

* Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, Kwiatkowski DJ.  "Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function."  Journal of Neuroscience, May 21, 2008, Vol. 28(21), pp. 5422-32.

** Zeng LH, Xu L, Gutmann DH, Wong M.  "Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex."  Annals of Neurology, April 2008, Vol. 63(4), pp. 444-53.

*** Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, Ramesh V, Silva AJ. "Reversal of learning deficits in a Tsc2(+/-) mouse model of tuberous sclerosis."  Nature Medicine, published online June 22, 2008.


Last Modified December 8, 2008