Solving a Deep-Rooted Problem: Research Yields Promise for a Rare Disorder
Drawing on the familiar to describe the mysterious, French neurologist Désiré-Magloire Bourneville first named the strange syndrome that ravaged and eventually took the life of his young teenage patient after the root vegetables
that grew in his garden.
That was in 1879. And still today, the disorder he called tuberous sclerosis – because of the potato-like growths Bourneville found in his patient’s brain – remains a perplexing, often debilitating, problem with no cure. Doctors at Cincinnati Children’s, however, have made significant advances in managing the disease, including a treatment that halts and even reverses the disease’s effects.
Experience Yields Insight – and Breakthroughs
The disorder is now referred to as tuberous sclerosis complex (TSC), to avoid confusion with Tourette syndrome. Cincinnati Children’s TSC clinic is the largest in the world, currently following more than 600 children and adults with the disease, which causes non-cancerous tumors to form in organs throughout the body.
Neurologist David Neal Franz, MD started the clinic in 1992 and has made the disorder his life’s work. Bourneville’s patient had suffered from paralysis and retardation due to the tumors in her brain. Her face was dotted with small growths, angiofibromas, that also can be symptomatic of the disease. While some patients still suffer severe impairments, they are not the norm, says Franz.
“It used to be thought that if you had this disease you invariably had mental retardation, growths on the face and intractable seizures,” Franz says. “But that only applies to a third of the patients. Many people with TSC have normal intelligence and live normal lives.”
TSC is a genetic disorder, caused by mutations in the TSC1 and TSC2 genes that regulate a protein called mTOR, which stands for “mammalian target of rapamycin.” mTOR is important in regulating cell growth. Healthy TSC genes slow mTOR down, so cells grow at a normal rate. When the genes lack the regulating proteins, cells overgrow and cause the malformations characteristic of TSC.
Discovering a Breakthrough Treatment
Franz and his colleagues went looking for a way to compensate for the deficient TSC genes. They found the answer in an unlikely place.
“We found that rapamycin (a chemical originally discovered in the soil on Easter Island) bound to mTOR,” says Franz. “That’s how it got its name ‘target of rapamycin.’” Rapamycin was already known for its immunosuppressive properties, but its affinity for mTOR meant it could be put to another use. “It also works to suppress the growth of tumors,” says Franz.
The idea was tested in a trial led by Cincinnati Children’s nephrologist John Bissler, MD, who worked with Franz and others to see if sirolimus, another name for rapamycin, could replace the function of the deficient genes caused by TSC. The findings were published in 2008 in the New England Journal of Medicine, where researchers documented successful shrinking of tumors in patients with both TSC and a rare lung disease. These encouraging findings also revealed, however, that treatment with rapamycin must be continuous, or the tumor will recur. It is not without side effects, but they seem to be minor and tolerable for most patients.
Further Study, Further Success
Franz is now conducting a further study with RAD 001, another form of rapamycin, to see if it helps the TSC-related brain lesion subependymal giant cell astrocytoma (SEGA) and is working on a second placebo-controll ed, multinational trial for this treatment. The study, which started in 2007 and will run until 2014, is showing great success. The drug’s ability to stop and even reverse tumor growth is drawing patients from all over the country. Franz brings up image after image on his computer screen of patients whose fist-sized tumors – in brains, hearts, kidneys – have shrunk to nearly nothing. “We’ve gone from having nothing to offer to having a treatment for the disease,” he says. What makes the findings even more encouraging, he adds, is that the treatment has potential for many other conditions. “mTOR is overactive or dysregulated in a lot of other conditions besides tuberous sclerosis – Alzheimer’s disease, autism, Parkinson’s and Huntington’s disease, some types of epilepsy. It’s mutated in certain forms of cancer – lung, prostate and breast cancer. So TSC is a model for treating children – and adults – with a variety of diseases.”
