Since the early 1990s, scientists have made great progress in tuberous sclerosis complex research, gaining insights about the underlying cause, especially the role genes and proteins play in abnormal cell development related to TSC. A key part of this work was finding the specific genes that, when mutated, result in TSC. In 1993, researchers identified the TSC2 gene on chromosome 16. Five years later, the TSC1 gene was identified on chromosome 9. Because of this research, the first genetic test for TSC became available in 2002.
Research has also revealed more about the specific functions of the proteins produced by the TSC genes. Through this work, possible drug targets have been identified, and drug trials for treatment of TSC tumors are under way.
Currently, researchers are trying to understand more about the variability of the disorder. This work could lead to new and better treatments for people living with TSC.
Understanding the Function of the TSC Proteins
A discovery in 2002 helped scientists understand how mutations in the TSC genes cause tumors to grow. Researchers at Harvard Medical School and Yale University who were studying how cells grow in response to growth factors found that the TSC protein tuberin is a critical part of a pathway within the cell that helps control cell growth and division. (For more information, see Cause.) The TSC proteins, tuberin and hamartin, are referred to as tumor suppressors because their normal function is to regulate other proteins, allowing cell growth only when necessary. One of the proteins regulated by the TSC proteins is the TOR protein. TOR's function is to send signals to the cell to grow and divide. Scientists discovered that a mutation in either the TSC1 gene or the TSC2 gene leaves TOR unregulated, which causes cells to grow out of control, giving rise to the tumors that are characteristic of TSC.
TOR stands for target of Rapamycin. As the name suggests, the TOR protein is a target for the drug Rapamycin. Rapamycin is an FDA-approved drug developed to suppress the immune system and is often used in transplant surgery. More recently, stents used in cardiac angioplasty to keep arteries open have been seeded with Rapamycin to help prevent tissue from growing around the stent. Rapamycin is used for this purpose because it has been found to be effective at inhibiting cell growth.
Because Rapamycin has a cell-growth-inhibiting function that is similar to that of tuberin and hamartin, scientists think Rapamycin may also be helpful for treating the tumors associated with TSC, possibly replacing the function of these proteins and stopping cells from growing out of control.
Dr. Lewis Cantley of Harvard Medical School says, "That was an exciting connection, because it's one of those rare cases where you go quickly from that eureka moment of 'I suddenly understand why this protein is causing this disease' to 'Oh, by the way, there may already be a drug that's used for something else, that can be of use for TSC patients who otherwise really did not have effective treatments.'"
This research breakthrough led almost immediately to drug trials to see if people with TSC might benefit from treatment involving Rapamycin or drugs like Rapamycin.
Rapamycin Clinical Trials
In 2003, Cincinnati Children's Hospital Medical Center enrolled participants in the first clinical trial for Rapamycin. The study began with a small number of individuals with TSC who have kidney and lung involvement. Rapamycin had gone through the rigorous and controlled testing procedure required for the FDA to approve any drug, and was already in use for other medical purposes. The TSC Rapamycin clinical trial was therefore a Phase II trial, which meant it was designed to test the safety and efficacy, or effectiveness, of the drug when used to treat the tumors associated with tuberous sclerosis complex.
Based on the success of the Cincinnati trial, Rapamycin is now being tested in a multicenter study involving six TSC clinics throughout the United States. Each clinic is enrolling a small number of individuals with TSC who have at least one angiomyolipoma (AML) measuring two centimeters or larger. Participants in this trial are being followed over the course of two years and will receive periodic kidney MRIs and blood tests to evaluate the effectiveness of the drug, as well as possible side effects.
Although the trial is targeting Rapamycin's effect on kidney lesions, doctors will monitor lung involvement, brain lesions, facial angiofibromas, and kidney cysts to see if Rapamycin might also have an effect on these growths.
Research has already shown that Rapamycin reduces the size of kidney lesions in rat and mouse models. Based on these findings, scientists are optimistic that Rapamycin or similar drugs will be useful in treating kidney lesions and other tumors in people with TSC, as well as pulmonary lesions in people with LAM.
Modifier Genes Study
In 2006, the Herscot Center for Children and Adults with Tuberous Sclerosis Complex, in collaboration with Massachusetts General Hospital, will begin a new study designed to identify modifier genes that may play a role in the variability of TSC. A modifier gene is a gene that changes or influences the way in which or degree to which other genes manifest themselves. Such genes may explain why two individuals with the same TSC mutation can experience very different symptoms.
In this study, researchers hope to answer the question, Why do only some people with TSC have autism, infantile spasms, or intractable seizures? The study will enroll sibling pairs with TSC in which one sibling has a history of autism, infantile spasms, or intractable seizures, and the other sibling does not. Researchers will then examine the genome of both siblings to look for a modifier gene that either predisposes one sibling to the debilitating symptom, or protects the other sibling from the symptom.
TS Alliance's TSC Natural History Database
The TS Alliance is in the process of building a national database to help scientists understand and characterize the natural history of TSC. Researchers hope to gain insight about the variability of TSC, including how and why the organ systems are affected at different times in people's lives, and what role, if any, a specific type of mutation plays in the severity and type of symptoms. The database will contain information from people of all ages who are living with TSC, including their specific mutation as well as a detailed account of their medical history. An important goal of the database is to create a research tool for TSC clinics and scientists studying the disorder, making it easier to contact individuals who may be good matches for specific research.
The TSC natural history database is expected to be piloted at two TS clinics in 2006. Keep an eye on the TS Alliance Web site for more information about the database as well as other research information.