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What is tuberous sclerosis complex (TSC)

Tuberous sclerosis complex (TSC) is a rare genetic condition that affects an estimated 1 million people worldwide. People who live with tuberous sclerosis have benign (non-cancerous) tumours growing in various organs of their bodies. This causes problems because the tumours start crowding out places in the body that need space to function (e.g. kidneys).

TSC is present from birth, although it may not cause obvious problems immediately. Some patients will be diagnosed very early in life while others may not be diagnosed until later childhood, adolescence or adulthood.

TSC is caused by mutations in either the TSC1 or TSC2 genes. Both of these genes are involved in regulating cell growth and division: they code for proteins which inhibit other proteins, known as mTOR proteins, which instruct cells to divide. In TSC patients, the mutations in the TSC1 or TSC2 genes mean that the inhibiting proteins are not produced, leading to uncontrolled cell growth and division.

Find out more about TSC on the Tuberous Sclerosis Association (TSA) website

Symptoms of TSC

The symptoms of TSC differ from person-to-person depending on where the tumours grow. They also differ in severity: some people are so mildly affected that they experience very few problems, whereas others may be more severely affected.

 Symptoms can include:

  • Neurocognitive problems – e.g. epilepsy, learning disabilities, and developmental disorders
  • Skin abnormalities – e.g. reddish bumps, differently pigmented regions of skin, rough dimpled areas of skin
  • Kidney problems – tumours can interrupt their filtering function, which can cause internal bleeding, stomach pain, and kidney failure
  • Lung problems – tumours can cause breathing difficulties
  • Brain tumours – e.g. SEGA tumours, a type of brain tumour, occurs in 15% of TSC patients. Brain tumours can block fluid movement which can cause headaches, neck pain, blurred vision, difficulty walking, and decreased bladder and bowel control

 The symptoms tend to gets worse as patients age. 

Treatment of TSC before everolimus

Before everolimus, there was no treatment for TSC. Patients were treated for the individual problems TSC causes, such as controlling epilepsy with medication or surgically removing brain tumours.

In this lesson we will cover: 

  • Early TSC research: the role of the TSA
  • Identifying potential drugs 
  • Repurposing everolimus

Early TSC research: the role of the TSA

In the early 1970s, doctors were good at diagnosing TSC from its symptoms, but no one knew what caused it or how to treat it. The Tuberous Sclerosis Association (TSA) formed in 1977 to support affected families, encourage research, and provide information. They started with a membership of 50 families and £25.

The TSA worked hard to generate £30,000 for research into TSC. They advertised a research grant in the British Medical Journal and, after two attempts, received two positive responses. The money was awarded and the research into finding the genetic mutations behind TSC began.

 At the same time, the TSA set up the first international TSC conference for researchers. This stimulated TSC research by facilitating interactions between researchers and giving them a platform to speak about their work. Furthermore, the TSA set up specialist clinics and ran both patient and professional days through them, keeping all stakeholders engaged.

By 1993, a large UK research team had isolated the TSC2 gene. Five years later, the TSC1 gene was found. The functions of the genes took a further five years to figure out, as the pathway the genes were associated with was unknown. A lucky break came when a scientist was investigating the genes behind the growth pathway in yeast. He realised the growth inhibiting mechanism looked very similar to that previously identified in TSC patients.

More research found the TSC genes code for a protein which inhibits another protein called mTOR. mTOR instructs cells to grow and divide. In TSC, the inhibiting protein is not produced correctly, meaning mTOR is not inhibited and cells divide uncontrollably. This finding meant researchers could start identifying drugs which would reduce the activity of mTOR.

Identifying potential drugs

mTOR inhibitors are a type of drug which interrupt the chemical reactions needed for tumours to grow. When researchers realised reducing the activity of mTOR proteins could treat TSC, many pharmaceutical companies were already trying to develop mTOR inhibitors to treat cancers.

 TSC patient groups funded small pre-clinical investigations into mTOR inhibitors with successful results, so the idea was taken to small clinical trials. In 2006, a small clinical trial in the US tested the impact of mTOR inhibitors on four TSC patients with SEGA (a type of brain tumour). The results showed significant reduction in tumour size and improvement in patient outcomes over a 2.5 to 20 month period.

 Another phase II trial investigated the use of sirolimus, an mTOR inhibitor, on TSC patients with angiomyolipoma (a type of kidney tumour). This research was funded by the LAM Foundation and the TSA and it had successful outcomes.

 The TSA used the results of these successful research projects to approach pharmaceutical companies, asking them to include TSC in their investigations into the mTOR inhibitors they were working on.

Repurposing everolimus

The continuing significant results from small research projects caught the attention of advisors at Novartis, a pharmaceutical company. At the time, the company was looking into cancers that everolimus, an mTOR inhibitor they owned, could treat. They sent representatives to an international TSC research conference in Rome and asked if they could collaborate in a large phase II randomised international trial.

What is everolimus?

Everolimus is a type of mTOR inhibitor. It is marketed under several names, including Afinitor and Votubia in oncology.

History of Everolimus

In the early 1970s, a group of scientists from Canada were searching for new antibiotics. They stumbled across a curious molecule that they named rapamycin. A Canadian pharmaceutical company patented it as an antifungal compound in 1974.

 Rapamycin was later found to have immunosuppressant functions. It was acquired by Pfizer, a pharmaceutical company, who developed it as a drug to stop transplants being rejected by the body’s immune system. It has been marketed as an immunosuppressant after being approved by the US FDA since 2001.

 Everolimus is a derivative of Sirolumus developed by Novartis. Novartis was able to change Sirolimus’s structure enough to get a new patent while retaining its therapeutic properties. Everolimus is primarily used as an immunosuppressant to prevent the rejection of organ transplants, but it is also being investigated as therapy for a number of cancers.

Clinical research into everolimus

In 2007, Novartis funded a phase II trial which investigated the effects of Afinitor (another name for everolimus) on TSC in 30 American patients. Then in 2008, another phase II trial investigated the long-term effects of using Afinitor in treating angiomyolipoma (a type of kidney tumour TSC patients can get) in 10 patients. They later launched a phase II clinical trial to investigate the effects of everolimus on TSC epileptic seizures using a sample of 20 patients.

The results from all three trials were positive. The regulators approved the use of Everolimus for SEGA (a type of brain tumour), angiomyolipoma and epilepsy. The TSA, however, had to do a lot of lobbying to get the drug funded by the NHS. Through the TSA being assertive from the outset, the NHS has agreed to fund these drugs for the given indications.