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Application of mTOR inhibitors as first line therapy for tuberous sclerosis-associated kidney disease


Cardiff University research leads to the effective treatment of renal tumours in people affected by TSC, improving prognosis and quality of life.

Tuberous sclerosis complex (TSC) is a currently incurable genetic condition which affects around 1 in 10,000 people worldwide. The condition causes the growth of benign tumours, most commonly in the kidneys, brain and lungs. Although the tumours are generally non-malignant, they can lead to life-threatening complications. In adults, angiomyolipomas (kidney tumours) are a leading cause of death from TSC.  Other common symptoms of TSC include skin abnormalities, epilepsy, behavioural problems and learning difficulties.

Medical research

Cardiff University has a well-established track record of research into the causes and management of TSC. Prior to 2000, a Cardiff University team led the research consortium that identified the TSC2 gene, and were members of the consortium that identified the TSC1 gene. These studies also identified the genetic mutations in TSC1 and TSC2 that cause the disease.

"The evidence provided by Cardiff University’s research was an essential factor in the process leading to the change in policy and clinical practice that has now become established globally."
The Tuberous Sclerosis Alliance (USA)

Identifying a new treatment pathway

Before the Cardiff University research, led by Professor Julian Sampson, all treatments for TSC-related renal tumours carried risks of immediate complications and permanent damage.

The university researchers showed that disease-causing genetic mutations in TSC patients resulted in altered mTOR signalling, a growth-regulating protein that affects cell growth, survival, metabolism, and immunity.

The discovery of the link between the TSC1/2 genes, mTOR signalling and tumour growth in TSC presented the possibility that TSC tumours could be treated with the existing drug rapamycin, rather than through surgery. Cardiff University researchers carried out studies to explore the broader implications of mTOR inhibition in mice, using both rapamycin and related mTOR inhibitors.

Subsequent clinical studies by the university team showed that mTOR inhibitors could be used as novel therapies for TSC, shrinking renal tumours and also helping to alleviate some of the wider disease symptoms.


Proving effectiveness via clinical trial

A clinical trial, called TESSTAL, was designed to assess the effectiveness and safety of rapamycin in treating TSC patients with renal tumours. The trial found that across two years, the renal tumour burden was reduced in all patients.

Of the 23 tumours treated, 21 shrank in size and 50% of patients had responses that saw a 30% or more reduction in the size of their tumours. The study also found that sustained treatment maintained the reduction in tumour size.

Establishing the use of inhibitors across patient groups

TSC patients may have a range of genotypes, with a variety of mutations in either TSC1 or TSC2. Prior to the research by the university team, it was not known whether patient responses to treatment with mTOR inhibitors depended on mutation.

In a joint study between Cardiff University and international collaborators, no correlation was seen between type of mutation and response to therapy, concluding that mTOR inhibitor therapy could be used across all TSC patients, regardless of their underlying genetics.

The university team’s rigorous investigation of mTOR signalling in the pathology and treatment of TSC provided important evidence needed to implement mTOR inhibitor therapy into the clinical management of the disease worldwide.

Key impact

The Cardiff University team’s research on the molecular mechanisms underlying tumour growth in TSC patients and the effectiveness of mTOR inhibitors to reduce tumour growth in the TESSTAL clinical trial resulted in changes to international guidelines on management of the disease.

Their work also gave weight to a successful lobbying campaign by the UK charity, the Tuberous Sclerosis Association, for the NHS to commission mTOR inhibitors for TSC patients.

In 2015, NHS Wales was the first UK health service to commission mTOR inhibitors for the treatment of renal tumours in TSC.

Following the success of trials, including Cardiff University’s TESSTAL trial, the Tuberous Sclerosis Association campaigned for mTOR inhibitors to be commissioned by NHS England for the treatment of TSC patients in England too.

As a result, in 2016 NHS England announced that it would allow the treatment for children aged three and above, as well as adults living with TSC.

The research contributed to the 2013 publication of Surveillance and Management Clinical Guidelines, which recommend mTOR inhibitors as first line treatment for renal angiomyolipomas, and are considered the international gold standard for clinical management of TSC.

Medical research

"The impact of successful treatment of renal angiomyolipoma with mTOR inhibitors on patient quality of life has been immense as the treatment can be taken by patients orally within the comfort of their home, while previous surgical and embolization approaches required hospital admission and caused permanent damage to renal function. As it is directed to the underlying disease mechanism, the treatment also benefits patient’s skin lesions and epilepsy, further contributing to improvement in quality of life."
Tuberous Sclerosis Association

Key facts

  • Professor Sampson was also an author of new 2019 UK Guidelines for Management and Surveillance of TSC, which were developed through repeated online surveys of 86 UK clinicians and researchers, as well as consultation with the Tuberous Sclerosis Association.
  • The Tuberous Sclerosis Alliance (TS Alliance) is a US-based charity which commands a multi-million-dollar research budget and aims to improve treatment options, access to care and awareness of TSC both in the US and internationally.
  • In 2017, the TS Alliance awarded Professor Sampson their highest honour, the Manual R. Gomez Award, in recognition of Cardiff University’s impactful research.

Meet the team

Key contacts