ICF: mTOR Pathway Diseases node

This application is for an 'mTOR Pathway Diseases' node, part of the UK Rare Disease Research Platform.

-What is the mTOR pathway and why is it important?
The mTOR pathway is a set of molecules in our cells that sense a wide range of inputs and regulate key processes, such as cell growth and metabolism. In most people the mTOR pathway keeps us healthy, but in rare cases genetic mutations cause the pathway to go into overdrive and cause disease.

mTOR pathway hyperactivity causes a group 14 of rare diseases affecting 10,000 patients in the UK. mTOR pathway disease patients suffer from a range of symptoms, from benign tumours in multiple organs, to brain malformations causing epilepsy, which can start in infancy. The most common mTOR pathway disease, tuberous sclerosis complex (TSC), can cause epilepsy, autism and learning difficulties from birth. PIK3CA-related overgrowth spectrum (PROS) and Smith-Kingsmore syndrome also cause neurological problems in children and adults. By contrast Peutz-Jeghers syndrome (PJS) causes tumours in the intestine, while lymphangioleiomyomatosis (LAM) causes cysts in the lungs and problems with breathing in adults.

-Why does this area need to be addressed?
mTOR pathway diseases share a common cause and so patients with different diseases can potentially be treated using the same drugs. For example, there is a drug that is used to treat TSC patients that is not used in other mTOR pathway diseases. These patients are unable to access a treatment that could improve their symptoms and the lives of their carers.

The wide range of symptoms in mTOR pathway diseases means patients are seen by different, dis-connected, medical specialities and clinics. This makes doing drug trials very difficult because the numbers of patients with each individual mTOR pathway disease is very small.

The mTOR Pathway Diseases node will unite rare individual mTOR pathway diseases as a single group. We will bring together clinicians, researchers, charities, industry and not-for-profit organisations to improve the diagnosis, treatment and clinical outcomes for mTOR pathway disease patients.

-What are the challenges?
The major challenges we face in this project include the difficulty in identifying and engaging mTOR pathway disease patients; standardising genetic diagnoses, collection and description of patient data; recruiting patients for clinical trials and obtaining patient tissue to study underlying disease mechanisms.

-How will we overcome these challenges to achieve our goals?
1. We will partner with the Tuberous Sclerosis Association and Epilepsy Research UK to recruit patient representatives who will be involved at every stage of the project and sit on the steering committee.
2. Working with patient representatives, we will organise patient public involvement and engagement activities for the mTOR pathway disease community.
3. Annual symposia will be held for our partners, the wider research community and patient/public representatives, to present our research, facilitate networking and enable progress.
4. We will establish a UK patient registry of mTOR pathway diseases, which will engage patients and facilitate clinical trials.
5. We will develop resources and use state-of-the art techniques to analyse patient cells and tissue, which will accelerate understanding and lead to new treatments.
6. We will develop new guidance for doctors to identify, diagnose and treat mTOR pathway diseases and investigate new technologies for diagnosis.

-What are the overall benefits of this project?
We will establish mTOR pathway diseases as a coherent patient population. This will be supported by researchers and clinicians with the resources for basic research and partnerships to develop new diagnostic tools and drug trials, to benefit patients and their families. Over five years we will transform the mTOR pathway disease landscape in the UK.

The mechanistic target of rapamycin (mTOR) signalling pathway regulates fundamental cellular processes including growth control, autophagy and metabolism. mTOR pathway hyperactivation causes 14 diverse, rare, early-onset, hard-to-treat genetic diseases affecting 10,000 people in the UK, with symptoms ranging from benign tumours in multiple organs to brain malformations causing epilepsy, each of which is managed in separate, non-coherent medical disciplines. The challenge is that since mTOR pathway diseases share common molecular mechanisms, clinical phenotypes and drug targets, there is an opportunity to improve diagnosis and outcomes across this disease cluster by connecting disjointed populations, basic and translational research resources with clinical, patient and industry stakeholders. To overcome these challenges and enable progress the node will: (1) improve pathways to treatment by creating a drug-disease database and the first mTOR pathway disease registry; (2) understand the mechanisms underlying mTOR pathways diseases by assembling a patient tissue repository and peripheral blood mononuclear cells panel, as well as performing proof-of-concept studies using phospho-proteomic analysis of patient tissue and cerebral organoids models; (3) improve mTOR pathway disease diagnosis by developing a policy for NHS mTOR pathway disease clinics and adding an mTOR Pathway Diseases panel to the NHS National Genomic Test Directory, as well as investigating the feasibility of non-invasive genetic testing for mosaic neurological mTOR pathway diseases. Working with our academic, industrial and third sector partners, the success of these scientific aims will be maximised through networking, coordination and patient and public involvement and engagement activities including annual symposia, skills workshops and outreach activities. Over five years we will transform the mechanistic understanding, diagnosis and treatment of mTOR pathway diseases.