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Research Portfolio

GRANT TITLE:

Lysine metabolism as a therapeutic target for epilepsy in tuberous sclerosis complex (TSC)

GRANT TYPE:

ENDEAVOUR PROJECT GRANT

grant amount:

£174,495 over 36 months, awarded in 2023

lead investigator:

Dr Felix Chan

Co-Investigators:

- Professor Gavin Woodhall (Aston University)
- Professor Wyatt Yue (Newcastle University)

institution:

Aston University

Background

Tuberous sclerosis complex (TSC) is a genetic disease caused by mutations in TSC1/2 genes, which causes tumours to grow in various parts of the body, including the brain, and can cause many health problems, including epilepsy, which effects 80% of people with TSC. Currently, a drug called everolimus is the main treatment for TSC. While effective for other symptoms of TSC, everolimus only controls epilepsy in 30-60% of patients. As a result, many patients continue to have seizures, which negatively affects their quality of life and carries risk of injury or tragically, death.

To identify better treatments, there is a need to understand the causes of epilepsy in TSC. Dr Chan and colleagues previously collected surgical brain samples from TSC patients and found an increase in the breakdown of a substance called lysine. Lysine is an amino acid (a building block of proteins) which cannot be made by the body – it comes from food. Lysine is broken down into a substance called 2-aminoadipate by the enzyme AASS. In people with TSC, we see higher levels of AASS and an accumulation of 2-aminoadipate in the brain. We also know that 2-aminoadipate causes seizures in experimental models. So, we suspect that the accumulation of 2-aminoadipate in the TSC brain, caused by increased AASS levels, may contribute to epilepsy in TSC.

"Our brain needs lots of energy during seizures; some are needed but some can perpetuate the seizures, trapping the brain in this continuous cycle. We want to understand carefully which source of energy is needed and which is feeding the seizures. Perhaps, then, we can design creative dietary regime or new drugs to starve the seizures of these toxic energy source and create impact for patients with hard-to-treat epilepsy.

The Study

This study will use experimental models of TSC gene mutations and reduce lysine breakdown in various ways to determine its effect on epilepsy. The research team will then investigate various mechanisms of lysine breakdown, including a low lysine diet, genetic modification to exclude the AASS enzyme, and drugs that stop the AASS enzyme from working.

Significance

This research will determine if targeting lysine breakdown is a viable target to develop new treatments for TSC-associated epilepsy, which are so urgently needed.