Project Information

Identifying existing drugs to repurpose for treating AT

Principal researcher: Dr Richard Tuxworth

Institute: University of Birmingham, UK

Cost: £249,332 over 32 months in partnership with Action for A-T (UK), AEFAT (Spain) and BrAshA-T (Australia)

Start date: 1st November 2024

What are you proposing to do?

We know that children with AT have poorly coordinated movement because nerve cells in one part of the brain start to malfunction and eventually die. We think that a particular process known as autophagy is defective in the AT nerve cells. Autophagy is how cells recycle materials and old components for re-use. This recycling process is known to be defective in almost every form of neurological disease, including in other rare inherited disorders affecting the nervous system. Many existing drugs are known to increase the levels of recycling in cells. In this project we are going to search the collection of drugs to try to identify one or more that can restore recycling in AT nerve cells with the hope that these drugs could be re-purposed to treat patients.

Why?

In almost every inherited neurodegenerative disorder where researchers have looked, the recycling process is disrupted. We are already growing nerve cells in our laboratory for two inherited neurodegenerative disorders, and we see defective recycling. Importantly, treating the nerve cells with drugs that restore recycling can prevent premature death in both cases and we think this may also work for nerve cells from AT patients. If we show this to be true, the drugs would be candidates to test rapidly to see if they can help prevent or slow down neurological symptoms in AT patients. How will you do the research? In this project we first will grow AT nerve cells in the laboratory and test a collection of the drugs that are known to enhance recycling. If some look promising, we will then test them in two more complex models of AT. First, we will use fruit flies that we have engineered to mirror what happens in AT. Fruit flies, while much simpler than humans, have a complex nervous system and show complex behaviour. We will be looking to see if any of the drugs correct the structural changes to nerves that we see in our AT flies that are due to defective recycling. We will also test if the drugs are able to correct the movement deficits the flies show. In the final stage of the project, we will grow mini-brains in the laboratory. Over many weeks these mini-brains – known as organoids – develop into complex 3D structures with many different types of 2 cells and features reminiscent of a brain. We know already that in brain organoids grown from AT cells the genes associated with the autophagy recycling process are not being turned on and off correctly and that there is increased death of nerve cells. We are hoping that the drugs shown to work in the cells and the fruit flies will be able to reverse the defective recycling in the brain organoids and protect the nerve cells from dying.

How could it make a difference to the lives of those affected by AT?

The drugs we will test have been deliberately selected to make it quicker and simpler to move into early-stage clinical trials. All the drugs are old and commonly used, meaning they are cheap with no patent issues, plus their safety profiles and any possible side-effects are well-understood. Importantly, all are known to get into the brain, and several are already used to treat neurological conditions, including childhood-onset conditions such as epilepsy. If we can see positive effects of one or more drugs in our cells, fruit flies and mini-brains, we would be excited to get to the next stages: clinical trials to test if they are able to help AT patients maintain neurological function for longer.