Half-a-million pound investment to develop new approach to delivering gene therapies for MND

This year, we are funding research into new treatments for MND via our Advancing Treatments Awards. We announced the three researchers whose work we will be funding last month. One of those researchers is Professor Pietro Fratta of University College London. Alongside Dr Oscar Wilkins, Professor Fratta is developing a new way to deliver MND gene therapies, in an approach that could benefit nearly all people living with the condition.

Gene therapies are an exciting new avenue of research in MND. They target the causes of MND at the genetic level. Since the Foundation was set up in 2017, we have invested over £2.5m into projects to develop gene therapies for MND. This project is different – it aims to create a completely new approach to make gene therapies in MND safer and more effective by targeting only sick motor neurons.

What is a Gene therapy?

Gene therapies are treatments that target a disease at the genetic level. They involve the insertion of a missing gene or molecule into target cells to silence, replace, or manipulate a faulty gene. Examples include antisense therapies and adeno-associated virus gene replacement therapy.

Targeting an out-of-control molecule

Many gene therapy approaches have aimed to correct mutations that cause familial (inherited) MND, such as tofersen, which is now approved by regulatory authorities in the US and Europe to treat MND in people with mutations in the SOD1 gene. But the great majority of people living with MND have sporadic (non-inherited) disease. It has been unclear what drives sporadic disease, so finding targets for new therapies has been challenging.

Recent research identified an important new target – a molecule called TDP-43, which forms toxic clumps in motor neurons in around 97% of MND cases. Professor Fratta and Dr Wilkins are turning TDP-43 into a beacon to guide gene therapies.

Signed, sealed, and delivered

Professor Fratta and his team have developed a technology that only targets cells affected by harmful TDP-43, i.e. sick motor neurons in MND. It limits treatments – specifically, gene therapies – to act on these cells alone. It also includes a built-in switch that turns off the treatment once it has fulfilled its mission. These innovations should improve the safety and efficacy of gene therapies that use this technology.

Imagine that a gene therapy is like an email you want to send to a friend for whom you only have a partial email address. One solution would be to keep spamming emails to all possible address combinations until you get a response, but this is not a very efficient technique – and many other people with similar addresses might get ticked off at their overflowing inboxes.

The new approach still sends the email to all addresses, but it only arrives in the inbox of the correct one and ends up in the junk folder otherwise. Even better, the message can be swapped out easily, meaning different gene therapies can be sent as needed.

The preliminary data that this new technology is based on was published earlier this month in the prestigious journal, Science. The work we are now funding will put this technology to the test.

The reason TDP-43 goes haywire in MND is not clear, but reducing levels of a gene called ATXN2 appears to be beneficial. Professor Fratta and Dr Wilkins will use this new technology to reduce ATXN2 only in diseased cells, with the aim of improving cell survival. They will first test it in human cells, and will then move into animal models – the final steps before clinical trials in humans.

Why is this research important?

This work could, in theory, benefit the ~97% of people living with MND who have toxic build-ups of TDP-43. A therapy helping this many people would be transformational.