C9orf72 associated motor neurone disease (MND): investigating the genetic penetrance, expressivity, metabolic and inflammatory clinic-ready biomarkers

Dr Arianna Tucci
PI Dr Arianna Tucci
Co-investigators Dr Alexander Murley
Prof. Henry Houlden
Prof. Andrea Malaspina
Prof. Henrik Zetterberg
Collaborators Prof. Pietro Fratta
PI organisation Queen Mary University of London
Funding awarded £670,046
Completion date 30th November 2025 (18 months)

Finding a treatment that slows down MND progression depends on our understanding of those factors that contribute to the initiation and progression of disease. The discovery of mutations in the C9orf72 gene in a percentage of individuals with MND and in others that develop frontotemporal dementia, as the commonest genetic cause of these disorders, has reinvigorated the search for “disease modifiers”: the molecular changes that alter disease progression and the clinical presentation. The fact that people with C9orf72 sometimes do not develop disease is also of great importance, for genetic counselling and for clinical trials. Addressing these questions has been challenging due to lack of genetic and clinical information on large populations. We will use the power of UK Biobank, a collection of genetic and clinical information on 500,000 people, and utilise the latest genomic and biomarker technology to investigate large C9orf72 cohorts at UCL, QMUL and Cambridge to address these fundamental questions.

Dr Arianna Tucci

Multimodal remote monitoring of C9orf72 hexanucleotide repeat expansion carriers (MONITOR-C9)

Dr Alexander Thompson
PI Dr Alexander Thompson
Co-investigators Prof. Kevin Talbot
Prof. Martin Turner
Prof. Aiden Doherty
Prof. Jonathon Rohrer
Dr Rhian Convery
Dr Andrew Douglas
PI organisation University of Oxford
Funding awarded £712,536
Completion date 31st July 2026 (24 months)

Around one in ten cases of amyotrophic lateral sclerosis (ALS, also known as motor neuron disease, MND) and frontotemporal dementia (FTD) cases are caused by an abnormality in a gene called C9orf72. Not everyone with the abnormal gene will develop ALS or FTD and we cannot currently predict who will be affected or when. We urgently need to develop treatments that prevent people who carry the C9orf72 genetic abnormality developing ALS or FTD, but the lack of a means to predict who the disease will strike or when is a major barrier. This project will use measurement of physical activity, brain function and blood tests to develop ways to predict who will develop ALS or FTD and when, and to measure the effect of preventative treatment.

Dr Alexander Thompson

Identification of druggable targets for C9orf72-related toxicity via an innovative CRISPR/Cas9 kinome-wide screen

PI Dr Arpan Mehta
Co-investigators Dr Wenting Guo
Collaborators Prof. Kevin Talbot and Prof. Colin Smith
PI organisation University of Dundee
Funding awarded £356,937
Completion date 1st October 2025 (18 months)

This study aims to identify a class of proteins called “kinases” that may act as pivotal cellular switches in the ALS/MND disease process. There’re currently >100 approved drugs that target kinases; yet, in ALS, there’s been little dedicated research on kinases, meaning that there’s an urgent unmet need. By studying the commonest genetic cause of ALS/MND—a fault in the C9ORF72 gene—we’ll harness state-of-the-art human stem cell and gene-editing technologies to screen for novel druggable targets. We’ll examine for kinases that modulate motor neuron death when harmed with excessive glutamate neurotransmitter and toxicity imparted by immune cells (mimicking the toxicity seen in real life). We’ll then validate the top kinase potential targets by multiple methods, including via human postmortem tissue. Ultimately, this groundbreaking foundational work will set the scene for the next stage of discovery using the results generated, aiming to uncover druggable targets that prevent MN death.

Muscle ultrasound-derived fasciculation characterisation as a marker of MND progression

Prof. Emma Hodson-Tole
PI Prof. Emma Hodson-Tole
Co-investigators Dr Adrian Davison
Dr Amina Chaouch
Prof. Moi Hoon Yap
Collaborators Dr James Bashford, Professor Jonathon Rohrer,
Mr Greg Broadhurst
PI organisation Manchester Metropolitan University
Funding awarded £410,010
Completion date 2nd March 2026 (18 months)

We aim to develop a sensitive and pain-free way of monitoring muscle health in MND that will make it easier to diagnose MND earlier. Then, when treatments become available, people can start them before the disease has affected them too much. Improving how sensitively we measure muscle health will also mean fewer people would need to take part in treatment trials, because the effects of the treatment would be spotted more easily. This would make trials faster and cheaper and speed up treatment discovery.

Changes in muscle cause the physical problems in MND. Recording videos of muscles using ultrasound imaging reveals important changes in their health. We have already begun developing software that automatically detects some changes and propose developing this into a tool that will give a simple and easy to interpret readout that would help clinicians to diagnose MND sooner and assess the effects of new MND treatments.

Prof. Emma Hodson-Tole

Sterol biomarkers for ALS

PI Prof. William Griffiths
Co-investigators Prof. Yuqin Wang
Collaborators Prof. Martin Turner,
Prof. Robert Brown,
Prof. David Skibinski
PI organisation Swansea University
Funding awarded £308,495
Completion date 31st December 2025 (18 months)

Despite advances in knowledge about MND, diagnosis and treatment have lagged behind because we lack effective biomarkers – biochemical signatures that indicate presence of a disease and give information about disease type and progression. Currently there are no biomarkers that are specific to MND.

Cholesterol is essential for motor neurons, but studies have identified high blood-cholesterol levels as a risk factor for MND. Other studies show links between disturbed cholesterol production and genetic mutations that cause MND. Disturbed cholesterol production leads to abnormal cholesterol metabolites (substances created when cholesterol is broken down) in blood, something we found in pilot work. We will now expand earlier studies to a large number of blood samples from people with MND, to establish definitively how cholesterol and its metabolites change at disease presentation and during progression. This should identify biomarkers that could be used to diagnose MND earlier and monitor disease progression and treatment response.

Target induction of the cold-shock protein RBM3 to prevent synapse loss and neurodegeneration in ALS/FTD

PI Dr Marc-David Ruepp
Co-investigators Dr Andrea Serio
Collaborators Prof. Pietro Fratta and Prof. Rickie Patani
PI organisation King’s College London & UK DRI
Funding awarded £428,829
Completion date 31st December 2025 (19 months)

In MND the connection between different nerve cells, synapses, are lost very early on, even before any clearly visible disease symptoms. The aim of this project is to establish whether RBM3, a cold-shock protein that was shown to be neuroprotective in Alzheimer’s and prion disease by preserving synapses could be harnessed also as therapeutic approach for ALS/FTD. For this, we plan to exploit a novel system we developed that allows recreating complex but controlled networks of neurons in a dish to assess whether synapse health in diseased neurons improves upon delivery of therapeutic antisense RNAs that increase RBM3 levels. We will establish here whether increasing RBM3 levels can preserve synapses in MND and therefore whether it can be harnessed as a therapeutic approach.

Exploiting state-of-the-art mass spectrometry to identify blood-based biomarkers for TDP-43 driven MND

Dr Raja Nirujogi
PI Dr Raja Nirujogi
Co-investigators Prof. Dario Alessi
Dr Bhuvaneish Selvaraj
Prof. Suvankar Pal
PI organisation University of Dundee
Funding awarded £348,462
Completion date 31st December 2025 (18 months)

Clinical diagnosis of MND, a debilitating and fatal disease is often challenging and a protracted process (up to 1 year). This reflects lack of specific blood-based tests for early diagnosis and measuring/predicting disease progression. Recent studies have identified several small fragments of proteins called “cryptic peptides” that are present in brain samples from people living with MND (pwMND) but not healthy individuals. In this study, we aim to develop an improved test to identify/quantify the levels of those peptides that are present in the blood samples of pwMND. We will develop methods to accurately identify and measure them using an ultra-sensitive technique called mass spectrometry. Finally, we will verify MND-specific peptides in blood samples generously donated by pwMND to a large-scale biobank anchored in Edinburgh. Our efforts would result in the development of a simple blood-based test for MND and open new avenues for diagnosis and clinical management for pwMND.

Dr Raja Nirujogi

Identifying biomarkers of disease onset and progression for translation into early diagnosis and measures of efficacy in C9orf72-ALS/FTD clinical trials

Prof. Dame Pamela Shaw
PI Prof. Dame Pamela Shaw
Co-investigators Prof. Guillaume Hautebergue
Prof. Mimoun Azzouz
Dr Jonathon Foley
Dr Amanda Heslegrave
PI organisation University of Sheffield
Funding awarded £598,880
Completion date 31st October 2025 (18 months)

ALS/MND is a progressive neurodegenerative condition where the motor neurons, enabling movement through our muscles, die, causing disability in walking, talking, eating, and breathing. Average life expectancy is 2-3 years from symptom onset. Treatments to slow the loss of motor neurons are urgently needed.

An expanded section of DNA in the C9orf72 gene causes ALS/MND in 10% of cases. The expansion varies in size and produces 5 different toxic proteins that injure motor neurons to varying degrees, though their relative impacts are incompletely understood. Crucible is developing a potential treatment that stops toxic protein production and has plans to evaluate this in clinical trials. Using samples donated by patients and clinical data, we aim to develop tests to reliably measure the toxic proteins as biomarkers to rapidly demonstrate treatment effects and reduced motor neuron injury, aiming to accelerate the development of new treatments for people with C9orf72-MND.

Prof. Dame Pamela Shaw

Development of a fluid biomarker for C9orf72 antisense repeat-derived proteins

Prof. Adrian Isaacs
PI Prof. Adrian Isaacs
Co-investigators Dr Amanda Heslegrave
Prof. Henrik Zetterberg
Prof. Andrea Malaspina
Prof. Jonathon Rohrer
PI organisation University College London & UK DRI
Funding awarded £560,432
Completion date 31st March 2026 (21 months)

A mutation in the C9orf72 gene is the most common known cause of ALS. The C9orf72 mutation generates two types of damaging proteins, termed ‘sense’ and ‘antisense’ proteins. Recently two clinical trials that reduced only the levels of the sense proteins failed to show any benefit for C9orf72-ALS patients. This suggests that we also need to target the antisense proteins to successfully treat C9orf72-ALS. However, we currently have no way to measure the amount of antisense proteins. Without a test to measure the antisense proteins, it will not be possible to tell whether a drug has successfully reduced these proteins, which is a barrier to starting clinical trials with promising new drugs. We therefore plan to develop a test that can measure the amount of antisense proteins and can be used in clinical trials, greatly facilitating our ability to test new drugs and find a treatment for C9orf72-ALS.

Prof. Adrian Isaacs

Targeting neuronal excitability in MND for high-throughput drug screening

Dr Matthew Livesey
PI Dr Matthew Livesey
Co-investigators Dr James Alix
Prof. Dame Pamela Shaw
PI organisation University of Sheffield
Funding awarded £368,914
Completion date 31st March 2026 (18 months)

 

This proposal focuses on the electrical changes within the brain and nerves of MND patients, which play an important role in the disease. Our goal is to accelerate research into new medications that can modify these changes, thereby slowing down MND.

To do this, first we will study the electrical signals from the brain and nerves of patients in the clinic. Then, using human stem cell technology, we will make nerve cells from patient blood cells in the laboratory to study electrical changes in detail. We will then test drugs that can rescue the electrical changes, vastly speeding up drug discovery well beyond our current capabilities.

By linking the electrical signals in patients to lab-grown nerve cells, we will be able to tailor different drugs to specific patients. This groundbreaking approach will usher in an era of personalised medicine for MND patients and increase the chances of identifying new treatments.

Dr Matthew Livesey