Identification of translational biomarkers for disease onset, early diagnosis and therapeutic efficacy in C9orf72 ALS/FTD

Motor neuron disease (ALS/MND) is a fatal progressive neurodegenerative condition affecting the motor neurons that enable movement through our muscles. Degeneration of the motor neurons causes progressive disability in walking, talking, eating, and breathing. Average life expectancy is 2-3 years from the time of symptom onset. Up to 5000 people in the UK are living with ALS/MND at any one time. Treatments to protect the motor neurons and slow down their loss are urgently needed. An expanded section of DNA in a gene called C9orf72 is the most common cause of ALS/MND underlying up to 40% of inherited cases and 10% of the total cases of ALS/MND. The C9orf72 gene expansion varies in size from patient to patient and produces 5 different toxic proteins that injure motor neurons to varying degrees, though their relative impacts are incompletely understood. The toxic proteins are termed either 'sense' or 'anti-sense' according to the direction the cellular machinery produces them from the DNA instructions. Previously two genetic therapy trials for C9orf72-MND conducted by Biogen and Wave Life Sciences targeted only the 'sense' proteins and failed to show beneficial effects. Some evidence suggests that the anti-sense proteins are especially damaging to motor neurons which could be why these trials were unsuccessful, though more research is needed to confidently link the particular protein types with disease severity. Currently only 2 of the 5 toxic proteins have been shown to be measurable in cerebrospinal fluid that bathes the brain and spinal cord, but these are two that don't correlate well with disease severity in patients. We have developed a novel therapeutic strategy that lowers all 5 toxic C9orf72 proteins, both the sense and anti-sense varieties, that stops disease progression in preclinical models of MND. Our partners in Crucible Therapeutics plan to evaluate this approach in clinical trials. In this project we will develop and optimise tests to reliably measure all 5 toxic C9orf72 proteins. The majority of clinical trials of new neuroprotective treatments for ALS/MND use the ALS functional rating scale or a single clinical functional test as the primary way to measure disease progression and see if a drug is having a beneficial effect. These measurements lack sensitivity to detect any difference at an early stage in the intervention and typically take 12 months or longer to see a significant effect. Wide variation in the natural disease progression rate between patients means that large cohorts are required to participate in trials over a prolonged timescale to evaluate potentially futile treatments. This places an undue burden on patients and risks exposure for longer than necessary to ineffective treatments that have no benefit . We plan to develop biological markers for our C9orf72 genetic therapy approach to rapidly show that the therapy reaches its intended target and confers a beneficial biological effect at an early stage of treatment in a small-scale early phase study to give confidence to progress into larger confirmatory trials for approval by the medicines regulators. Using samples donated by patients and clinical data, we aim to develop tests to reliably measure the toxic proteins produced by the C9orf72 expansion to rapidly demonstrate treatment effects and reduced motor neuron injury. These biomarkers will be transferrable to other trials targeting C9orf72, as well enabling the accelerated development of new treatments for people with C9orf72-MND.