Title: SRSF1-targeted gene therapy for C9ORF72-linked Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Funder: LifeArc

Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable and fatal adult-onset neurodegenerative diseases. Someone in the world is diagnosed with ALS or FTD every few minutes. People with ALS lose nerve cells in the motor system – leading to progressive paralysis and death, usually within 2-5 years of the first symptoms. In people with FTD, nerve cells in the frontal and temporal lobes of the brain die, affecting cognitive function and behaviour. A fault in a gene known as C9ORF72 is the most commonly known genetic cause of both conditions. There is currently no treatment for FTD. The current treatment for ALS patients, riluzole, only marginally extends survival – typically by around three months – and does not relieve the symptoms of progressive paralysis. In both conditions, the gene is copied into the cells by a protein, which the team identified as SRSF1. In C9orf72-linked ALS and FTD, one the main drivers of disease is the transport of pathological, C9orf72 repeated RNA molecules from the nucleus to the cytoplasm where neurotoxic dipeptide repeat proteins (DPRs) are generated. The team identified a particular protein called SRSF1 which binds to the pathological repeated RNA molecules and transports them out of the cell centre, effectively overriding the gatekeeping machinery within the nucleus by opening a back door. The team had already shown that, by using a gene therapy comprising interfering virus vehicles to reduce the levels of SRSF1 protein, there was a reduction in nuclear transport of pathological RNA molecules and generation of neurotoxic DPRs – addressing a root cause of the diseases. In the laboratory, this gene therapy approach promotes the survival of patient-derived nerve cells and has no detrimental effects at the genome-wide level or in control cell cultures. The team also demonstrated that SRSF1 depletion prevents paralysis in a fly model of C9ORF72-ALS/FTD, and also that this intervention is safe in healthy mice. The purpose of this project is to conduct further studies to optimise the gene therapy treatment strategy ahead of developing a clinical trial application as follows: Evaluate the best delivery route for gene therapy. Define the dose of gene therapy needed to achieve the best reduction of SRSF1 in a mouse model of C9ORF72 disease. Conduct a pilot study to assess the therapeutic efficacy and any potential long-term adverse effects of the therapeutic gene therapy. Identify the biological processes which are modulated in the mouse brain after treatment and compare them to data available in patient-derived brain cells. Seek advice from regulatory bodies for a pre-clinical package to facilitate future clinical development. The Motor Neurone Disease Association (MND Association) contributed £50,000 to the project. This new research will be conducted in collaboration with the Cell and Gene Therapy Catapult which will provide support with designing the clinical vector and a detailed non-clinical safety strategy as well as regulatory advice to guide the team at the University of Sheffield through interactions with the Medicines and Health Regulatory Agency (MHRA).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL