A single protein, SRSF1, acts as a molecular taxi that shuttles toxic RNA from the nucleus of a nerve cell into its cytoplasm, where the RNA is turned into poisonous proteins that kill the cell. Researchers at the University of Sheffield have already shown that blocking this taxi service can protect nerve cells in models of ALS and frontotemporal dementia. They now want to test whether the same approach works for Fragile X-associated tremor/ataxia syndrome (FXTAS), a fatal neurodegenerative disease that affects roughly 1 in 8,000 people and currently has no treatment beyond symptom management. If successful, this project would produce a preclinical proof-of-concept package—safety and efficacy data in patient-derived nerve cells and in mice—that could attract translational funding or private investment to launch a clinical trial. The work builds on an existing spinout company, Crucible Therapeutics, which is already developing SRSF1-interfering gene therapies for C9orf72-ALS/FTD. A repurposed application to FXTAS would extend that pipeline to a second, currently untreatable repeat-expansion disorder, potentially offering a disease-modifying therapy where only palliative care now exists.
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Microsatellite repeat expansion disorders are a group of over 50 neurological conditions that collectively affect 1 in 3,000 adults worldwide. There is no cure and in addition to unmet medical needs, they lead to profound distress for carers and economic burden in an ageing world population. Fragile X-associated tremor/ataxia syndrome (FXTAS) is a debilitating neurodegenerative disorder characterised by progressive loss of nerve cells in the brain, tremor, balance problems, cognitive decline and death within 5-25 years from symptoms onset. It is more common in males than females over 50 years of age and manifests in people carrying 55-200 microsatellite repeats of the trinucleotide CGG in the fragile X mental retardation 1 (FMR1) gene. The precise mechanisms leading to disease are still being elucidated, however one key driver of neuronal injury involves production of abnormal toxic poly(glycine) repeat proteins known as FMRpolyG. FXTAS affects approximately 1 in 8,000 people. Symptomatic treatments only can be provided to patients. They include beta-blockers and anti-epileptic medications, psychological counselling or rehabilitative speech, occupational and physical therapies. Developing a disease-modifying therapy that treats the root cause of FXTAS is therefore of paramount importance. We recently developed promising gene therapy approaches for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a spectrum of other incurable neurodegenerative diseases caused by GGGGCC microsatellite repeat expansions in the C9orf72 gene. They work in cell and animal models by diminishing the transporter function of Serine/Arginine-Rich Splicing Factor 1 (SRSF1) that carries disease-altered repeat RNA molecules from their synthesis site in the cell’s nucleus into the surrounding compartment, the cytoplasm, where they serve as instruction manuals for the manufacturing of faulty and toxic proteins. This work also led to granted and pending patents as well as to founding Crucible Therapeutics, a University of Sheffield spinout company developing SRSF1-interfering gene therapeutics with a potential clinical trial envisaged for C9orf72-ALS/FTD patients within the next few years. In this grant proposal, we present pilot data showing that lowering SRSF1 also reduces the production of toxic FMR-polyG proteins and restores the growth of FXTAS cell models, supporting the investigation of a repurposed application to FXTAS. We now aim to test two SRSF1-interfering gene therapy modalities, based on viral and non-viral approaches, to reduce the cytoplasmic transport of CGG repeat transcripts and production of toxic FMR-polyG proteins in disease-relevant models. The main objectives of the research proposal are to: Aim 1: To demonstrate the neuroprotective potential of lowering SRSF1 in vitro in nerve cells grown from FXTAS patients. Aim 2: To demonstrate the safety and efficacy of lowering SRSF1 in vivo in FXTAS mice. Aim 3: To identify all changed RNA molecules to understand the global mechanisms protecting nerve cells from death and assess potential inaccurate effects in nerve cells grown from patients and in mouse brains treated with SRSF1-interfering gene therapeutics. Overall, the research proposed here aims to expand our gene therapy approaches developed for C9ORF72-ALS/FTD for potential future application to the treatment of FXTAS patients. If successful, it will generate a robust preclinical proof-of-concept package allowing protecting new intellectual property and incentivise future translational funding or private investments to fast-track a clinical trial for FXTAS patients. Our work is also regularly presented and discussed in outreach events involving local schools, the public and patients with neurodegenerative conditions.
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