Targeting RNA nuclear export: A disease-modifying treatment for ALS/FTD

Crucible Therapeutics is developing an innovative gene therapy addressing the urgent need for effective treatment options for amyotrophic lateral sclerosis (ALS), a debilitating and uncurable neurodegenerative condition. The most common form of motor neurone disease, ALS affects ~25,000 patients in the UK and US, causing devastating progressive muscle paralysis and, ultimately, death within 2-5 years of diagnosis. Current treatments offer limited benefit, only slightly slowing the disease progression by mere months. Crucible's approach targets a nuclear export factor involved in ALS-related nerve cell damage. By reducing levels of the nuclear export factor, the production of toxic proteins responsible for nerve cell degeneration in most ALS patients, including those with both sporadic and familial forms of the disease, is restricted, halting or even reversing disease progression. This broad-spectrum approach offers potential benefits for up to 97% of ALS patients, providing hope for thousands of people. Building on extensive research from neuroscience experts at the University of Sheffield, where the basic biology was discovered and neurotoxicity in ALS neurons characterised, this project sees Crucible collaborating with University of Sheffield to advance this pioneering therapy through critical preclinical pharmacology and toxicity studies, targeting human clinical trials in 2028\. This breakthrough has potential to not only transform the treatment of ALS, but also wider neurodegenerative diseases, such as frontotemporal dementia (FTD) and Alzheimer's disease, affecting millions of patients worldwide.