ACT for FXTAS- Getting ready for clinical trials in Fragile X Tremor Ataxia Syndrome

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a progressive late-onset neurodegenerative disease characterized by action tremor, cerebellar gait ataxia, parkinsonism, and cognitive decline. There are currently no approved treatments for FXTAS. However, ongoing studies in the Todd lab and elsewhere aim to develop therapeutic strategies for FXTAS based on antisense oligonucleotides (ASOs) that target the repeat-containing mRNA, agents that suppress cellular stress cascades, and small molecules that lower neuroinflammation and reduce repeat associated non-AUG (RAN) translation. However, without fully validated fit-for-purpose clinical outcome assessments (COAs) and sensitive markers of treatment response, these future pivotal trials may not come to fruition and fail to provide conclusive, clinically meaningful, and impactful results for this devastating and rare disorder. To this end, this project seeks to validate key clinical tools needed to perform future successful clinical trials. Currently underway at the University of Michigan, Rush University in Chicago, and the University of California at Davis. Reach out to our coordinator Teresa Scerbak or Peter Todd if you are interested in participating!

N=1 Therapy Development at the University of Michigan

1 in 10 people in the world suffer from a “rare” genetic disease. Until now, people with genetic conditions faced limited or no options for diagnosis and treatment. Now there is hope. Genetic diseases have a discoverable root cause, a mutation in a gene. Over the past decade, medicine has developed modular tools that can precisely and specifically fix mutated genes or bypass the dysfunction caused by mutations. Learning how to treat genetic disease systematically and precisely is a gateway to treating more common diseases with unknown origins. At Michigan, we envision a world where genomic testing performed at or before the onset of symptoms allows for rapid individualized gene-targeted therapy design, production, and delivery in the order of months in patients with otherwise untreatable conditions. This vision is not a fantasy, but a reality we can begin realizing right now by implementing existing tools, engaging key stakeholders, and bridging the gap between infrastructures that are already in place or rapidly coming online.

To this end, in 2024 we launched the Genomic Therapy Advancement Council (GTAC- which is also the four DNA bases). This group of physicians, geneticists, and scientists is creating rapid, equitable, and ethical assessments for which patients are eligible for these experimental approaches while building pipelines linking clinical diagnosis to therapy design in real time. While still in its infancy, we are actively evaluating cases and developing therapies as we speak. The future is now.