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

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a rare, inherited, X-linked, late-onset, progressive neurodegenerative disease characterized by intention tremor, cerebellar gait ataxia, parkinsonism, and cognitive decline. Although there are no proven treatments for FXTAS, ongoing studies demonstrate that therapeutic strategies will be available soon in the form of antisense oligonucleotides (ASOs) that target the repeat-containing mRNA, agents that suppress cellular stress cascades, and 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.

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. Knowing the cause of a disease makes it treatable, because we have tools now that can precisely and specifically fix mutated genes. Learning how to treat genetic disease systematically and precisely is a gateway to treating more common diseases with unknown origins. UM has the expertise to be a leader in this new way of treating disease. 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. Our initiative brings together physicians, scientists, ethicists, faculty from the Ross School of Business, public health experts, and our patients to transform how the University of Michigan will practice medicine in the 21st century and beyond.

This program is about accelerating and engineering the timeline for adoption of emerging technologies and applying them first to those who have the most to gain (Impact Area #5). Our milestone goal over the next 4 years is to design treatments for 90% of our candidate UM rare disease patients and bring novel nucleotide-based therapies for at least five of these patients to the clinic. Achieving this goal will create a pipeline for scalable assessment and delivery for an increasingly larger set of Michigan patients – positioning us as a national leader in the implementation of these nascent technologies in healthcare. This work will be done alongside ethicists, public health experts, and faculty in the business school who will guide us in creating a self-sustaining program that achieves engagement with our local and national communities, equity in our care model, and provide education directed both across and between these diverse stakeholders about how these emergent approaches to clinical care will transform healthcare delivery and economics. Our success will bring patients from around the globe to “Look to Michigan” for better health and a brighter future.