Translational Paradox of Triplet Repeat Expansion Disorders: Synthesizing Clinical Trial Failures to Guide Future...

The comprehensive understanding of triplet repeat expansion (TRE) disorders as monogenic neurodegenerative diseases presents a fundamental challenge for developing treatments capable of modifying the disease course, as neurogenetic research indicates. The past 30 years reveal that preclinical results demonstrating strong effectiveness have not translated into success in human clinical trials, with multiple phase II and III studies for polyglutamine and non-coding, loss-of-function repeat disorders yielding unfavorable outcomes. This review emphasizes that clinical systems, which measure target engagement do not generate effective outcomes for these TRE neurodegenerative conditions. We highlight that these failures arise not from a fundamental misunderstanding of the underlying genetic mutations, but from recurring methodological and pharmacological limitations across the translational pipeline. The main reasons for these unsuccessful clinical trials include two factors: the necessity for clinicians to monitor pharmacodynamic biomarkers indicating central nervous system target engagement, and the reliance on traditional clinical rating scales that linearly assess disease progression in patients with complex medical conditions. The use of non-selective gene silencing methods can lead to unexpected toxic effects, especially when treatments begin after patients reach an advanced disease stage, causing irreversible brain cell damage. The field of precision neurogenetics must advocate for future trials to employ objective fluid and digital biomarkers, utilize allele-specific treatments, and prioritize patients who have not yet experienced severe brain cell loss. We further propose evidence-based design principles to improve the probability of clinical success in future TRE disease trials.