Objective: The aim of this study is the identification of progression and treatment response outcomes for POLR3A-associated spastic ataxia caused by the recurrent intronic c.1909+22G>A variant in a prospective international multicenter natural history study (NHS). Preclinical development of a splice-modulating antisense oligonucleotide (ASO) is underway in the TreatHSP and 1M1M consortium. Therefore, obtaining run-in natural history data that will allow evaluation of treatment effects in a clinical trial is time critical.

Background: Heterozygous intronic variants in the POLR3A gene, especially the c.1909+22G>A variant, have been identified as a cause of autosomal recessive spastic ataxia. Patients present with adolescent-onset progressive spastic ataxia with tremor, bladder dysfunction and mild hypodontia. The c.1909+22G>A variant activates a cryptic splice site that can potentially be targeted by a splice modulating ASO; preclinical studies of therapeutic ASOs targeting this variant are underway.

Method: 1) Establishment of a platform for fit-for-purpose outcome development: patient-relevant health concepts will be elucidated and then used to anchor indirect clinical outcome assessments to patient-relevant concepts according to regulatory guidelines.

2) Clinical outcome assessments: Standardized, longitudinal clinical data will be captured in a clinical database. Camera-based motion capture as well as digital-motor outcomes using wearable sensors in clinic-based and ‘real-world’ environment will be employed.

3) Biomarkers: Longitudinal biosamples will be collected in a biobank. MRI, neurophysiological, and molecular outcomes will be captured, evaluated and validated. Multimodal biomarkers will be cross-validated with clinical measures.

4) Pathophysiology: To study its molecular basis, we will perform multimodal –omics analyses. Primary cells will be used for in-depth analysis of mutation effects and preclinical therapeutic trials.

Results: A POLR3A study group comprising > 15 study sites in 12 countries was established. The detailed study protocol will be presented.

Conclusion: This registry-based standardized prospective NHS aims to capture the longitudinal phenotype and progression in POLR3A-associated spastic ataxia, define trial-relevant disease stages, develop multimodal biomarkers, and establish the basis for trial readiness.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/preparing-for-a-clinical-trial-a-run-in-natural-history-study-in-polr3a-associated-spastic-ataxia-with-intronic-mutations-amenable-to-splice-modulating-therapeutic-approaches/