Spinocerebellar ataxia clinical trials: opportunities and challenges

Abstract

The spinocerebellar ataxias (SCAs) are a group of dominantly inherited diseases that share the defining feature of progressive cerebellar ataxia. The disease process, however, is not confined to the cerebellum; other areas of the brain, in particular, the brainstem, are also affected, resulting in a high burden of morbidity and mortality. Currently, there are no disease-modifying treatments for the SCAs, but preclinical research has led to the development of therapeutic agents ripe for testing in patients. Unfortunately, due to the rarity of these diseases and their slow and variable progression, there are substantial hurdles to overcome in conducting clinical trials. While the epidemiological features of the SCAs are immutable, the feasibility of conducting clinical trials is being addressed through a combination of strategies. These include improvements in clinical outcome measures, the identification of imaging and fluid biomarkers, and innovations in clinical trial design. In this review, we highlight current challenges in initiating clinical trials for the SCAs and also discuss pathways for researchers and clinicians to mitigate these challenges and harness opportunities for clinical trial development.

FIGURE 1

Schematic summary of challenges facing clinical research in the spinocerebellar ataxias and proposed elements that are critical to support clinical trial readiness.

FIGURE 2

Schematic summary of major therapeutic agents being tested for the SCAs. Major agents that have been successful in preclinical disease models are summarized, including gene silencing strategies, neurotrophic agents, and ion channel modifiers. Current agents being tested in active clinical trials in the United States were identified from clinicaltrials.gov.