Considerations and Advances in Huntington’s Disease Clinical Trial Design

Abstract

The characterization of the Huntingtin gene in 1993, 10 years after it was the first disease-associated gene to be mapped to a chromosome in humans, brought with it much anticipation that treatment or a cure would soon follow. In 2023, clinical trials for HD are still ongoing, with many structured around therapies that aim to lower Huntingtin mRNA or protein levels. Clinical trial design, including the appropriate selection of a target population, outcome measures, and safety markers, is paramount to the success of such trials. The analysis of biomarkers, including volumetric neuroimaging and cerebrospinal fluid or blood protein levels, is also now an essential requirement for clinical trial design. This chapter will cover the types and methodologies of current trials investigating Huntingtin-lowering therapies, as well as touch on past and present studies targeting other mechanisms downstream of the Huntingtin mutation. Advances in clinical trial design also include recent efforts to recruit participants who are earlier in their disease progression – prior to the onset of motoric symptom manifestation and a clinical motor diagnosis. In this chapter, we will thus present past and present means of quantifying disease stage and estimated disease progression and discuss the potential for neuroimaging and fluid biomarkers to be incorporated into these measures.