Huntington’s Disease Integrated Staging System (HD-ISS): A Novel Evidence-Based Classification System For Staging

Background Despite the monogenic autosomal dominant nature of Huntington9s disease (HD), the current research paradigm is still based on overt clinical phenotypes and does not address disease pathobiology and biomarkers that are evident decades before functional decline. A new research framework is needed to standardize clinical research and enable interventional studies earlier in the course of HD. Methods The HD Regulatory Science Consortium (HD-RSC), a precompetitive Critical Path Institute initiative that includes 37 member organizations, created the Regulatory Science Forum working group (RSF), which includes industry and academic representatives. To generate a new evidenced-based HD Integrated Staging System (HD-ISS) using a formal consensus methodology, the RSF considered prognostic biomarkers, signs, and symptoms of HD, and performed empirical data analysis. We used observational data to calculate healthy-control-based landmark variable cut-offs for Stage classification and to internally validate the framework. Findings The HD-ISS starts with Stage 0, which comprises individuals with ≥ 40 cytosine-adenine-guanine repeats (CAG) in the huntingtin gene (HTT), before detectable indications of disease. We concluded that detectable HD progression is verified with measurable indicators of underlying pathophysiology (Stage 1), proceeds to a detectable clinical phenotype (Stage 2), and continues to a decline in function (Stage 3). Operationally, individuals can be unambiguously classified into Stages 1-3 based on CAG-independent thresholds of landmark assessments. Both cross-sectional status and longitudinal HD-ISS Stage progress align with HD natural history, and Stage transitions accelerate as CAG increase. Interpretation The HD-ISS encompasses the full course of HD starting at birth, defined by the presence of the genetic expansion. This new framework aims to standardize language for clinical research and its immediate use will enable further validation. The HD-ISS provides structure to harmonize clinical study populations and facilitates the clinical assessment of interventions earlier in HD to prevent or slow disease progression.