Objective: To propose a new HD framework, referred to as the HD-ISS, that comprises an HD biological research definition and evidence-based staging centered on prognostic biological, clinical, and functional landmarks.

Background: HD is an inherited autosomal dominant neurodegenerative disease. While there is biological certainty that individuals with a pathogenic expansion in the huntingtin gene (HTT) will develop the signs and symptoms of HD within a normal lifespan, this is not reflected in presently-used terminology. Current staging methods do not address disease progression before an overt clinical phenotype, despite well-accepted biomarkers of neurodegeneration predating clinical diagnosis.

Method: This framework is the result of a formal consensus process by the HD-RSC’s Regulatory Science Forum (RSF), a working group of expert representatives from industry and academia. The RSF considered biomarkers as well as signs and symptoms of the disease to formulate the HD-ISS. Observational data was employed to calculate “cut-offs” using the extreme values in models of the control population to define the HD-ISS Stages and to evaluate the framework.

Results: The HD-ISS characterizes individuals based on genetic expansion and allows for common terminology to enable cohesive clinical research and the development of interventional studies on the early phases of HD. The HD-ISS incorporates landmarks demonstrating robust prognostic value to classify individuals into each Stage and data-driven landmark thresholds to define Stage boundaries that are not CAG-dependent. Individual study visits, participant Stage progression, and longitudinal models of Stage progression align with the natural history of HD and with increased CAG predicting accelerated transitions.

Conclusion: The RSF has developed a biological definition of HD and an evidence-based staging system that encompass the full course of the disease and are unconstrained by concepts such as “manifest,” “pre-manifest,” or “prodromal.” The HD-ISS is primarily intended for research settings and provides a new structure to anchor and harmonize clinical study populations and will facilitate assessment of interventions that prevent or delay the onset of HD symptoms. The research use of the HD-ISS will allow for further validation. We hope that the HD-ISS will enable the HD community to work together to change the future of HD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/development-of-the-huntingtons-disease-integrated-staging-system-hd-iss/