A biological classification of Huntington's disease: the Integrated Staging System.

The current research paradigm for Huntington's disease is based on participants with overt clinical phenotypes and does not address its pathophysiology nor the biomarker changes that can precede by decades the functional decline. We have generated a new research framework to standardise clinical research and enable interventional studies earlier in the disease course. The Huntington's Disease Integrated Staging System (HD-ISS) comprises a biological research definition and evidence-based staging centred on biological, clinical, and functional assessments. We used a formal consensus method that involved representatives from academia, industry, and non-profit organisations. The HD-ISS characterises individuals for research purposes from birth, starting at Stage 0 (ie, individuals with the Huntington's disease genetic mutation without any detectable pathological change) by using a genetic definition of Huntington's disease. Huntington's disease progression is then marked by measurable indicators of underlying pathophysiology (Stage 1), a detectable clinical phenotype (Stage 2), and then decline in function (Stage 3). Individuals can be precisely classified into stages based on thresholds of stage-specific landmark assessments. We also demonstrated the internal validity of this system. The adoption of the HD-ISS could facilitate the design of clinical trials targeting populations before clinical motor diagnosis and enable data standardisation across ongoing and future studies.
Competing Interests: Declaration of interests SJT reports personal fees from F Hoffmann La Roche, Annexon, PTC Therapeutics, Takeda Pharmaceuticals, Vertex Pharmaceuticals, Alnylam Pharmaceuticals, Alphasights, Genentech, LoQus23 Therapeutics, Triplet Therapeutics, Novartis, Atalanta, Spark Therapeutics, Horama, University College Irvine, and Guidepoint; a patent application (2105484.6) and structural analogues licensed to Adrestia Therapeutics; funding from the CHDI Foundation, the UK Dementia Research Institute that receives its funding from DRI, the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK, and the Wellcome Trust (200181/Z/15/Z). SSc is a full-time employee of F Hoffmann La Roch. ECG and CS are employees and receive salaries from CHDI Management. CS has received consultancy honorariums (unrelated to Huntington's disease) from Pfizer, Kyowa Kirin, vTv Therapeutics, GW pharmaceuticals, Neuraly, Neuroderm, Green Valley Pharmaceuticals, and Pinteon Pharmaceuticals. AM is a consultant to CHDI Management. BB is an employee of Novartis Pharmaceuticals. PK is Chief Scientific Officer and cofounder of VectorY. TAM has received speaker honorariums from Abbvie and the International Parkinson and Movement Disorder Society; consultancy fees from CHDI Foundation and CHDI Management, Sunovion, Valeo Pharma, Roche, nQ Medical, and Merz; advisory board fees from Abbvie, Biogen, Sunovion, Medtronic; and research funding from the EU Joint Programme—Neurodegenerative Disease Research, uOBMRI, Roche, Ontario Research Fund, CIHR, MJFF, Parkinson Canada, PDF/PSG, LesLois Foundation, PSI Foundation, Parkinson Research Consortium, and Brain Canada. JP and APM are full-time employees of Wave Life Sciences. CAR reports grants from CHDI Foundation, outside the submitted work; consultancy fees from HSG, Annexon, Mitoconix, NeuBase, NeuExcell, Roche/Genentech, Sage, Spark, Teva, uniQure, and Wave. MZ is an employee of Vaccinex and has a patent issued. KR, SSi, and ECT declare competing interests. JDL reports grants from CHDI; personal fees from F Hoffmann La Roche, uniQure biopharma BV, Triplet Therapeutics, PTC Therapeutics, Remix, Vaccinex, and Wave Life Sciences USA.
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