title: Huntington Disease: Linking Pathogenesis to the Development of Experimental Therapeutics.
abstract: Huntington disease (HD) is an autosomal dominant neurodegenerative condition caused by a CAG trinucleotide expansion in the huntingtin gene. At present, the HD field is experiencing exciting times with the assessment for the first time in human subjects of interventions aimed at core disease mechanisms. Out of a portfolio of interventions that claim a potential disease-modifying effect in HD, the target huntingtin has more robust validation. In this review, we discuss the spectrum of huntingtin-lowering therapies that are currently being considered. We provide a critical appraisal of the validation of huntingtin as a drug target, describing the advantages, challenges, and limitations of the proposed therapeutic interventions. The development of these new therapies relies strongly on the knowledge of HD pathogenesis and the ability to translate this knowledge into validated pharmacodynamic biomarkers. Altogether, the goal is to support a rational drug development that is ethical and cost-effective. Among the pharmacodynamic biomarkers under development, the quantification of mutant huntingtin in the cerebral spinal fluid and PET imaging targeting huntingtin or phosphodiesterase 10A deserve special attention. Huntingtin-lowering therapeutics are eagerly awaited as the first interventions that may be able to change the course of HD in a meaningful way.
authors.affiliation: Parkinson's Disease and Movement Disorders Center, Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, The University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario, Canada.
authors.forename: Tiago A
authors.initials: TA
authors.lastname: Mestre
authors.affiliation: CHDI Management/CHDI Foundation, 155 Village Boulevard, Suite 200, Princeton, USA. cristina.sampaio@chdifoundation.org.|Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal. cristina.sampaio@chdifoundation.org.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sampaio
mesh_terms: D000818:Animals; D006801:Humans; D000071058:Huntingtin Protein / Q000134:cerebrospinal fluid / Q000187:drug effects*; D006816:Huntington Disease / Q000000981:diagnostic imaging / Q000235:genetics*; D058990:Molecular Targeted Therapy / Q000379:methods*; D059906:Neuroimaging; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D049268:Positron-Emission Tomography
chemical_list: D000071058:Huntingtin Protein; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: Disease-modifying therapies; Huntingtin; Huntington disease