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Therapeutic approaches to Huntington disease: from the bench to the clinic

Abstract

The 25 years since the identification of the gene responsible for Huntington disease (HD) have stood witness to profound discoveries about the nature of the disease and its pathogenesis. Despite this progress, however, the development of disease-modifying therapies has thus far been slow. Preclinical validation of the therapeutic potential of disrupted pathways in HD has led to the advancement of pharmacological agents, both novel and repurposed, for clinical evaluation. The most promising therapeutic approaches include huntingtin (HTT) lowering and modification as well as modulation of neuroinflammation and synaptic transmission. With clinical trials for many of these approaches imminent or currently ongoing, the coming years are promising not only for HD but also for more prevalent neurodegenerative disorders, such as Alzheimer and Parkinson disease, in which many of these pathways have been similarly implicated.

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Figure 1: Pathogenesis of Huntington disease.
Figure 2: HTT-targeted therapeutic approaches for Huntington disease.
Figure 3: CRISPR-mediated HTT inactivation.
Figure 4: Immunomodulatory therapy for Huntington disease.
Figure 5: Synaptic modulation therapeutics for Huntington disease.

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Acknowledgements

The authors thank M. Pouladi, M. Schmidt, F. Lemarié and C. Kay for their critical review of the manuscript. Funding was provided by a Canadian Institute for Health Research Foundation grant (FDN-154278 to M.R.H.).

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Correspondence to Michael R. Hayden.

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Competing interests

M.R.H. was formerly chief scientific officer and president of global research and development at Teva Pharmaceuticals. He no longer has any competing interests. E.R.D. was previously Chair of the Huntington Study Group, which has research contracts with Teva Pharmaceuticals and Vaccinex. He also directs the University of Rochester's Center for Health + Technology (CHeT), which also receives money for research efforts from Vaccinex.

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Glossary

Unified Huntington's Disease Rating Scale

(UHDRS). A standardized clinical rating scale used to evaluate the motor function, cognitive function, behaviour and functional capacity of an individual with Huntington disease.

Chorea

An involuntary movement disorder that is characterized by jerky, dance-like movements.

Prodromal

The period when subtle clinical changes are present, sometimes accompanied by neuroimaging changes.

Medium spiny neurons

(MSNs). GABAergic inhibitory neurons of the striatum that project to other regions of the basal ganglia.

Cortical projection neurons

Glutamatergic excitatory neurons that project from the cortex to other cortical and subcortical structures.

Excitotoxicity

Cellular toxicity resulting from excessive excitatory neurotransmission.

BACHD mouse model

Transgenic mouse model of HD expressing full-length human HTT with 97 glutamines.

R6/2 mouse model

Transgenic mouse model of HD expressing exon 1 of human HTT with 115–160 glutamines.

Intrastriatal injection

Route of administration involving the stereotaxic injection of an experimental therapeutic into the striatum.

Intrathecal (IT) infusion

Route of administration involving infusion of an experimental therapeutic into the subarachnoid space of the spinal canal so that it reaches the cerebrospinal fluid.

YAC128 mice

Transgenic mouse model of HD expressing full-length human HTT with 128 glutamines.

Experimental autoimmune encephalomyelitis

An animal model of inflammatory demyelinating disease of the CNS with pathological similarities to multiple sclerosis.

Bradykinesia

A condition that involves slowness of movement.

Dystonia

An involuntary movement disorder that is characterized by repetitive or sustained muscle contractions causing abnormal postures.

Q175 mouse

HD mouse model harbouring a knock-in of human HTT exon 1 with an expanded CAG tract within the mouse Htt locus.

Postsynaptic density

A dense structure of cytoplasmic and membrane-bound proteins localized at the synapse.

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Caron, N., Dorsey, E. & Hayden, M. Therapeutic approaches to Huntington disease: from the bench to the clinic. Nat Rev Drug Discov 17, 729–750 (2018). https://doi.org/10.1038/nrd.2018.133

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