Targets for future clinical trials in Huntington's disease: what's in the pipeline? - PubMed (original) (raw)

Review

. 2014 Sep 15;29(11):1434-45.

doi: 10.1002/mds.26007. Epub 2014 Aug 25.

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Free PMC article

Review

Targets for future clinical trials in Huntington's disease: what's in the pipeline?

Edward J Wild et al. Mov Disord. 2014.

Free PMC article

Abstract

The known genetic cause of Huntington's disease (HD) has fueled considerable progress in understanding its pathobiology and the development of therapeutic approaches aimed at correcting specific changes linked to the causative mutation. Among the most promising is reducing expression of mutant huntingtin protein (mHTT) with RNA interference or antisense oligonucleotides; human trials are now being planned. Zinc-finger transcriptional repression is another innovative method to reduce mHTT expression. Modulation of mHTT phosphorylation, chaperone upregulation, and autophagy enhancement represent attempts to alter cellular homeostasis to favor removal of mHTT. Inhibition of histone deacetylases (HDACs) remains of interest; recent work affirms HDAC4 as a target but questions the assumed centrality of its catalytic activity in HD. Phosphodiesterase inhibition, aimed at restoring synaptic function, has progressed rapidly to human trials. Deranged cellular signaling provides several tractable targets, but specificity and complexity are challenges. Restoring neurotrophic support in HD remains a key potential therapeutic approach. with several approaches being pursued, including brain-derived neurotrophic factor (BDNF) mimesis through tyrosine receptor kinase B (TrkB) agonism and monoclonal antibodies. An increasing understanding of the role of glial cells in HD has led to several new therapeutic avenues, including kynurenine monooxygenase inhibition, immunomodulation by laquinimod, CB2 agonism, and others. The complex metabolic derangements in HD remain under study, but no clear therapeutic strategy has yet emerged. We conclude that many exciting therapeutics are progressing through the development pipeline, and combining a better understanding of HD biology in human patients, with concerted medicinal chemistry efforts, will be crucial for bringing about an era of effective therapies.

Keywords: HDAC inhibition; Huntington's disease; MAPK; gene silencing; glial cells; kynurenine monooxygenase; phosphodiesterase inhibition; therapeutics.

© 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Figures

FIG 1

FIG 1

Schematic depicting current priority preclinical therapeutic targets under investigation for Huntington's disease. HTT, huntingtin; KMO, kynurenine monooxygenase; NMDA, N-methyl-D-aspartate; PDE, phosphodiesterase; BDNF, brain-derived neurotrophic factor; HDAC, histone deacetylase; Trk, tropomyosin-related kinase. Adapted from Ross et al.

FIG 2

FIG 2

Schematic illustration of the three main approaches to lowering huntingtin expression. Zinc finger protein (ZFP) therapeutics aim to reduce transcription of the huntingtin gene. Translational repression can be attempted at the pre-mRNA level using DNA-based antisense oligonucleotides (ASOs) or on mature mRNA using short interfering RNA (siRNA) compounds. Different cellular mechanisms degrade the bound mRNA.

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