PMID- 25155142
OWN - NLM
STAT- MEDLINE
DCOM- 20150515
LR  - 20240306
IS  - 1531-8257 (Electronic)
IS  - 0885-3185 (Print)
IS  - 0885-3185 (Linking)
VI  - 29
IP  - 11
DP  - 2014 Sep 15
TI  - Targets for future clinical trials in Huntington's disease: what's in the 
      pipeline?
PG  - 1434-45
LID - 10.1002/mds.26007 [doi]
AB  - 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.
CI  - (c) 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on 
      behalf of International Parkinson and Movement Disorder Society.
FAU - Wild, Edward J
AU  - Wild EJ
AD  - Department of Neurodegenerative Disease, UCL Institute of Neurology, National 
      Hospital for Neurology & Neurosurgery, Queen Square, London, WC1N 3BG, UK.
FAU - Tabrizi, Sarah J
AU  - Tabrizi SJ
LA  - eng
GR  - MR/L02053X/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20140825
PL  - United States
TA  - Mov Disord
JT  - Movement disorders : official journal of the Movement Disorder Society
JID - 8610688
RN  - 0 (HTT protein, human)
RN  - 0 (Huntingtin Protein)
RN  - 0 (Nerve Tissue Proteins)
RN  - EC 3.5.1.98 (Histone Deacetylases)
SB  - IM
MH  - Animals
MH  - Clinical Trials as Topic/*methods/*trends
MH  - Gene Silencing
MH  - Genetic Therapy/*methods
MH  - Histone Deacetylases/genetics
MH  - Humans
MH  - Huntingtin Protein
MH  - Huntington Disease/genetics/*therapy
MH  - Nerve Tissue Proteins/genetics/metabolism
PMC - PMC4265300
OTO - NOTNLM
OT  - HDAC inhibition
OT  - Huntington's disease
OT  - MAPK
OT  - gene silencing
OT  - glial cells
OT  - kynurenine monooxygenase
OT  - phosphodiesterase inhibition
OT  - therapeutics
EDAT- 2014/08/27 06:00
MHDA- 2015/05/16 06:00
CRDT- 2014/08/27 06:00
PHST- 2014/07/25 00:00 [received]
PHST- 2014/07/28 00:00 [revised]
PHST- 2014/07/30 00:00 [accepted]
PHST- 2014/08/27 06:00 [entrez]
PHST- 2014/08/27 06:00 [pubmed]
PHST- 2015/05/16 06:00 [medline]
AID - 10.1002/mds.26007 [doi]
PST - ppublish
SO  - Mov Disord. 2014 Sep 15;29(11):1434-45. doi: 10.1002/mds.26007. Epub 2014 Aug 25.