PMID- 23151521
OWN - NLM
STAT- MEDLINE
DCOM- 20131101
LR  - 20130606
IS  - 1476-5462 (Electronic)
IS  - 0969-7128 (Linking)
VI  - 20
IP  - 6
DP  - 2013 Jun
TI  - In vivo delivery of DN:REST improves transcriptional changes of REST-regulated 
      genes in HD mice.
PG  - 678-85
LID - 10.1038/gt.2012.84 [doi]
AB  - Current therapeutic strategies for Huntington's disease (HD) are focused on 
      symptom management of disease progression. Transcriptional dysregulation is one 
      of the major characteristics in HD. REST is a transcriptional repressor that 
      silences gene expression through binding to RE1/NRSE sites found in the 
      regulatory regions of numerous neuronal genes. Dysregulation of REST and its 
      targeted genes has been reported in different cell and mouse HD models, as well 
      as in biopsies from human patients. In this work, we characterized 
      transcriptional dysregulation associated with REST in two different HD mouse 
      models and assessed the therapeutic effect of interfering with REST function by 
      overexpressing a dominant-negative form (DN:REST). We show that delivery of 
      DN:REST in the motor cortex restores brain-derived neurotrophic factor (BDNF) 
      mRNA and protein levels by reducing endogenous REST occupancy at the Bdnf locus. 
      Similarly, expression of other REST-regulated genes such as Synapsin I (Syn1), 
      Proenkephalin (Penk1) and Cholinergic receptor muscarinic 4 (Chrm4) were restored 
      to normal levels while non-REST-regulated genes were unaffected. This is the 
      first study conducted to investigate REST's role in vivo in a neurodegenerative 
      disease. Our data show that DN:REST in motor cortex reversed RESTs repressive 
      effects on target genes. However, the lack of therapeutic effect on motor 
      function suggests that a more widespread rescue of REST-regulated sites in the 
      affected brain regions may be necessary.
FAU - Conforti, P
AU  - Conforti P
AD  - Center for Stem Cell Research, Universita degli Studi di Milano, Milan, Italy.
FAU - Mas Monteys, A
AU  - Mas Monteys A
FAU - Zuccato, C
AU  - Zuccato C
FAU - Buckley, N J
AU  - Buckley NJ
FAU - Davidson, B
AU  - Davidson B
FAU - Cattaneo, E
AU  - Cattaneo E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121115
PL  - England
TA  - Gene Ther
JT  - Gene therapy
JID - 9421525
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (RE1-silencing transcription factor)
RN  - 0 (Repressor Proteins)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*genetics/metabolism
MH  - Disease Models, Animal
MH  - Gene Expression Regulation/genetics
MH  - Gene Transfer Techniques
MH  - *Genetic Therapy
MH  - Humans
MH  - Huntington Disease/*genetics/pathology/therapy
MH  - Mice
MH  - Motor Cortex/metabolism
MH  - Neurons/metabolism/pathology
MH  - Repressor Proteins/*genetics/therapeutic use
EDAT- 2012/11/16 06:00
MHDA- 2013/11/02 06:00
CRDT- 2012/11/16 06:00
PHST- 2012/11/16 06:00 [entrez]
PHST- 2012/11/16 06:00 [pubmed]
PHST- 2013/11/02 06:00 [medline]
AID - gt201284 [pii]
AID - 10.1038/gt.2012.84 [doi]
PST - ppublish
SO  - Gene Ther. 2013 Jun;20(6):678-85. doi: 10.1038/gt.2012.84. Epub 2012 Nov 15.