PMID- 23765441
OWN - NLM
STAT- MEDLINE
DCOM- 20140429
LR  - 20211021
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 21
IP  - 10
DP  - 2013 Oct
TI  - Toward RNAi therapy for the polyglutamine disease Machado-Joseph disease.
PG  - 1898-908
LID - 10.1038/mt.2013.144 [doi]
AB  - Machado-Joseph disease (MJD) is a dominantly inherited ataxia caused by a 
      polyglutamine-coding expansion in the ATXN3 gene. Suppressing expression of the 
      toxic gene product represents a promising approach to therapy for MJD and other 
      polyglutamine diseases. We performed an extended therapeutic trial of RNA 
      interference (RNAi) targeting ATXN3 in a mouse model expressing the full human 
      disease gene and recapitulating key disease features. Adeno-associated virus 
      (AAV) encoding a microRNA (miRNA)-like molecule, miRATXN3, was delivered 
      bilaterally into the cerebellum of 6- to 8-week-old MJD mice, which were then 
      followed up to end-stage disease to assess the safety and efficacy of anti-ATXN3 
      RNAi. Despite effective, lifelong suppression of ATXN3 in the cerebellum and the 
      apparent safety of miRATXN3, motor impairment was not ameliorated in treated MJD 
      mice and survival was not prolonged. These results with an otherwise effective 
      RNAi agent suggest that targeting a large extent of the cerebellum alone may not 
      be sufficient for effective human therapy. Artificial miRNAs or other 
      nucleotide-based suppression strategies targeting ATXN3 more widely in the brain 
      should be considered in future preclinical tests.
FAU - Costa, Maria do Carmo
AU  - Costa Mdo C
AD  - Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
FAU - Luna-Cancalon, Katiuska
AU  - Luna-Cancalon K
FAU - Fischer, Svetlana
AU  - Fischer S
FAU - Ashraf, Naila S
AU  - Ashraf NS
FAU - Ouyang, Michelle
AU  - Ouyang M
FAU - Dharia, Rahil M
AU  - Dharia RM
FAU - Martin-Fishman, Lucas
AU  - Martin-Fishman L
FAU - Yang, Yemen
AU  - Yang Y
FAU - Shakkottai, Vikram G
AU  - Shakkottai VG
FAU - Davidson, Beverly L
AU  - Davidson BL
FAU - Rodriguez-Lebron, Edgardo
AU  - Rodriguez-Lebron E
FAU - Paulson, Henry L
AU  - Paulson HL
LA  - eng
GR  - N038712/PHS HHS/United States
GR  - P01 NS050210/NS/NINDS NIH HHS/United States
GR  - NS067111/NS/NINDS NIH HHS/United States
GR  - R01 NS085054/NS/NINDS NIH HHS/United States
GR  - P01 NS50210/NS/NINDS NIH HHS/United States
GR  - NS072158/NS/NINDS NIH HHS/United States
GR  - R21 NS067111/NS/NINDS NIH HHS/United States
GR  - R01 NS038712/NS/NINDS NIH HHS/United States
GR  - K08 NS072158/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130614
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (MicroRNAs)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Repressor Proteins)
RN  - EC 3.4.19.12 (ATXN3 protein, human)
RN  - EC 3.4.19.12 (Ataxin-3)
SB  - IM
MH  - Animals
MH  - Ataxin-3
MH  - Cerebellum/metabolism/pathology
MH  - Dependovirus/genetics
MH  - Disease Models, Animal
MH  - Female
MH  - Genetic Vectors
MH  - Humans
MH  - Machado-Joseph Disease/metabolism/pathology/physiopathology/*therapy
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - MicroRNAs/*genetics
MH  - Motor Activity
MH  - Motor Neurons/metabolism/pathology
MH  - Nerve Tissue Proteins/*genetics/*metabolism
MH  - Nuclear Proteins/*genetics/*metabolism
MH  - *RNA Interference
MH  - Repressor Proteins/*genetics/*metabolism
MH  - Transduction, Genetic
PMC - PMC3808129
EDAT- 2013/06/15 06:00
MHDA- 2014/04/30 06:00
PMCR- 2014/10/01
CRDT- 2013/06/15 06:00
PHST- 2013/03/01 00:00 [received]
PHST- 2013/06/04 00:00 [accepted]
PHST- 2013/06/15 06:00 [entrez]
PHST- 2013/06/15 06:00 [pubmed]
PHST- 2014/04/30 06:00 [medline]
PHST- 2014/10/01 00:00 [pmc-release]
AID - S1525-0016(16)32256-0 [pii]
AID - 10.1038/mt.2013.144 [doi]
PST - ppublish
SO  - Mol Ther. 2013 Oct;21(10):1898-908. doi: 10.1038/mt.2013.144. Epub 2013 Jun 14.