Sustained effects of nonallele-specific Huntingtin silencing.
OBJECTIVE
Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (htt) protein. No cure is available to date to alleviate neurodegeneration. Recent studies have demonstrated that RNA interference represents a promising approach for the treatment of autosomal dominant disorders. But whether an allele-specific silencing of mutant htt or a nonallele-specific silencing should be considered has not been addressed.


METHODS
We developed small hairpin RNA targeting mutant or wild-type htt transcripts, or both.


RESULTS
We confirmed the therapeutic potential of sihtt administered with lentiviral vectors in rodent models of HD and showed that initiation of small interfering RNA treatment after the onset of HD symptoms is still efficacious and reduces the HD-like pathology. We then addressed the question of the impact of nonallele-specific silencing and demonstrated that silencing of endogenous htt to 25 to 35% in vivo is altering several pathways associated with known htt functions but is not inducing overt toxicity or increasing striatal vulnerability up to 9 months after treatment.


CONCLUSIONS
These data indicate that the coincident silencing of the wild-type and mutant htt may be considered as a therapeutic tool for HD.
Drouet
Valérie
V
Commissariat à l'Energie Atomique, Institute of Biomedical Imaging (I2BM) and Molecular Imaging Research Center, France.
Perrin
Valérie
V
Hassig
Raymonde
R
Dufour
Noëlle
N
Auregan
Gwennaelle
G
Alves
Sandro
S
Bonvento
Gilles
G
Brouillet
Emmanuel
E
Luthi-Carter
Ruth
R
Hantraye
Philippe
P
Déglon
Nicole
N