TY - JOUR
T1 - Toward RNAi therapy for the polyglutamine disease Machado-Joseph disease
AU - Do Carmo Costa, Maria
AU - Luna-Cancalon, Katiuska
AU - Fischer, Svetlana
AU - Ashraf, Naila S.
AU - Ouyang, Michelle
AU - Dharia, Rahil M.
AU - Martin-Fishman, Lucas
AU - Yang, Yemen
AU - Shakkottai, Vikram G.
AU - Davidson, Beverly L.
AU - Rodríguez-Lebrón, Edgardo
AU - Paulson, Henry L.
N1 - Funding Information:
We thank the members of Paulson Lab for fruitful discussions. M. do C.C. was a recipient of fellowships from Fundação para a Ciência e a Tecnologia (FCT), Portugal (SFRH/BPD/28560/2006), and National Ataxia Foundation (NAF Research Fellowship Award 2011). V.G.S. was funded by NIH NS072158 and the Mateus Ataxia Research Fund. B.L.D. was funded by NIH P01 NS50210. E.R.-L. and H.L.P. were funded by NHI NS067111. H.L.P. was also funded for this work by NIH N038712 and the Mateus Ataxia Research Fund. The authors declared no conflict of interest.
PY - 2013/10
Y1 - 2013/10
N2 - 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.
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.
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U2 - 10.1038/mt.2013.144
DO - 10.1038/mt.2013.144
M3 - Article
C2 - 23765441
AN - SCOPUS:84885023000
SN - 1525-0016
VL - 21
SP - 1898
EP - 1908
JO - Molecular Therapy
JF - Molecular Therapy
IS - 10
ER -