Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA.
Huntington's disease (HD) is an autosomal dominant inheritable neurodegenerative disorder currently without effective treatment. It is caused by an expanded polyglutamine (poly Q) tract in the corresponding protein, huntingtin (htt), and therefore suppressing the huntingtin expression in brain neurons is expected to delay the onset and mitigate the severity of the disease. Here, we have used small interfering RNAs (siRNAs) directed against the huntingtin gene to repress the transgenic mutant huntingtin expression in an HD mouse model, R6/2. Results showed that intraventricular injection of siRNAs at an early postnatal period inhibited transgenic huntingtin expression in brain neurons and induced a decrease in the numbers and sizes of intranuclear inclusions in striatal neurons. Treatments using this siRNA significantly prolonged model mice longevity, improved motor function and slowed down the loss of body weight. This work suggests that siRNA-based therapy is promising as a future treatment for HD.
Wang
Yu-Lai
YL
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan.
Liu
Wanzhao
W
Wada
Etsuko
E
Murata
Miho
M
Wada
Keiji
K
Kanazawa
Ichiro
I
D000818:Animals; D001835:Body Weight / Q000235:genetics; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D007276:Injections, Intraventricular; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use*; D015996:Survival Rate; D019076:Transgenes / Q000235:genetics; D016896:Treatment Outcome; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D034741:RNA, Small Interfering; C097188:polyglutamine