Research for development of therapy of Machado-Joseph disease by siRNA

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Machado-Joseph disease is a progressive heredodegenerative disease that is caused by unstable expansions of CAG repeats in MJD which is located at chromosome 14q32.1. The mutant ataxin-3, the gene product of MJD, carrying the expanded polyglutamine stretch gains an adverse function and causes dysfunction of neurons, leading to neuronal death. No effective therapeutics has been established. If the expression of the mutant protein could be inhibited, we could treat the disease very well. Short interfering RNA (siRNA) would be a good candidate to establish an effective therapeutics.Huntington's disease is also one of the polyglutamine diseases and cased by an abnormally expanded CAG repeats in exon 1 of the HD gene. It was investigated that the effects of siRNAs directed against the HD gene in order to knock down its expression in cultured cells. One siRNA, named as siRNA-HD-Exon1, which is targeted against the region at immediate upstream of the CAG repeats, can efficiently and specifically inhibit the expression of HD exon 1-EGFP fusion mini-gene. It also did efficiently suppress the endogenous huntingtin expression in cultured cell lines derived from human neuroblastoma (Proc Japan Acad 79(Ser B) : 293-298, 2003).There are several single nucleotide polymorphisms (SNPs) in the MJD gene. In Japanese population, there are two haplotypes of those SNPs. One is c527T-c669A-c987C-c1118A and the other is c527C-c669G-c987G-c1118C.Disease chromosomes which carry the abnormally expanded CAG repeats show exclusively the former haplotype. If the expression of the allele carrying that haplotype could be specifically and effectively inhibited by a suitable siRNA, it would be the first step toward the development of a radical therapy for MJD. Two research groups reported successful suppression of the haplotype-specific expression by the siRNA of which the target is the sequence surrounding c987C/G SNP.