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Challenge of Neuroscience against Amyotrophic Lateral Sclerosis

開催日 2014/9/12
時間 9:00 - 11:00
会場 Room E(301)
Chairperson(s) 永井 真貴子 / Makiko Nagai (北里大学医学部 神経内科 / Department of Neurology, Kitasato University, Japan)
横田 隆徳 / Takanori Yokota (東京医科歯科大学大学院脳神経病態学 / Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan)

Oligonucleotide Gene Therapy for ALS

  • S2-E-1-3
  • 横田 隆徳 / Takanori Yokota:1 
  • 1:東京医科歯科大学大学院脳神経病態学 / Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan 

Two major types of oligonucleotide drugs for gene silencing, siRNA and antisense oligonucleotide (ASO), bind to RNA by base pairing a sequence-specific manner and downregulate gene expression by inducing enzyme-dependent degradation of targeted RNA. It has now been over a decade since the discoveries of RNA interference (RNAi) and siRNAs, but despite some promising clinical trial results pharmaceutical company remains cautious about the therapeutic potential of RNAi-based drugs. ASO gapmers containing 2 to 5 chemically-modified nucleotides,locked nucleotide acid (LNA)1-3, or 2'Z-O-methoxyethyl (2'-MOE)4,5 at each terminus flanking a central 5-to10-base 'gap' of DNA, enable cleavage of target RNA by ribonuclease H (RNase H), which recognizes the DNA/RNA heteroduplex6,7. Unlike siRNAs, which tolerate only limited modifications without loosing
compatibility with the RNAi effector complex, extensive chemical modifications in ASO gapmers do not abrogate RNase H activity. Mipomersen, a 2'-MOE phosphorothioate ASO gapmer targeting the human apolipoprotein B (APOB) gene, was recently approved for treatment of familial hypercholesterolemia. Phase I clinical trial of ASO targeting SOD1 by intrathecal infusion was reported with eight patients with SOD1-positive amyotrophic lateral sclerosis (Lancet Neurol. 2013;12(5):435-42.) C9ORF was also a candidate gene for ASO.
Recently, we developed a new class of exceptionally potent heteroduplex antisense oligonucleotide. When conjugated with vitamin E to the HDO, the silencing effect of HDO was 10-50 fold greater than that of ASO for endogenous gene of the liver. We furthermore investigated a devise for penetrating blood-brain-barrier of ASO.
We will discuss the feasibility of ASO gene therapy of ALS.

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