世迷い独り言

以前このブログでも書いたデコイの新型の論文がJournal of Gene Medicineに出ました。

デコイの最大の欠点は、血液中で容易に分解されてしまうことで、そのため局所投与しかできないという弱みがありました。

今回の発表論文は、その弱み解消のため、食べられやすい３’側をリボン（ループ)状にして、３’末端をなくしたことです。そのため、エクソヌクレアーゼという３’側を食べる酵素が食べれず、血液中でも安定になるというアイデアです。

今回の論文の中でも、血液中で安定であることを示していますが、他の実験ではリウマチ患者さんの関節液でも安定であることがわかっています。

現在は、関節内への投与を行う臨床研究ですが、静脈投与での有効性を出したいと思っており、現在進めています。

静脈投与で可能であれば、今大流行の抗体医薬のようになるのではないか、あるいは、抗体医薬との併用での有効性を示せるのでは、考えています。

ちなみに、今回の論文の筆頭著者は、ブラジルからの留学生で日系３世の女性で、我々の教室に参加して、最初の論文になりました。コメントを聞きましたので、書きますね。

彼女は、英語とポルトガル語しかできませんので、英語でご勘弁ください。

Ribbon-type Oligonucleotide Decoy: A new blocker for NF-kappaB

    The devices originated from molecular biology research have provided new strategies to interfere in gene expression such as antisense nucleotides, siRNA, and decoy oligonucleotides, which have been showing applicability and efficiency in a variety of animal models and targeted genes. To translate them into devices, a series of optimization have been largely pursued. For example, substitution of phosphorus group for a sulfur group (phosphorothioation) in the backbone of oligonucleotides proved to highly increase its resistance against nucleases and its ability to bind to transcription factors like NF-kappaB, c-myc, and ets-1. The efficiency of these chemical modified decoy oligonucleotides has been shown by our and others groups, and to mention only the studies targeting NF-kappaB, the efficiency is reported in models ranging from myocardic reperfusion, restenosis, rheumatoid arthritis, to atopic dermatitis; with clinical trials going on nowadays.
    Since that chemical modification has been pointed as cause for toxicity and non-specific effects, in the recent article (Osako MK et al. 2007 J Gene Med) we report a further progress in the optimization of decoy oligonucleotides: the development of a non-chemical modified oligo targeting NF-kappaB. We designed a phosphodiester nucleotide sequence for acquiring a dumbbell shape structure, which proved to protect the oligo extremities from exonuclease attack and delayed the degradation by nucleases present in serum. This new oligonucleotide, named Ribbon-type decoy, together with the stability, showed higher efficiency than the phosphorothioated oligo, and high specificity in blocking NF-kappaB. From our work, ribbon-type decoy rises as a candidate for replacing phosphorothioated decoy oligo in further studies: it is an efficient tool for inhibiting gene activation by NF-kappaB in basic research, and due to its non-modified composition, ribbon-type decoy has also potential for clinical applications.
     
Mariana Kiomy Osako BS., MSc