Science and Technology Platform Program for Advanced Biological Medicine


Development of a new generation platform for oligonucleotide therapeutics that combines delivery and safety

<Project Leader> Satoshi Obika

Graduate School of Pharmaceutical Sciences, Osaka University

Satoshi Obika

Recently, a great deal of attention has been paid to oligonucleotide therapeutics that control the expression of genes responsible for diseases and realize treatment and prevention thereof. Oligonucleotide therapeutics can control the expression of a target gene in a sequence-specific manner. Therefore, it is expected that this technique will lead to novel treatment strategies for many refractory diseases, for which effective therapy remains to be developed. Clinical trials on more than 140 therapeutic synthetic oligonucleotides are currently ongoing all over the world; however, to maximize their clinical applications, solving critical problems regarding delivery technology and ensuring safety have been recognized as urgent issues.
We had previously developed two elemental technologies to solve the aforementioned challenges: 1) a modified nucleic acid technology to enhance efficacy, and 2) a modified nucleic acid technology method to enhance safety. In this study, we will develop two additional technologies, namely: 3) a conjugation technology method to expand the range of targeted tissues, and 4) a toxicity reduction/evaluation technology to ensure safety. By combining these four elemental technologies, we aim to build a platform to develop an antisense nucleic acid that shows efficacy in tissues other than liver and maximizes human safety.
To achieve this objective, we will design and synthesize ligand-oligonucleotide conjugates using our own nucleic acid technology. We will also proceed with the search for additional ligands to deliver antisense oligonucleotides to the desired tissues using both in vitro activity evaluation methods for cell panels derived from individual organs or tissues and in vivo pharmacokinetic evaluation methods. Based on these investigations, we hope to identify several promising ligand molecules and demonstrate their efficacy in vivo. In addition, the characteristics of sequences that induce off-target effects will be elucidated using pre-mRNA databases and a microarray data. In silico strategies to reduce the off-target effects will be developed and verified. Furthermore, the usefulness of this strategy will be verified using human liver chimeric mice. Finally, with regards to novel antisense nucleic acids generated via this platform that exhibit effective activities in organs other than liver, they will be tested in appropriate model animals and their efficacy and safety values will be evaluated.
The scope of oligonucleotide therapeutic research will be greatly expanded if its safety is improved and the range of targeted tissues are expanded by the research proposed here. By using this technology, other novel methods will be adopted for the treatment of many refractory diseases for which no treatment has been established so far.

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