Oligonucleotide therapeutics are single- or double-stranded DNA or RNA-based molecules consisting of short strand of nucleotides (generally 10-50 nucleotides). They are manufactured by chemical synthesis and act directly on RNA or protein. In recent years, oligonucleotide therapeutics, such as antisense oligonucleotides (ASOs), siRNAs, miRNAs, aptamers or CpG-motif oligodeoxynucleotides (CpG ODN), are active areas of drug development designed to treat a variety of genetic and/or intractable diseases. So far, eight oligonucleotide therapeutics have achieved marketing authorization in USA or Europe, i.e. fomivirsen (Vitravene^®), pegaptanib (Macugen^®), mipomersen (Kynamro^®), eteplirsen (Exondys 51^®), nusinersen (Spinraza^®), inotersen (Tegsedi^®), patisiran (Onpattro^®), and hepatitis B vaccine containing CpG ODN (CpG1018) as adjuvants (HEPLISAV-B^®), and more than 150 oligonucleotide therapeutics are currently in clinical development. In this review, I outline classification, modifications and mechanism of actions of oligonucleotide therapeutics, and introduce the current status of development of RNA-targeted oligonucleotide therapeutics (ASOs, siRNAs and miRNAs).

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More than 25 years have passed since the world’s first gene therapy trial for adenosine deaminase deficiency in the United States in 1990. Dramatic therapeutic effects were reported in the several clinical trials, on the other hand, therapeutic effects did not reach anticipated levels in many cases. Furthermore, severe side effects were found in a few clinical trials. Gene therapy suffered a period of winter-like hardship. However, 7 types of gene medicines, including a lipoprotein lipase-expressing adeno-associated virus vector (Glybera) in 2012, has been successively approved afterwards due to the continuous efforts by researchers. Now gene therapy is becoming a reality. In this review, I describe the current status and future prospects of virus-based gene medicines.

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Twelve years ago, the author introduced the situation of research and development of nucleic acid/gene medicines at the Annual Meeting of the Pharmaceutical Society of Japan. It was anticipated that the main R&D theme in industries would be shifted to nucleic acid medicines more, because nucleic acid medicines have some advantages compared to plasmid DNAs for gene therapy which are used with liposomes and so on, in terms of chemical modification, transfection efficiency, chemical stability, and etc. The current situation after 12 years is different from the above prediction. In fact, there are some nucleic acid medicines such as antisense, siRNA, etc. on the market as exactly expected. While at the same time, seven kinds of gene therapy medicines using virus vectors have been also launched out during 5 years, which is contrary to the author's prediction. The contribution of DDS (drug delivery system) technologies seems to be still low, but in the near future DDS will be undoubtedly needed in order to improve the efficacy and safety of nucleic acid/gene medicines. Exosomes, which recently receive a lot of attention, may give us some kinds of suggestions for the issue resolution.

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For clinical applications of genes and nucleic acids as medicines, a development of delivery technology is a major challenge. Recently, various delivery systems controlled physical energies, such as ultrasound, pressure, electric force, magnetic force, electric force, and light, have been developed. In particular, there is an increasing interest in ultrasound-mediated gene and nucleic acid delivery due to its safety. The use of ultrasound in combination with nano/microbubbles allows for enhanced effects not only of imaging but also of gene and nucleic acid delivery. We developed lipid bubbles entrapping an ultrasound contrast gas and evaluated the efficacies of lipid bubbles as tools for gene and nucleic acid delivery. In this review, we describe current knowledge and future perspectives of ultrasound theranostics, which refers to the combination of diagnosis and therapy, and discuss the feasibility of lipid bubbles for therapeutic delivery of genes and nucleic acids.

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The gene and nucleic acid medicines have attracted attention as novel drugs by advance of molecular biology and genetics. The gene and nucleic acid medicines are used to age-related macular degeneration and spinal muscular atrophy in clinical practice. However, it is not enough for gene and nucleic acid medicines to integrate the information on quality and safety. Their target diseases and administration routes are limited by low bioavailability because of low stability and poor membrane permeability. Clinical development of gene and nucleic acid medicines need to integrate non-clinical and clinical information and create adequate regulation. It is also necessary to develop chemical modification and DDS for the gene and nucleic acid medicines to increase the stability and organ delivery. Many studies have not produced practical DDS for gene and nucleic acid medicines. Safety and biocompatibility of DDS are very important for clinical use. Most DDS has been developed by the seeds, not healthcare needs. So, we have developed the multi-functional and effective DDSs (Nano-ball) constructed with safe materials of medicines and foods. The spleen targeting Nano-ball have been developed to show its high efficiency as cancer vaccine and infectious vaccine after extensive screenings. siRNA Nano-ball showed therapeutic effect against metastasis of melanoma and peritoneal dissemination of colon cancer in mice. The lung targeting Nano-ball showed a relationship between Nano-ball contents and organ distribution. Nano-ball was able to be prepared by sterilized mass production. Early clinical use of Nano-ball is expected because of their efficacy and safety. We would like to discuss advancement of the gene and nucleic acid medicines from a standpoint of healthcare needs.

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