Functional RNA

February 29, 2008
HARAKENZO World Patent & Trademark
Naoki Aono

      Functional RNA is literally “RNA having some sorts of functions.” Though finding of RNAi (RNA interference) put functional RNA into a positive light, such RNA had been known even before. In 1980’s, T.Cech and S.Altman, with each colleagues, found that RNA having a catalytic property exists in organisms (Cech and Altman won the Novel Prize in Chemistry in 1989, by finding ribozyme). By this, it was found that not only protein but also RNA itself could function as catalyst. Ignited by this finding, the functions as well as the importance of the existence of RNA were reassessed drastically. Later, development of a SELEX process (in vitro selection process), a process of screening RNA having a particular function, made it possible to create new ribozyme, which led to application of ribozyme as drug medicine. Besides, RNA aptamer, which can be also created through the SELEX process, has been developed. RNA aptamer binds to a target substance and blocks its function. The target substance of RNA aptamer is not limited only to nucleic acid or protein, but also includes a low molecular compound and a virus. Therefore, RNA aptamer has attracted attention as new material for drug medicine. In fact, in the United States, it has already been put to practical use, as some sort of curative drug. Since the finding of RNAi, functional RNA has now attracted a great deal of attention. Patent application relating to RNAi has increased rapidly since 2001, and the Japan Patent Office released in 2006 the investigative report on a technology direction of patent application.

      RNAi, which is widely seen among various kinds of organism species from yeast to human, is a phenomenon that, when double stranded RNA having an identical sequence as a target gene is implemented in a cell, the identical part of mRNA of the target gene is specifically broken down, and thereby gene expression is inhibited. RNAi was found in 1998 in the experiment using Nematodes, which was conducted by A.Fire and C.Mello, with their colleagues (Fire and Mello won the Novel Prize for Physiology or Medicine in 2006, by finding RNAi). The double stranded RNA is digested with the Dicer, a type of RNaseIII, into small RNA fragments of 21 to 23mer, which is referred to as siRNA. Then, complementary mRNA is broken down by a complex of siRNA and RICS. Within a few years after the finding, RNAi has rapidly become common as a standard tool for gene functional analysis. Besides, RNAi has stronger specificity and activity, as compared to antisense and ribozyme; therefore, industrial application of RNAi for drug medicine and medical care has rapidly increased.

      In RNAi research, fundamental research from the finding of the phenomenon to the clarification of the mechanism has mostly been initiated in Europe and the United States, while Japanese research has committed little contribution to technologies recognized as fundamental patents. In addition, Japan has filled less patent application and published fewer nonpatent literatures in the basic fields, as compared to Europe and particularly to the United States. The number of companies, especially the number of venture companies, relating to RNAi in Europe and the United States outnumbers that in Japan. Advantages of Europe and the United States in the RNAi relating business are partially attributed to establishing a system earlier, the system which stimulates (i) the RNAi relating research by promptly transferring, to research supporting industries, achievement in the fundamental research conducted by universities and official bodies and thereby using the achievement as test reagent and the like, and (ii) research in applied fields such as drug medicine and the like by further transferring, to the venture companies, the achievement gained in the research supporting industries. The number of the venture companies relating to RNAi, which receive the achievement transferring from the universities and the official bodies, has also increased in Japan; however, still it is not sufficient to establish a business framework.

      In consideration of the situation in the RNAi field in Japan, the investigative report proposes (i) establishing, on industry-academia-government collaboration, a foundation of effectively developing new drug medicine, (ii) developing drug medicine possessing RNAi features (RNAi drug medicine), and (iii) technology integration. Moreover, the investigative report suggests that it is necessary to advance research and development in a field of functional RNA including non-coding RNA, RNA which has drawn major attention recently.
Non-coding RNA (ncRNA) is RNA not translated to protein, and includes from: miRNA (microRNA), which is about 20-base, having a function of working on a target mRNA sequence-specifically and then inhibiting the translation of it and the like; to enormous ones such as Xist which is involved in inactivation of X-chromosome via histone modification. It is estimated that 97 to 98% of genomic information transcribed to RNA are ncRNA. Besides, while a region which encodes protein accounts for 2% of an entire region in human genome, ncRNA accounts for even 40%. As described above, ncRNA exists in large number within an organism; however, many of them remain unclear. Yet, it has recently become clear that a gene expression regulation mechanism of ncRNA plays an important role in cell differentiation, cell growth, and development of organisms. In addition, it has been reported that ncRNA relates to various types of disease, since the finding in 2002 that a particular miRNA is lacked and expression inhibition occurs in a specific tumor cell. Now, ncRNA draws a major attention, from perspectives of analysis of a disease mechanism and development of medical treatment. Besides, in patent application, the number of patent application relating to either miRNA or ncRNA has rapidly increased since 2002.

      In Japan, a five-year plan of “the functional RNA project” (by the Ministry of Economy, Trade, and Industry), which conducts development of a bioinformatics technology making a prediction of functional RNA, development of new supporting technology and tools, and functional analysis of functional RNA, was launched in 2005 (the project was relegated to the Neo Energy Industrial Technology Development Organization in 2006 and has been put into execution ever since). Specifically, the project is aimed at (1) establishing the bioinformatics technology which makes a prediction of functional RNA candidates from genome, by also considering similarity in a secondary structure, (2) establishing a new process for understanding functional RNA with high sensitivity, quantitatively, and comprehensively, and (3) establishing tools for analyzing functional RNA genome-widely. Then, the project is designed to analyze, by using these tools, functional RNA relating to a human disease and the functional RNA candidate(s) which shows important effect to cell functions such as development and differentiation. By this, the project is aimed at acquiring fundamental knowledge useful for developing drug medicine, regeneration medicine, and the like and to establish a fundamental technology. Through these, the project is aimed at identifying functional RNA having functions such as an inducible factor for cell differentiation, an inhibitory factor for gene expression, a regulatable factor for protein translation and the like, and aimed at patenting the achievement promptly. It is expected that new industry will be created by stimulating industrial application such as regeneration medicine, RNA medicine, gene treatment, disease treatment, and the like, if industry, academia, and government collaborate with each other effectively by combining the acquired knowledge, new technology, and achievement. Furthermore, drastically advancing the research and development in functional RNA will lead to establishment of Japanese advantage in this field. Hope that industry, academia, and government collaborate well with each other and advance the research and development effectively so as not to be left behind by Europe and the United States as in the case of the research and development in the RNAi field.

      While the RNA field has been growing drastically, in Japan, the RNA Society of Japan was established in 1999 so as to ensure further development of the RNA research. In 2005, the RNA Society of Japan was recognized as an academic society admitted by the Japan Patent Office, which is able to receive the application of Patent Low Section 30 (exceptions to lack of novelty of invention). Thus, it is expected that research and development focusing on patent application will be advanced hereafter. Though it still remains unclear how ncRNA keeps intellectual property rights, hope that Japan takes a lead over the world in the field holding various promises, on the foundation of the industry- academia-government collaboration.


Reference:
Paten Office. (2007). Heisei 18 Tokkyosyutsugan Gijyutsudoko Chosahokokusho RNAi (RNA Kannshou) (Investigative report on a technology direction of patent application RNAi (RNA interference)). Tokyo; Patent Office.

Functional RNA Project. (n.d.).
http://www.nedo.go.jp/activities/portal/p06011.html

Nakamura, Y. and Shiomi, H. (2004). Jikkenigaku zokan: Yakushinsuru RNAkenkyu (Experimental medicine extra number: Advancing RNA research).Tokyo; Yodosya.