Development of novel RNAi therapeutics with higher chemical and biological stability, and activity based on completely new ideas
In 2010, Bonac was founded and entered the field of RNAi therapeutics in spite of already big western venture companies developing these therapeutics. Why was a small venture like our company able to develop original intellectual properties (IPs) not infringing on existing them? Now, untold story behind the development will be introduced by me, chairman of Bonac, previously director of laboratory of a pharmaceutical company.
Tadaaki Ohgi, Ph.D.
Co-founder and Chairman of Bonac
“Carring out strategic research and exploring the new ideas beating stereotype
due to analyzing the current and past developing situations as a follower company”
In 2006, a Nobel Prize was awarded for the discovery of ribonucleic acid interference (RNAi) and subsequently development of using this concept and technology had been spread across the world. In 2010, the year Bonac was founded, most IPs regarding RNAi were held by a big venture company in the US. We had explored the original IPs not supposed to infringe on those of other companies by deeply analyzing their patents because our IPs were needed to have unique and original concepts and ideas to show our presence and value.
“Challenging to make long single stranded RNA oligomers with two innovative issues,
development of 1) their practical synthetic method and
2) more stable RNA structure comprising all natural components in vivo”
There has been a big problem in double stranded short interfering RNAs (siRNA), though they are mostly popular and developed in the western countries as RNAi therapeutics. Naked and unmodified siRNAs are too unstable in vivo to be delivered to the target organs.
Therefore their structures are chemically modified and complexed with liposomes and others to increase their stability in vivo. On the other hand, mainly by the above reasons there had been no company to deal with long single stranded RNA oligomers as therapeutics. Because, generally long single stranded RNAs are relatively more unstable than siRNAs and easily digested their single stranded regions. Also, long single stranded RNAs are very difficult to be chemically synthesized so that their practical method had been developed at that time. If these issues on long single stranded RNAs such as their practical method and improvement of stability in vivo were dissolved, the possibility of developing novel and original RNAi therapeutics, Bonac Nucleic Acids would be high. Bearing these issues in mind, basic research on long single stranded RNAs had been carried out so that new scientific data were accumulated one after another.
Advantages of long single stranded RNAs
- Stability: more chemical and biological than siRNA (except loop regions)
- Productivity: One running of solid-phase synthesis for long single stranded RNAs is needed, while two runnings for siRNA are required.
Introduction of ideas from adjacent science into Bonac Nucleic Acids
Generally, most of scientists are apt to be engaged in their expertise, conservative in some ways, for instance, experts of nucleic acids doing research with nucleic acids, other experts doing with substances well employed in other fields. I have an experience as a synthetic chemist in the fields of not only nucleic acid and amino acids, but also saccharides and lipids. I had come up with replacing loop (hairpin) region of long single stranded RNAs with an amino acid (Proline) derivative. Because, Proline is known as a representative ofβturn inducers in protein to maintain the secondary, βturn structure. I utilized Proline to keep the secondary structure of long single stranded RNAs. At that time, in the field of nucleic acid chemistry, there had been no examples of incorporating amino acids into nucleic acid oligomers.
Additionally, advantages of using amino acids in nucleic acid oligomers give them more resistance to RNase and safety to body. Because most nucleic acid oligomers developed in the world have been chemically, artificially modified and could more lead to exert their toxicity.
Long single stranded RNAs synthesized based on the above concept have many effects to be desired for RNAi therapeutics more than expected.
Development of unique long single stranded RNA, “PnkRNA®” with amino acid, Proline
PnkRNA was designed by replacing two loop regions of nkRNA® , firstly developed in Bonac, with two Proline derivatives. In consequence, much improvement has been accomplished in efficacy of RNAi therapeutics such as chemical and biological stability leading to a desirable medicine.
For the patients suffering from Idiopathic pulmonary fibrosis (IPF)
as soon as possible
Bonac Nucleic Acids developed via background story described above have been patented in Japan, the United States and Europe. At present, Bonac has allied with a major company aiming to develop RNAi therapeutics of intractable disease, IPF, and enter the clinical stage by 2018. In IPF, only conventional medicines with low molecular weight have been launched onto the market but unsatisfactorily accepted so far. A new comer medicine based on a sophisticated concept has been deeply desired, in which RNAi therapeutics could contribute to one of the expected ones. Bonac has been struggling for delivering proper RNAi medicines to patients as quickly as possible.