Newsletter

From KING SKYFRONT to the world - NanoMedical Innovation

December
2017

4

Vol.

New Route to Innovative Treatment
of Central Nervous System Disease
with Nanomachines
Contents
2

6

8

Talking about Theme 2

Drug Delivery to Brain via“BBB-Crossing
Nanomachines”!

Yasutaka ANRAKU, Mariko TOSU, Hirokazu IWASAKIInterview with Researcher

Development and Evolution of Hetero-Duplex
Oligonucleotide Expected to be an Innovative Nucleic
Acid Drug
Takanori YOKOTA

Research Highlights

Light to Treatment/Diagnosis of Central Nervous
System Disease!! Development of Nanomachine to
Deliver Drugs from the Blood to the Brain
Yasutaka ANRAKU

Development of Hetero-Duplex Oligonucleotide toRegulate a Specific Gene far more Efficiently thanPrevious Nucleic Acid Drugs
Hiroya KUWAHARA

12 iCONM Round-table Talk

iCONM Trainees Talk about their Activities

Shigehito OSAWA, Ai KOHATA, Noriko NAKAMURA, Akitsugu MATSUI, Takamasa MAJIMA

14 Activity Report

・8th General Meeting
・Topics
・Editor’s noteTalking about
Theme 2

Drug Delivery to Brain
via“BBB-Crossing
Nanomachines”!

Recently, in COINS Theme 2“Innovative technology for the treatment of central
nervous system diseases”, a paper on BBB- Crossing Nanomachines has been
published in English scientific journal “Nature Communications”. Dr. Yasutaka
Anraku, Assistant Professor, Department of Bioengineering, Graduate School ofEngineering, The University of Tokyo, Mr. Hirokazu Iwasaki, Leader of COINS
Research Promotion which supports research and social implementation (ViceDirector of Innovation Center of NanoMedicine (iCONM) and Dr. Mariko Tosu,
Representative Director & CEO, Braizon Therapeutics, Inc. talked about theprospects of nanomachines.

Yasutaka ANRAKU

Mariko TOSU

Hirokazu IWASAKI

Assistant Professor, Department of
Bioengineering, Graduate School ofEngineering, The University of Tokyo;
Visiting Scientist,
Innovation Center of NanoMedicine,
Kawasaki Institute of Industrial Promotion

Representative Director & CEO,Braizon Therapeutics, Inc.

COINS Research Promotion Leader&ViceDirector,
Innovation Center of NanoMedicine,
Kawasaki Industrial Promotion

She graduated Tokyo University of Pharmacy andLife Sciences. She obtained a Doctor of Pharmacy.
After working as a researcher at National Cancer
Center and The Institute of Medical Science,
The University of Tokyo for 12 years, she joined
a foreign affiliated firm dealing with researchequipment and supplies as a principle investigatorof one of the N EDO research projects. She
continued her career at another foreign affiliatedfirm in the same industry as a marketing manager
and division manager. From 2013 to February
2017, she took office as representative director
at Fluidigm Co., Ltd. In March 2017, she joined
Braison Therapeutics, Inc. as a Representative
Director & CEO.

In 1975, he graduated Department of Industrial
Chemistry, Faculty of Engineering,The Universityof Tokyo. Then he joined Showa Denko K.K.
In 1979, he became a full-time official of thecompany's labor union, Chairman of the Central
Executive Committee, Chairman of the ChemistrySociety, and Union Central Executive Committee.
In 1999, he returned to Showa Denko K.K. andserved as Corporate Officer; General Manager
of Intellectual Property Office, Director; Corporate
Officer; Executive Officer of Chemicals Sector andDirector; Corporate Officer in charge of factories,
etc. He was the first director who has an experience
as a chairperson of labor union. In 2014, he joined
COINS as a Research Promotion Leader andbecame iCONM Vice-Director in 2015. He plays
a key role in COINS / iCONM management byusing broad management know-how such as fromlabor to intellectual property and business strategy.
In June 2015, he became a Director of Kawasaki
Institute of Industrial Promotion.

In 2007, he completed his master’s degree atGraduate School of Science and Engineering for
Education, University of Toyama, and in 2010,
he finished his PhD. at Department of Materials
Engineering, Graduate School of Engineering,
The University of Tokyo. He is at current position
since 2016. He is also a part-time lecturer at
Graduate School of Medical Dental Sciences,
Tokyo Medical and Dental University and National
Institutes for Quantum and Radiological Scienceand Technology, and a Scientific Advisor at
Braizon Therapeutics Inc. He is engaged inresearch of polymer chemistry, colloid interface
chemistry, and biomaterial chemistry.

2 | NanoSky VOL.04 DECEMBER 2017

Establish a venture company witha patent on “Drug delivery to brain
via BBB-crossing Nanomachines”.
■ Let us know about your work first.
Anraku: I’ve been working on polymer synthesis since
my college days, and I specialized in polymer micelles(Fig. 1) as nanomachines in the laboratory of Professor
Kazunori Kataoka in the Graduate School of Engineering, The University of Tokyo, to which I belong fromthe doctoral course (Prof. Kataoka is currently Director
General of iCONM , Project Professor of Policy Alternatives Research Institute, The University of Tokyo). We
were first targeting cancer but in Theme 2, we are targeting cranial nervous diseases.
Tosu: In March 2017, I assumed the position of Representative Director & CEO of Braizon Therapeutics,
Inc., a company that was spun out with the technologies of Dr. Anraku and coworkers. I graduated fromFaculty of Pharmaceutical Sciences and worked on research for about 12 years at universities and research
institutes. Then, I was engaged in the sales of analytical devices and reagents. When I was offered this position, I recognized the social contribution of this technology if it were to be implemented and the importance ofthe role of bio-ventures. So, I daringly accepted the offer.
Iwasaki: I’m in charge of Research Promotion Leader
in COINS and I am also a Vice-Director of iCONM. In
both, I am responsible for facilitating everything fromplanning to routine operations, as a “Banto” head-clerk
or “Joudaigaro” Chief retainer of his lord’s castle.

■ An article on“Drug delivery to brain via BBBcrossing Nanomachines” has recently been
published in Nature Communications and is
attracting a great deal of attention. Would you
please explain the research?
Anraku: The brain has a barrier called the blood-brain
barrier (Fig. 2). This barrier protects the brain by

Figure 2. Blood-brain barrier (BBB)

Blood-brain barrier (BBB)

Figure 1. Polymer micelle

A molecule that recognizes
the cancer fociblocking substances other thanglucose and amino acids essential for the brain. In other words,
drugs for brain diseases do noteasily reach the brain. As society
has aged, brain diseases such as
Alzheimer’s disease and stroke
have increased, and such diseases elevate the social need fortechnologies to deliver drugs tothe brain. Here we developed ananomachine with glucose molecules attached to the surface ofthe polymer micelle to make thenanomachine recognize glucose
transporter GLUT1 involved inglucose uptake of the brain (p.8). This nanomachine
has a surprisingly higher accumulation in the brain
than previous drugs for cranial nervous system diseases. Because the structure of polymer micelle allows forthe encapsulation of various substances, if nucleic aciddrugs or antibody drugs are contained in it, a more effective drug can be obtained.
Iwasaki: It is generally unknown that drugs cannot
reach the brain easily. When we explain that to visitors
to iCONM, they present high expectations such as“brain surgery seems terrible, so treatment withdrugs is desirable.” After the publication of this paper,
we can provide information on our work actively. We
think our research can make people around the world
happy.
Tosu: This technology is interesting in that a drug forwhich development was discontinued in phase III or an
already marketed drug might be able to have its effectenhanced by carried in a nanomachine. This will havea significant impact on medical economy. Indeed, we
received inquiries from various Japanese and foreign
pharmaceutical companies even before the article were
published. Although research is being advanced in thisfield around the world, few results have been obtained.
So, we think this article had a significant impact.

The barrier strictly limiting drug transportation between
circulatory blood and the cranial nervous system

A shell to evadethe bio-protection
systemVascularendothelial
cells
Drug
Vascularlumen

A core containing
an anti-cancer drug

A nanomachine containing an anticancer drugBrainparenchyma
BBB (blood-brain barrier): Strictly limits drug transportation

NanoSky VOL.04 DECEMBER 2017

|3

TALK
Anraku: The article was so innovative, nobody believed
the results and there was difficulty in accepting the article (laughter).

■ Why was the research successful?
Anraku: This is because the accurate design of nanomachines such as introducing glucose molecules to thesurface of polymer micelle in an appropriate form istactically combined with physiological blood glucose
regulation properties. First, we simply administered
this to full-stomach mice or fasting mice, and accumulation increased in such experiments. Some mice ate alot, and other mice ate a little, resulting in great data
variation, because we couldn’t force them to eat. In
mice, the glucose level was controlled by glucose injection. In humans, it is easier because they eat when
they are hungry.

Need for fostering humanresources to further refine thetechnology

in research.” These words remained in my head for along time. Then we set up the venture company, obtained the patent, and issued the article. It has been
five years now since the start and I can eventually proceed with this concept securely.
Tosu: We first obtained the Japanese patent in February 2017, and the U.S. and European patents are now
being reviewed. After we obtain the Western patents,
it will be easier to negotiate with Western pharmaceutical companies. From now on, we are accelerating its
actual utilization by defining target diseases, proceeding with the development, tying up with other companies, and licensing it. I think, if we design the nanomachine, it seems better for us to limit its target diseases
to rare diseases such as pediatric brain tumors, seek apartner for this, and proceed with the development.
Iwasaki: The issue of the patent and the publication of
the paper have offered the rationale for determining
the importance of the theme. More research may be
performed in cooperation with iCONM. It is essential
for the research and its social implementation to proceed with the triad of R&D strategy, business strategy,
and IP strategy.

■ What are the current issues?
■ Braizon Therapeutics is the first venturecompany resulting from COINS activities. What do
you think about your strategy?
Iwasaki: The Center of Innovation (COI) Program aims
at “vision-oriented challenges and high-risk R&D considering the image of society to be realized 10 years in
the future” and is looking for research that will significantly change the world.
Research becomes valuable
only if it is accepted by society. Although many companies pa rticipate in
COINS, no company has
participated in Theme 2 before. Because it was important to develop nanomachines reaching the brain
first, setting up a venturecompany to achieve social
implementation was considered to be better taking
commercialization into consideration. Setting up a venture company meets the philosophy of COI.
Anraku: Since the start of COI, there has been a policythat Theme 2 accepts no companies but instead createsa venture company, posing pressure to produce results.
Dr. Yuzuru Matsuda, Director of the Kato Memorial
Bioscience Foundation, is the Visionary Leader of “COI
STREAM” Vision 1 “Ensuring Sustainability as an Advanced Low-Birth Rate Aging Country” and stated:“PPP (paper, patent and platform) should be achieved
4 | NanoSky VOL.04 DECEMBER 2017

Anraku: In the use of polymer micelle as a nanomachine, solid cancer is easier to target because the cancer cells are concentrated. In brain diseases, on theother hand, the target differs by disease such as thenerve cells and glial cells, and therefore, its selectivity
beyond the blood-brain barrier needs to be higher.
In addition, I didn’t notice before I joined in COINS
that, while “attractive” research is required to issue articles, social implementation requires both high functionalization and simplicity. I feel like these things
make me refrain from writing articles. This is a dilemma.
Tosu: The problems of venture companies are entirely
human resources, material resources, and financial resources. Now we particularly need human resources.
As for material resources, as Dr. Anraku said, researchrequires brilliant results and actual utilization requires
simplicity and high reproducibility. A company mustrefine technology from a perspective different fromthat of research. This may be a hurdle that needs to becleared.
Anraku: A nanomachine itself is very stable and noteasily broken down. However, it also needs to be broken down in response only to the brain environmentand release the drug there. From now on, we will also
research therapeutic effects using disease model mice
kept in iCONM. Furthermore, because this is a totallynovel technology, unknown potential adverse reactions
are also great issues. We will confirm adverse reactions
using marmosets in institutes such as the Central Institute for Experimental Animals, a partner institute of
COINS.

Tosu: We would also like to cooperate with various research institutes working to overcome brain diseases.
Iwasaki: iCONM, the core institute of COINS, is a neworganization. We have improved the system like a venture company, by fostering human resources, looking
for management methods, and responding to requests
from the outside. The industry-ready staff members
have made great efforts since the inauguration, butthey will retire some day and the organization needs tochange. Young staff members have been fostered. It is
important to sustain the current strengths of activeness and flexibility along with removing dependence on
individual skills to construct a stable organization. For
this goal, I think it is also important to foster young
talents through OJT (On the Job Training) and to leave
operations to the next generation.

■ Tell us your future resolution
Anraku: I’d also like to deliver nanomachines to sitesthat are difficult to reach other than the brain, such as
the eyes, ears, and muscles. This technology should be
required to realize an “in-body hospitals”*. Other
Themes define their target diseases and nano-machines
are being created for these targets. In Theme 2, I’dlike to further proceed with research for the improvement of the performance of the nanomachine itself.
Tosu: If a drug can reach the brain via GLUT1, there
may be other candidates of nano-machines and DDS(Drug Delivery System) depending on the drug or purpose in addition to polymer micelle.
Braizon Therapeutics would like to increase the number of employees who sympathize with our mission andset up the business as soon as possible by improving
the laboratory set in iCONM.
Iwasaki: COI requires deciding and proceeding withwhat and how to research anddevelop through backcasting assuming the desirable form of
the future society. We have opportunities to consider what to
do now to create and realize“in-body hospitals,” the vision
for 30 years in the future. We
can discuss and learn about research, intellectual properties,
and social implementation in theface-to-face meetings and sitevisits of the Japan Science andTe c h no l og y Ag enc y ( JS T ) ,COINS Retreat Camp and General Meetings. Through theseopportunities, I would like to support the further progress of the COINS members proceeding to the realization of in-body hospitals.

■ As the research progresses further and thehuman resources are being fostered, looking
forward to the future. Thank you.
(Interviewer: Science Writer Ayumi KOJIMA)

Terminology＊in-body hospitals
A research and development concept targeted by COINS: “a smart
nanomachine circulates in the body 24 hours a day to detect the signs of adisease, treat it, and immediately transfer the information to the outside of
the body, so that serious diseases are detected and treated early on before
the person notices them.”

References
Y. Anraku, H. Kuwahara, Y. Fukusato, A. Mizoguchi, T. Ishii, K. Nitta, Y.
Matsumoto, K. Toh, K. Miyata, S. Uchida, K. Nishina, K. Osada, K. Itaka, N.
Nishiyama, H. Mizusawa, T. Yamasoba, T. Yokota, K. Kataoka, Glycaemic
control boosts glucosylated nanocarrier crossing the BBB into the brain.
Nature Communications 8: 1001（2017）

NanoSky VOL.04 DECEMBER 2017|5

Interview

Interview with Researcher
Development and Evolution of HeteroDuplex Oligonucleotide Expected to be
an Innovative Nucleic Acid Drug
Takanori YOKOTA
Professor,Department of Neurology and
Neurological Science,
Tokyo Medical and Dental University

COINS Theme 2 is developing basic technologies for drugs to handle central nervous system diseases
beyond the blood-brain barrier. Professor Takanori Yokota, Department of Neurology and Neurological
Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, isparticipating in Theme 2 and has been creating basic technologies for nucleic acid drugs through novel
ideas, such as the development of a hetero-duplex oligonucleotide different from antisense oligonucleotide
or siRNA (p. 10). We interviewed Professor Yokota about his previous work and future developments.

Conceives of an artificial nucleic
acid through a resolution to create
a new molecule by himself
The development of nucleic acid drugs which consists of
DNA and/or RNA targeted to messenger RNA (mRNA) or micro RNA (miRNA) to exert its effect is underway around theworld. While nucleic acid drugs can target a broader range ofmolecules than antibody drugs, they have problems such as thestability of nucleic acid, directivity to the target organ/tissue,
and adverse reactions of liver disorders etc.
In previous developments of nucleic acid drugs, the first
method used was the antisense method where single-stranded
DNA complementary to the target gene RNA (antisense oligonucleotide) suppresses gene expression, followed by RNA interference where short double-stranded (small interfering RNA:siRNA) cleaves RNA. Currently, treatment with direct genemodification by genome editing technology using CRISPR/Cas9
is also being focused on.
Professor Takanori Yokota, Department of Neurology and
Neurological Science, Graduate School of Medical and Dental
Sciences, Tokyo Medical and Dental University, has created ahetero-duplex oligonucleotide that is different from antisense oli-

Control

1.4

Figure 2
Core hetero-duplex oligonucleotide technology
with 5 coordinated component technologies

Nucleic acid drug contained in DDS[ Engineering ] (Takeshi Wada)
Regulation of phosphorus atom chirality
for resistance to RNase[ Engineering ] (Satoshi Obika)
Development of novel LNA withdrastically high gene binding force

Vitamin E-binding
hetero-duplex oligonucleotide

1.2
1
0.8

DDS ligand (2)[Medicine]( Takanori Yokota)

Target gene

0.6

LNA

0.4

Intestinal wallDNA
Molecule bound to duplex
oligonucleotide
RNA

LNA

DDS ligand (1)Target cell

0.2
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Expression level of target gene

Figure1g/kg）
ヘテロ核酸の投与でHigh-dose (50 mg/kg) hetero-duplex
oligonucleotide suppresses target genes、細織で標的遺伝子を抑制
in various organs and tissues

gonucleotide or siRNA and enhanced its targeting effect by attaching various ligands to it, attracting attention as a novel
drug discovery seed (p. 10).
Professor Yokota engaged in research on gene therapy in the
U.S.A. from 1998 to 2000, in Burnham Medical Research Institute, San Diego and Bach Neurodegenerative Disease Institute,
San Francisco. There, he was working on the synthesis of RNA
with enzymatic activity capable of cleaving RNA strands (ribozyme). Just in this period, the mechanism of RNA interference
was discovered enhancing the expectation that artificially introduced siRNA would achieve gene therapy. However, although a
Nobel Prize in Physiology or Medicine was awarded for the discovery of RNA interference in 2006, major Western pharmaceutical companies withdrew from siRNA research one after another. Professor Yokota returned to Japan and continued research
on RNA interference. However, the Budget Screening Process
under the cabinet of the Democratic Party of Japan in 2009 significantly affected his research funding. At this time, he resolved“If researching the application of a technology developedby someone, I would suffer from such events. I will create anovel nucleic acid by myself.”
Then he the conceived of the cleavage of RNA by artificial
hetero-duplex oligonucleotide formed by combining an antisense

Enables gene regulation in various organs
other than the liver!

肝臓以外の多くの臓器の遺伝子制御が可能に！

6 | NanoSky VOL.04 DECEMBER 2017

[Pharmacy](Masuo Kondo)
Development offunctional moleculesthat can beadministered orally[Chemistry][Engineering](Takeshi Wada)(Kazunori Kataoka)
Development of oligo-diamino
DDS micellesugar that stabilizes duplex
Ligand molecular designoligonucleotide in the intestineand broken down in the target cells

oligonucleotide to its complementary RNA strand.“I conceivedof it in the airplane on my way to see one of my coworkers Professor Satoshi Obika, Osaka University. I told Dr. Obika about itand he said that he had never seen such a substance. Then we
started development.”
Professor Yokota said with laughter,“It’s cherry picking, anidea like putting a square peg in a round hole.”However, after
the hetero-duplex oligonucleotide was created, experiments revealed that it has an accumulation in the cells that is about several dozen times higher than that of antisense oligonucleotide
or siRNA, respectively. It was later found that the mechanismsof action are totally different among them.

Strengthen DDS by attaching ligands
to hetero-duplex oligonucleotide
Professor Yokota has further enhanced its targetability by attaching ligands to the hetero-duplex oligonucleotide.
The first hetero-duplex oligonucleotide that exerted its effectwas one with vitamin E attached to it as a ligand (Fig. 1). Drugs
are recognized as foreign substances in the body and either
broken down in the liver or excreted through the kidneys. Nucleic acid drugs are characterized by being readily accumulated
in the liver in general, and hetero-duplex oligonucleotide accumulated in the liver as well.
Vitamin E was selected because it was a substance familiar
to Professor Yokota. In 1997, when Professor Yokota was in his
second year as a doctor, he reported a patient with spinocerebellar degeneration where motor dysfunction occurs because vitamin E cannot be taken up by the body, for the first time in
the world. Then he discovered that this disease is due to an abnormality in the gene responsible for producing vitamin E
transfer protein.“In this way, the source of my ideas is seeing
patients and examining questions generated in practice,”saidProfessor Yokota.
In the collaborative research with Director General, Dr. Kataoka of iCONM and Dr. Anraku Project Assistant Professor of
Department of Bioengineering, Graduate School of Engineering,
The University of Tokyo, Professor Yokota’s group proposed
the idea that the uptake of polymer micelle into the brain may
be improved by administering polymer micelle with glucose attached to it in a fasting condition followed by glucose administration. (p. 2, p. 8.) This was inspired by a PET to examine theoccurrence of cancer and the presence of metastasis. PET utilizes the characteristics of cancer cells of taking up more glucose than normal cells, and it depicts where glucose labelledwith positron nuclear species is taken up after it is administered.“Since glucose is the only energy source of the brain, thebrain takes up glucose and represented in black in PET, even if
the brain is intact. Because PET is performed in a fasting condition, we thought polymer micelle would reach the brain moreeasily if administered in a fasting condition followed by glucose.”After this idea was proposed, the accumulation of glucose-attached macromolecular micelle increased in several
months.
“In the blood-brain barrier, GLUT1 may migrate from thevessel side to the brain side at a certain probability as necessary and glucose-bound macromolecular micelle may be carriedaway at the same time, we think. Currently, we are developing
a seed for nucleic acid drugs with its ability to deliver to thebrain further enhanced by inserting hetero-duplex oligonucleotide in the inner space of the glucose-bound macromolecular
micelle.”In addition, hetero-duplex oligonucleotide with ligands attached is being developed as indicated in Fig. 2.“The cells recognize hetero-duplex oligonucleotide itself as a totally new sub-stance. Here, a new molecular biology is present. Althoughhetero-duplex oligonucleotide can be used alone, if its targetability is enhanced by ligands, the dose can be reduced while maintaining its effect, and adverse reactions can be reduced as well.”Currently commercialized nucleic acid drugs use nucleic acid
only and none of them have ligands attached.
In January 2015, Professor Yokota and his coworkers established Rena Therapeutics, a venture company originating from
Tokyo Medical and Dental University, which has already signed
contracts with pharmaceutical companies for technology provision.
In 2017, the antisense oligonucleotide drug nusinersen (trade
name: Spinraza) was approved in Japan as a drug for spinal
muscular atrophy, where systemic muscle power decreases.
“Although the number of patients with the target disease is notlarge and the treatment cost exceeds 100 million yen per patient in the first fiscal year, it is markedly effective comparedwith previous therapies. There have been few diseases that canbe cured in the neurological field, and doctors have sought tosupport patients rather than treat them. In this regard, thelaunch of a nucleic acid drug is very meaningful in the neurological field.”
In this way, there is a favorable trend for nucleic acid drugs,
while practical research should move forward in cooperation
with pharmaceutical companies, such as toxicity, pharmacology,
and dosage form, to make a pharmaceutical product from thehetero-duplex oligonucleotide.“To make a pharmaceutical product, we further need several steps of breakthroughs. I think
this is my role, as a doctor who attends patients,”said Professor
Yokota.“Although doctors cannot create things that will beseeds for drug discovery, we can dig into the need or think offor what existing things could be used, in cooperation with excellent scientists. Japanese are not good at creating a comprehensive concept, which is essential to create novel and globally
useful drugs. For example, although many parts of Japanese
patents are used in global products such as the iPhone and Boeing airplanes, but nobody knows these are Japanese products.
Now we have created hetero-duplex oligonucleotide, and I wish
we could create the concept of its use and the framework to
produce products.
Professor Yokota said that he did not think the research
could proceed to the current level in 6 years. There are various
diseases in the neurology field each with different pathologies,
such as dementia, cerebrovascular disorder, headache, epilepsy,
Parkinson’s disease, and ALS.“I would like to engage in research that is favorable for patients. It is tough to think of novel
things, but research is fun. Our research is progressing steadily
but more work will be needed from now on.”(Notes: science writer Ayumi KOJIMA)PROFILE
Takanori YOKOTA
In 1984, he graduated Tokyo Medical and Dental University Faculty of Medicine.
After training at Department of Internal Medicine, Musashino Red Cross Hospital, hecompleted Graduate School of Medicine Tokyo Medical and Dental University in 1990.
After working at Department of Neurology, Tokyo Metropolitan Neurological Hospital,
he moved to the Burnham Medical Research Institute, San Diego, and Bach
Neurodegenerative Disease Institute, San Francisco in 1998. In 2000, he returned
to his old school, and in 2004, took position of Associate Professor of Department of
Neurology and Neurological Science, Tokyo Medical and Dental University and has beenin present position since 2009.

Reference
K. Nishina, W. Piao, K. Yoshida-Tanaka, Y. Sujino, T. Nishina, T. Yamamoto, K.
Nitta, K. Yoshioka, H. Kuwahara, H. Yasuhara, T. Baba, F. Ono, K. Miyata, K.
Miyake, PP. Seth, A. Low, M. Yoshida, CF. Bennett, K. Kataoka, H. Mizusawa,
S. Obika, T. Yokota, DNA/RNA heteroduplex oligonucleotide for highly efficientgene silencing. Nature Communications 6: 7969 (2015)

NanoSky VOL.04 DECEMBER 2017|7

Reserch
Highlights

1

Theme 2

Light to Treatment/Diagnosis of Central Nervous
System Disease!! Development of Nanomachine
to Deliver Drugs from the Blood to the Brain
The blood-brain barrier (BBB) inhibits drug transportation from circulatory blood to the cranial nervous system, serving
as the greatest bottleneck in the treatment of cranial nervous system diseases. Here we have successfully developed
a nanomachine that crosses the BBB efficiently in response to external stimuli (glucose) and accumulates in the brain
several orders of magnitude more efficiently than previous technologies. This is a basic technology to deliver various
drugs to the brain. It is expected to evolve into the development of innovative drugs for cranial nervous systemdiseases, for which no truly effective treatments have been established, such as Alzheimer’s disease.

Yasutaka ANRAKU
Project Assistant Professor,
Department of Bioengineering, Graduate School ofEngineering,
The University of Tokyo

The aging of society has been progressing significantly in developed countries, and refractory cranial nervous system diseases such as Alzheimer’s disease poseserious social problems. Furthermore, the prevalence ofsuch diseases is also expected to increase significantly
in association with the ongoing increase in the aging
population. The greatest bottleneck that inhibits thetreatment of cranial nervous system diseases is the invivo barrier system called the blood-brain barrier (BBB).
The BBB is responsible of regulating the transportationof substances between circulatory blood and the cranial
nervous system. It selectively takes up nutrients essential for the brain to function, while it significantly limits
the delivery of drugs to the brain. Indeed, even drugs
currently used in the symptomatic treatment of Alzheimer’s disease in clinical settings accumulate at lessthan 0.1% by dose in the brain. Thus, development oftechnology that allows drugs to cross the BBB efficiently is being conducted around the world. In this context,
we successfully developed a “BBB-crossing nanomachine” *1 that crosses the BBB at a markedly higher efficiency than that of existing technology, in response to asimple stimuli of blood glucose change and further accumulates in the nerve cells in the brain.
The cerebrovascular endothelial cells that construct
the BBB have several orders of magnitude more glucose transporter 1 (GLUT1) to transport glucose, the energy source for the brain, than other transporters.
Therefore, the delivery of drugs to the brain by binding
glucose to the drug or its carrier has been attemptedaround the world, resulting in insufficient delivery. We
focused on the site in which GLUT1 is localized in the
cerebrovascular endothelial cells which varies in association with blood glucose change, and proposed that drugdelivery while smoothly crossing the BBB may beachieved by introducing a biological approach of admin-

8 | NanoSky VOL.04 DECEMBER 2017

istering glucose as an external stimulus.
Then, we appropriately introduced glucose in the superficial layer of nanomachines with polymer ensured
for their in vivo safety as component molecules, andconstructed a nanomachine of 30 nm in diameter that
accurately recognizes GLUT1 localized in the cerebrovascular endothelial cells (Fig. 1). By intravenously administering the nano-machines to fasting mice, thensubsequently administering glucose solution 30 minutes
later, it was confirmed that a maximum of about 6% of
the dose was accumulated in the brain. This accumulation is over 100-times higher than that of non-glucosebinding nano-machines (Fig. 2). The behavior of thenanomachines in the brain was microscopically observed, confirming that it has a smart function of crossing the BBB in response to glucose (Fig. 2) and that it isevenly distributed up to the deep regions of the brain(Fig. 3). Furthermore, we revealed that the nanomachines cross the BBB and are then taken up into thenerve cells in the brain (Fig .3). Drug delivery to thenerve cells is very important to achieve the treatmentof many cranial nervous system diseases.
In previous development of drugs for cranial nervous
system diseases, polymer drugs could not cross the
BBB, and low molecular drugs crossed the BBB inefficiently in many cases, resulting in insufficient therapeutic effects that are significantly limited in the development of drugs. Nanomachines significantly enhance theability to cross the BBB of any drugs and facilitate theenclosure of biological drugs that assume future advanced medicines such as antibody drugs and nucleic
acid drugs. Nanomachines are expected to have an inestimable impact on scientific disciplines, medical practiceand society as a great innovation in the development ofdrugs for cranial nervous system diseases.

BBB 通過型ナノマシンの構造

Polymer ensured for their in vivo safety

Figure 1. Structure of glucose-boundnano-machine

Glucose molecule(target oriented)

Hydrophilic block(biocompatibility)

Hydrophobic block(drug-carrying property)

Self-organizedin aqueous
solution
Electronic micrographNano-machines are constructed throughself- organization of macromolecules
ensured for their in vivo safety in aqueouss o l u ti o n s . M o r e t h a n o n e g l u c o s emolecule is mounted on the surface layer
for the recognition of GLUT1 and thediameter is about 30 nm.

Glucose molecule
100 nmDiameter: 30 nm

外部刺激に応答して脳へ集積するナノマシン

Glucose-bound nanomachines were confirmed
to accumulate in response to external stimuli
in an amount over 100 times as high as thatof a non-glucose bound nanomachine. This
results in an efficacy about 100 times as highas that of the d rugs cu rrently used insymptomatic therapy for Alzheimer’s disease.
Real-time behavior of the nanomachines inthe brain (red) was successfully observed
indicating the nanomachines that crossed the
BBB in response to external stimuli and werediffused in the brain parenchyma.

Accumulation of
nanomachines in the brain

120

Accumulation in the brain (relative value)

Figure 2. Nanomachines accumulate
in the brain in response
to external stimuli(glucose administration)

Nanomachines
crossing the BBB

10 minutes after: Glucose-boundnanomachines:Non-glucose-boundnanomachines100

administration of
nanomachines

80

Before external
stimulation:

Glucose-bound nanomachines are
only present in the blood stream

60

External stimuliOver
100 times
Increase

External stimuli(administration of
glucose solution)

40

60 minutes afteradministration of
nanomachines

20

0

Red: glucose-boundnanomachines

0

20

40

60

Time (min)80(administration of
glucose solution)

After external
stimulation:

The glucose-bound nanomachines
crossed the BBB and were diﬀused
in the brain parenchyma

100

BBB 通過型ナノマシンの脳内での挙動

Figure 3. Behavior of glucose-boundnanomachines in the brain

Observation of the brain afteradministration of nanomachines
Superﬁcial layerof the brain

Observation of brain section throughﬂuorescence immunostaining

0㎛

100 ㎛

200 ㎛

300 ㎛

400 ㎛

The glucose-bound nanomachines (red)were confirmed to cross the BBB andthen be evenly distributed up to the deep
regions of the brain. It was revealed thatthe nanomachines are taken up
particularly in the nerve cells in the brain
parenchyma.

500 ㎛

600 ㎛

700 ㎛

Red: nanomachines 800 ㎛

Glucose-bound nanomachines (red)crossed the BBB and were accumulated
in the nerve cells (green)in the brain parenchyma.

Terminology＊1 BBB-crossing nanomachine
BBB-crossing nanomachines are produced by introducing glucose into the surface layer of nano-particles
with component molecules ensured for their in vivo safety. They have smart functions of accurately
recognizing glucose transporter 1 (GLUT1) localized in the cerebrovascular endothelial cells and crossing
the BBB in response to external stimuli (glucose). Due to the fact that this nanomachine is covered by ashell made of polymer material with excellent biocompatibility, it can circulate in the blood stably without
being recognized as foreign material. Change in structure of the polymer constituting the nanomachines
enables the encapsulation of various drugs. Thus, this technology is expected to provide highly-versatilenanomachines that can be developed for the treatment of various cranial nervous system diseases.

References
Y. Anraku, H. Kuwahara, Y. Fukusato, A. Mizoguchi, T. Ishii, K. Nitta, Y. Matsumoto, K.
Toh, K. Miyata, S. Uchida, K. Nishina, K. Osada, K. Itaka, N. Nishiyama, H. Mizusawa,
T. Yamasoba, T. Yokota, K. Kataoka, Glycaemic control boosts glucosylated
nanocarrier crossing the BBB into the brain. Nature Communications 8: 1001
（2017）

NanoSky VOL.04 DECEMBER 2017|9

Reserch
Highlights

2

Theme 2Development of Hetero-Duplex Oligonucleotide
to Regulate a Specific Gene far more Efficiently
than Previous Nucleic Acid Drugs

While antisense oligonucleotide and siRNA are known as major nucleic acid drugs that treat by regulating a
specific gene, we are developing hetero-duplex oligonucleotide with a different molecular structure and mechanismof action. Hetero-duplex oligonucleotide has far higher effects than those of previous nucleic acid drugs. It is amolecular technology with versatility that can strengthen the effects of existing antisense oligonucleotides. I am
making every effort in the research with my coworkers in the hope of enabling hetero-duplex oligonucleotide to be
used as an innovative therapy for intractable diseases without effective treatments.

Hiroya KUWAHARA
Research Assistant Professor,
Department of Neurology and Neurological
Science, Tokyo Medical and Dental University

Nucleic acid drugs such as antisense oligonucleotide*1
and siRNA (small interfering RNA)* 2 are expected to be
developed as innovative drugs for refractory diseases
such as cancers or genetic diseases. While antibody
drugs, the mainstream of current molecular targeted
therapy, have their target molecules limited on the cellular surface, nucleic acid drugs can also target intracellular molecules. Therefore, as promising candidates forthe next generation core molecular targeted therapy,
the development of nucleic acid drugs is broadly promoted by from academic basic research to clinical development by companies.
Antisense oligonucleotide is the most developed nucleic acid drug. In 1998, a drug for cytomegalovirus retinitis in patients with AIDS (fomivirsen, intraocular) wasapproved for marketing and manufacturing, as were
drugs for familial hypercholesteremia (mipomersen, subcutaneous) in 2013, and for Duchenne muscular dystrophy (eteplirsen, intravenous) and spinal muscular atrophy (nusinersen, intrathecal) in 2016. In this way, while
antisense oligonucleotide is developed energetically, further improvement is required in the chemical modification of nucleic acid and in vivo delivery, which significantly affect safety and efficacy.
We have developed a double-stranded artificial functional oligonucleotide hetero-duplex oligonucleotide(HDO) that consists of a DNA strand with about 12 to
20 bases (primary strand) and its complementary RNA(Fig. 1). Taking a gapmer form where locked nucleic acids (LNA) are allocated at both ends of the DNA strand,
the central part of the double-stranded strands forms
hetero DNA/RNA oligonucleotide, which is recognizedby an intracellular ribonuclease RNase H and the complementary RNA strand and the delivery ligand bound10 | NanoSky VOL.04 DECEMBER 2017

to it is cleaved (Fig. 2). As a result, the primary DNA
strand becomes single-stranded and is bound to the target RNA strand, and again RNase H cleaves the target
RNA to exert a gene-suppressing effect (Fig. 2). The
characteristic of our molecular technology is that RNase
H plays dual roles of cleaving the complementary RNA
strand and the target RNA strand, and the ligand cantherefore be attached to the complementary RNA
strand without affecting binding affinity of the primary
DNA strand.
Hetero-duplex oligonucleotide with vitamin E (α-tocopherol) bound to it as a ligand has an effect about 20
times as high as that of antisense oligonucleotide. In intravenous injection research in disease model mice for*3
familial amyloid polyneuropathy to examine the suppression of the target gene in the liver (transthyretin),
the antisense oligonucleotide suppressed the gene byabout 50%, while the hetero-duplex oligonucleotide suppressed it by about 99% (Fig. 3). Hetero-duplex oligonucleotide is also characterized by the versatility that significantly enhances the efficacy of existing antisense
oligonucleotides like this. In addition, molecules such as
lipids, antibodies, peptides, or sugar chains that regulate/enhance drug delivery can be bound to the end of
the complementary RNA strand. Therefore, hetero-duplex oligonucleotide can be considered to be a novel nucleic acid drug with a built-in drug delivery system.
For the development of hetero-duplex oligonucleotide,
Rena Therapeutics Inc., a venture company originatingfrom Tokyo Medical and Dental University, was established in January 2015. Hetero-duplex oligonucleotide is
expected to be used practically for various intractablediseases in clinical settings as the first novel nucleic aciddrug from Japan.

図 1 ヘテロ核酸の分子構造

1. Antisense oligonucleotide
Single-stranded DNA
LNA

Major nucleic acid drugs
1. Antisense
oligonucleotide
Figure 1. Molecular structure of hetero-duplex
oligonucleotide
Single-stranded DNA

図 1 ヘテロ核酸の分子構造

LNA

DNA

LNA

DNA

LNA

RNA

dTdT

2. siRNA (small interfering RNA)
Double-stranded RNA
RNA

LNA

dTdT

LNA

2. siRNA (small interfering RNA)
Double-stranded RNA

Major nucleic acid drugs
1. Antisense oligonucleotide
Single-stranded DNA

DNA

dTdT

RNA

3. Hetero-duplex oligonucleotide (HDO)
Double-stranded DNA/RNA
LNA

dTdT

RNA

DNA
RNA

LNA

3. Hetero-duplex oligonucleotide (HDO)
2. siRNA (smallinterfering(3)RNA)
Hetero-duplex
oligonucleotide
has a structureof double-stranded
DNA/
Double-stranded
DNA/RNA
Double-stranded
RNA, contrary
to antisense RNA
oligonucleotide (1) or siRNA (2).
RNA

DNA
RNA

3. Hetero-duplex oligonucleotide (HDO)

Double-stranded
DNA/RNA
Figure 2. Mechanismof actionof hetero-duplex
oligonucleotide

図 2 ヘテロ核酸の作用機序
LNA

DNA

家族性アミロイドポリニューロパチーのSuppressive
effect on target gene in the liver byintravenous
administration to disease model mice for疾患モデルマウスへの静脈投与によるfamilial amyloid
polyneuropathy
肝臓における標的遺伝子の抑制効果

Cell
LNA

DNA

LNA

RNA

3ʼ
LNA

図 3 ヘテロ核酸の効果

Figure 3. Effect of hetero-duplex oligonucleotide

LNA

RNA

5ʼ

LNA

DNA

RNA

3ʼ

5ʼ

RNA

LNA

LigandExpression level of transthyretin

dTdT

LNA

dTdT

RNA

LigandRNase H

LNA

DNA

LNA

Target RNA
RNase HSuppression of RNA expression

For hetero-duplex oligonucleotide, RNase H is assumed
to play dual roles of cleaving both the complementary
RNA strand and the target RNA strand in the cell.

1.2
1.0

50%

99%

suppress suppress
ion
ion

0.8
0.6
0.4
0.2
0.0

HeteroControl Antisense
oligonucleotide duplex
oligonucleotide

U s e of h ete ro - d u plex oligo n u cle otid e m a rke dly
potentiates the su p pressive ef fect of a ntisense
oligonucleotide on the target gene

Terminology＊1 Antisense oligonucleotide
Antisense oligonucleotide is a single-stranded DNA with a length of 12 to 30
bases with a sequence complementary to a specific messenger RNA (mRNA),and in a more limited sense, it has an inhibitory effect on translation to protein bybinding to the mRNA of the target gene. In a broader sense, its effects include theregulation of splicing targeting pre-mRNA (e.g., exon-skipping) and the regulationof gene expression targeting micro RNA (miRNA).
＊2 siRNA（small interfering RNA）
siRNA consists of about 20 to 25 base pairs and has a structure of doublestranded RNA with 2 extruding bases at the 3’ends. It causes the phenomenonof RNA interference (RNAi) where gene expression is suppressed by the specificcleavage of the target mRNA, resulting in a strong suppressive effect on gene
expression and high specificity to the target gene.

＊3 Familial amyloid polyneuropathy
Familial amyloid polyneuropathy is a sort of amyloidosis where amyloid (a proteinwith a fibrous structure) deposits in the general organs resulting in dysfunction.
It is an intractable disease significantly presenting peripheral or autonomic
neuropathy, mostly caused by transthyretin gene mutation.

References
K. Nishina, W. Piao, K. Yoshida-Tanaka, Y. Sujino, T. Nishina, T. Yamamoto, K.
Nitta, K. Yoshioka, H. Kuwahara, H. Yasuhara, T. Baba, F. Ono, K. Miyata, K.
Miyake, PP. Seth, A. Low, M. Yoshida, CF. Bennett, K. Kataoka, H. Mizusawa, S.
Obika, T. Yokota, DNA/RNA heteroduplex oligonucleotide for highly-efficient genesilencing. Nature Communications 6: 7969 (2015)

NanoSky VOL.04 DECEMBER 2017

| 11

iCONM Round-table Talk

iCONM Trainees Talk
about their Activities
Innovation Center of NanoMedicine (hereinafter referred to as iCONM),
the core institution of COINS, is not only a research institute but also offers training
opportunities for students. It is our mission to give students a chanceto personally develop through research activities at iCONM as a trainee as well.
On this occasion, we asked the trainees to talk about what they had learnt throughthe activities at iCONM, what they felt was important, and are where
they expect iCONM to work more actively in the future.
Facilitator/ Shigehito Osawa
Participants /Ai Kohata, Noriko Nakamura, Akitsugu Matsui, Takamasa Majima (Japanese alphabetical order)

It is nice that we are able
to openly consult with many
people about the research.
Osawa: Do you feel any difference between university and iCONM as a research institute?
Matsui: The rules for using the facilities
are stricter here than university, but still
it is not as strict as companies. We canflexibly make our own schedule for experiments. I think iCONM has both good
points of university and companies.
Kohata: I was surprised to see so many
open spaces. Unlike university labs thatare partitioned, iCONM has multiple labs
in the same space and the common spaces
are also substantial, so I feel that the discussion is easy to create.
Majima: Sharing results is also active
compared to universities, and I get a feeling that I am a member of a big project.
Matsui: It is friendly atmosphere and we
can discuss casually. We can get andshare idea on points and tasks of the experiment frequently and easily.
Nakamura: Compared to universities, theratio of postdoctoral fellows is high, andso it is very good to be able to talk about
experiments at any time.
Osawa: I agree. iCONM style that everyone is in one large room gives us advantages. For example, when discussions
start around me, various people gather,and I learn a lot from them. I sometimes
feel pressure that I can’t say the wrong
thing, haha. But I think this tension-filled
discussion is a good training. Kohata sanand Majima san have joined iCONM lately. Could you tell me what kind of impression you have for iCONM?
Kohata: I was nervous to enter iCONM
at first because there are a diversity ofpeople.That is too different from traditional Japanese universities. Moreover, I feel
12 | NanoSky VOL.04 DECEMBER 2017

the security and professionalism are excellent here. We need a license card forentering and leaving the building.
Majima: I am learning techniques for using the in vivo confocal laser microscope
at iCONM and this started to benefit
works in our institute, too. There aremany open spaces in iCONM like themagnet area where we are talking now. It
is easy to come, isn’t it?
When physicians who worked in a hospital or a clinic like me want to obtain phD.,
their motivation may be getting good results in lab research and completing a dissertation to acquire the degree, but they
may not think well how their research
will contribute to society. In contrast, researches at iCONM have a clear objectiveof implementing“in-body hospitals”. By
joining iCONM research, I think we are
motivated well because purpose of research, our attitude and what we should
do are clarified without the singular purpose of acquisition of a degree.

It became easier to image acarrier after the graduate
schoolOsawa: Nakamura san and Matsui san,you have the desks in iCONM and you
are engaged in research as a full-timetrainee. Could you tell me your first impression , a nd current impression of
iCONM?
Nakamura: I came to iCONM only to use
experimental equipment at first. At thattime, my impression of iCONM is excellent facility having great equipment, thatall. Now, I feel iCONM activities expand
my research by collaborating with otherresearch groups working on similar nanomachines to my research topic. We aresharing results and establishing new experiments through demonstration of novel

Shigehito OSAWA
Research Scientist,
Kawasaki Institute of Industrial Promotion
Innovation Center of NanoMedicine
Earned a doctorate at Kataoka Kazunori
laboratory of Department of Materials
Engineering, Graduate School of Engineering,
The University of Tokyo. At the time ofProfessor Kazunori Kataoka’s retirement, hejoined iCONM as a postdoctoral fellow. He
is the youngest research scientist at iCONM.
His research field is polymer synthesis;
researching DDS micelles.

machines together, etc.
Osawa: You have good impression on
hardware of iCONM good, and you have
gradually got good impression on software of iCONM. Matsui san, you havebeen helping us to set up laboratories.
Matsui: When I came first, I thought I
could conduct experiment immediately,
but actually I couldn’t because the environment was immature. Currently, I havean impression that it finally became wellorganized experimental place by our effort of maintaining and adjusting theequipment and all kinds of advice about
environments from other researchers. In
order to further improve usability, I would
like people coming from outside to give acomment on our institute; it is really a
progressive learning environment!
Osawa: At iCONM, we ask trainees to dowork such as management of experimental equipment. We believe that having a
job with responsibility is also good training for students. Now, do you actually feelthat doing research at iCONM would be
useful for your future carrier?
Kohata: Most of the people here havehigher position than post-doctoral fellows.
This is excellent for me to look for a rolemodel and/or mentor as a researcher.
There are diverse teams with many female researchers and I can talk withthem about balancing family, research,and my future carrier. It is very helpful
for me.
Nakamura: For example, it is not easy to
imagine how our research could be translated and profitably applied to product inthe market when we only think about our
research from the narrow student's standpoint. But when I am in iCONM, it will
become easier to draw out the future vision of my work through learning manystories about how companies are advancing concretely towards commercialization.

Ai KOHATA

Noriko NAKAMURA

Akitsugu MATSUI

Takamasa MAJIMA

Trainee
M1 Takuzo Aida Laboratory, Departmentof Chemistry and Biotechnology, Graduate
School of Engineering, The University ofTokyo
She is engaged in DDS research that has
target direction by producing polymer coating
the surface of siRNA. For evaluating thepolymer made by herself in vitro and in vivo ,Prof. Takuzo Aida recommended her tocollaborate with Prof. Kazunori Kataoka’sgroup .She has just started her research at
iCONM.

Trainee
M2 Horacio Cabral Laboratory, Departmentof Bioengineering, Graduate School ofEngineering, The University of Tokyo
She is engaged in research looking to
improve the function of the nanomachine
targeting the brain. She attends iCONM asa trainee from this fiscal year, and conducts
various experiments from polymer synthesis
in vitro and in vivo.

Trainee
D4 Internal Medicine, Graduate School of
Medicine, The University of Tokyo
He has been studying therapeutic nucleic
acid at Prof. Keiji Itaka Group. He got
master degree at Prof. Kazunori Kataoka’sgroup. When the Prof. Kataoka lab. moved
to iCONM, he moved to Prof. Itaka lab. at
iCONM and he is continuing his research asa trainee.

Trainee
D2 Department of Neurology and
Neurological Science, Tokyo Medical and
Dental University
He entered the graduate school after working
as a neurologist for five years. Now he isengaged in research of therapeutic nucleic
acid delivery system and vascular endothelial
imaging., He is acquiring the in vivo confocal
laser microscope skills at iCONM, which isnecessary for DDS research of the nucleic
acid delivery.

Matsui: Furthermore, I think it will become an even better environment for us
to study if we are able to build up collaboration and cooperation with neighboringother research institutes such as National
Institute of Health Sciences and Central
Institute for Experimental Animals. It is
practically useful if we, students can learn
about social regulations and use it for our
future research.
Osawa: Social regulations may delaytranslation of your research into practicaluse. With knowledge that some specificchemicals cannot use for medicines, you
may be able to set up a research plan
more effectively.
Matsui: Majima san, from the point ofview of a physician, do you think that students and postdoctoral researchers shouldhave a mind to conduct research aimed atclinical trials?
Majima: Well, I think that it is necessary
to grasp the situation from a broader perspective of which stage the research is in
now.
Kohata: When I was engaged in researchof chemical synthesis, I was only concentrating on short-term experiments and I
had never thought about whether it could
be used clinically. However, after discussing with Prof. Kataoka, Director-Generalof iCON M , my way of t h inking haschanged to make something to advance toclinical use. I felt that there was a large
gap between disciplines.
Nakamura: When I was undergraduate,
my purpose were studying towards graduation and writing a thesis. When I was
asked how useful my research was, I
could answer but I did not think so deeply. Here I can learn about research that isclose to practical use, and with thisknowledge, I can easily assume potential
benefits of my research and which stage
my research is in now.

Osawa: Since iCONM is the core institution of COINS and can collaborate withmany universities / research institutes
and companies, I hope everyone also
shares information and develops broad research networks to accumulate the necessary context and knowledge for future innovation.

Students can also work in a place
where companies and universities
are mixed-“Under the one roof”
Osawa: Finally, do you have any requests
to iCONM?
Matsui: May be rent subsidy? It takes 15
mins from Kojimashinden station on foot,I am doing my best though….
Osawa: I agree. Usually, universities arelocated with good access, aren’t they? I
heard there are plans to improve public
transportation around the iCONM. I think
it will be improved soon.
Nakamura: I work in iCONM everyday.
So I know what devices are available andwhat I can do, but outside people do notknow such information. If the information
was more readily available, students canbe more motivated and actively come to
iCONM.
Kohata: I didn’t know anything about
iCONM either. I happened to know about
iCONM when I was searching Prof. Kataoka on the internet, but I couldn’t understand the relationship with Kawasaki cityand the COI program, and detailed formations etc.
Matsui: I think that it will be difficult for
students to come up with ideas to work inplaces where enterprises and universities
are mixed without opening more information on iCONM and its concept.
Osawa: I see. People do not know iCONM
well and this is a psychological barrier in
addition to the physical distance problem.
This makes it difficult for students totravel to iCONM.
For more students to use iCONM as aplace for research and study, it is necessary to transmit information on, for example, what kind of experiment we can doon the webpage in an easy-to-understandmanner in addition to the concept andgoal of research.
Thank you for your comments.

NanoSky VOL.04 DECEMBER 2017

| 13

ACTIVITY REPORT
8th General Meeting
The 8th General Meeting was held in the main conference room

discussed future guidelines and issues to overcome. Further,at the Life Science & Environment Research Center (LiSE) on

regarding utilization of researcher information filing tool "Pure"

Friday, June 2, 2017. This meeting is held semi-annually with all

system, Ms. Yoshiko Kakita from Elsevier B.V. gave presentation

participating institutions. COINS entered the second year ofand confirmed the effectiveness of using filing tool.

Phase 2 (Fiscal year 2016 - 2018) and Tokyo Science University,
AccuRna, Inc. and Brazison Therapeutics Inc. newly joined and a

In poster session, active discussion and exchange of information
were carried out among researchers with 35 posters.

system for accelerating R&D and social implementation has been

Finally, we had valuable advice from Dr. Tatsuro Irimura, COINS

in place. This time, under the theme of selection andAdvisor and Project Professor of Juntendo University, Mr. Toshio

concentration for realizing COINS' vision "Realization of in-body

Asano, Standing Counsellor of Asahi Kasei Co., Ltd. such as“For

hospitals", we aimed to take the opportunity to review all efforts

using a completely new viewpoint and approach to the project, wefrom the viewpoint of differentiation and advantage from theexpect especially young researchers to raise antenna to daily

existing technology. Thus, both theme leaders and participatingtasks”, the meeting became very meaningful to strengthen further

organizations gave presentation on research outcome andunity towards "Realization of in-body hospitals". You need toafterwards there was a panel discussion with presenters.

prepare that innovation inevitable takes long time, it is important

In the panel, they discussed on the theme of "Future

to deepen collaboration between companies and academia, butdevelopment of R&D for realization of in-body hospitals”andalso to fulfill each one of respective roles"How to connect outcome to social implementation”, and we

firmly along the way. As the first attempt at
this time, under the cooperation of theCentral Institute for Experimental Animals(CIEA) of the participating institution, CIEA
lab. tour was conducted for those who wereinterested. Visitors seemed to be thinking
about the next step of research whilelooking around valuable animal laboratory Tatsuro Irimuraand experimental equipment such as
marmosets that are not usually seen.

Project Professor, Juntendo
University

The meeting was a very meaningful which
could foster an atmosphere to further

Lively panel discussion

strengthen unity and accelerate towardrealization of in-body hospitals.

Toshio Asano

Standing Counsellor, Asahi
Kasei Co., Ltd.

Lecture by Ms. Yoshiko Kakita from Elsevier B.V.

Topics

December 2016 – June 2017◦12.14.2016【Activity】Newsletter「NanoSky vol.2」was published.
◦12.15.2016【Activity】The 3rd COINS International Symposium was heldat Kawasaki City Industrial Promotion Hall.
◦12.24.2016【News】The article about Prof. Nobuhiro Nishiyama, Laboratory for Chemistry and Life Science, Institute of Innovative Research,
Tokyo Institute of Technology (COINS Theme 5 leader) was appeared in
Nikkei Science 2017 Feb. issue under the title of“Drug delivery with highfunction nanomachines”◦1.13.2017【News】Introduction of Innovation Center of NanoMedicine

14 | NanoSky VOL.04 DECEMBER 2017

Lab. Tour of the Central Institute forExperimental Animals (CIEA)(iCONM) which is a core research center of COINS and interview of Prof.
Kazunori Kataoka, iCONM Director General (COINS Research leader)
was appeared in life style magazine“My way”commemorative Issue vol.
100 (Published by Hamagin Institute of Industrial Promotion). The title is“No side effect from targeting a cancer and practical use is at hand”.
◦1.16.2017【News】Special Issue: Macromolecular Bioscience (Volume
17, Issue 1, 2017) was published under the title on ”Special Issue: Dedicated to Kazunori Kataoka on the Occasion of his 65th Birthday”.
◦1.17.2017【Activity】COINS Seminar #23 was held at iCONM.
Lecturer: Prof. Ulrich S. Schubert（Laboratory of Organic and Macromo-

Activity Reportlecular Chemistry, Jena Center for Soft Matter, Friedrich Schiller University Jena）
Title：“Engineering pharmaceutical polymers and nanoparticle libraries”◦1.19.2017【Activity】COINS Seminar #24 was held at iCONM.
Lecturer: Prof. Mark E. Davis（Chemical Engineering, California Instituteof Technology）
Title：“Nanoparticle Therapeutics: From Concept to Clinic”◦1.26.2017【Activity】The 7th COINS General Meeting was held.
◦1.31.2017【News】Interview of Dr. Takanori Ichiki, Professor, Dept. ofMaterials Engineering, Graduate School of Engineering, The Universityof Tokyo (COINS Theme 4 leader) was introduced in Tokyo Electron web
Magazine "TELESCOPE Magazine" No.13 under the title of“Downsize
complete examination function of major hospital and detect diseases at
early stage”◦2.8.2017【Appoint】National Academy of Engineering (NAE) announced
newly elected members this year on February 8, and Kazunori Kataoka(Director General of iCONM, Kawasaki Institute of Industrial Promotion,
the Research Leader of COINS, Professor Emeritus, The University ofTokyo) was elected as a foreign member (NAE) for his pioneering contributions to the design of supramolecular nanostructures and their application to drug and gene delivery. Appointment ceremony will be held at the
National Academy's Headquarters in Washington DC, USA on October 8
this year.
◦2.15.2017【Activity】ASEAN Young Officers from Invitation Program of
JST visited iCONM.
◦2.22.2017【News】Prof. Kataoka Kazunori, COINS research leader'sinterview video was delivered on 10MTV Opinion. The delivery will be 5times in total from 2/22 (Wednesday) every other week.

Head, Section for Studies on Metastases Cancer Center Research Institute (COINS Theme 4) was published in Nikkei online and p.31 in Nikkei
Morning paper. The title was "Let's search the criminal who is causing arecurrence of cancer".
◦4.12.2017【Award】 Dr. Yasutaka Anraku, Assistant Professor, Department of Bioengineering, Graduate School of Engineering, The Universityof Tokyo (COINS Theme 2 Leader) was awarded The Young Scientist’s Prize for The Commendation for Science and Technology 2017 by the
Minister of Education, Culture, Sports, Science and Technology.
◦4.14.2017【Award】 Director General, Dr. Kazunori Kataoka was awarded to the 34th H. C. Brown Lecturer at Purdue University, USA.
◦4.21.2017【Activity】 The COINS Seminar #25 was held at iCONM at
16:00 – 17:00.
Speaker: Dr. Yuji Tanaka (Researcher, Riken)"An Engineering trial for eyes disease."◦5.17.2017【News】Article related to research of Dr. Shuhei Murayama,
Dept. of Molecular Imaging and Theranostics, National Institute of Radiological Sciences was published in Nikkan Kogyo Shimbun p.29 and Nikkan Kogyo online. The title is "Researcher who open the way".
◦5.17.2017【News】Articles related to research of Dr. Takahiro Ochiya,
National Cancer Center were published in Nikkei online and p.3＆p.26 in
Nikkei Morning paper. The title was "Cancer treatment Kaitai Shinsho (3)Cell garbage bag - actually a cause".
◦5.26.2017【Award】 Dr. Chika Sato, Dr. Ichio Aoki and others, NIRS,QST (COINS Theme 5) were selected for The Best Poster Presentation
Award from 12th Japanese Society for Molecular Imaging.
◦5.28.2017【News】Article related to research conducting at COINS andinterview with Dr. Kazunori Kataoka, COINS Research Leader, Dr. Yasuhiro Matsumura, Chief, Investigative Treatment Division, Research Center
for Innovative Oncology, National Cancer Center Hospital East (COINS
Theme 1) and Dr. Nobuhiro Nishiyama, Professor, Institute of Innovative
Research, Tokyo Institute of Technology were published in Yomiuri Shimbun p.34. The title is "Drug delivery directly to cancer cells".
◦5.29.2017【News】Articles related to development plan of KING SKYFRONT and iCONM were published in Kanagawa Shimbun p. 1 and Kanakoro Kanagawa Shimbun Web. The title was“Life Science Center headingfor new stage Kawasaki Tonomachi - Town will be completed within thisfiscal year”.

◦2.27 - 2.28. 2017【Activity】11th Annual Symposium on Nanobiotechnology organized by Kawasaki Institute of Industrial Promotion was held.
◦3.10.2017【Award】Mr. Daiki Sueyoshi, Cabral Lab. Dept. of Bioengineering, Graduate School of Engineering, The University of Tokyo, received Dean's Award from Graduate School of Engineering.
◦3.13.2017【News】 Articles related to the research of Professor Yoshihiro Muragaki, Faculty of Advanced Techno-Surgery, Institute ofAdvanced Biomedical Engineering and Science, Tokyo Women's Medical
University (COINS Theme 5) were posted on the Nihon Keizai Shimbun
electronic version and the Nihon Keizai Shimbun Morning edition p. 11.
The title was "Development of Pancreatic cancer therapy with molecules
and ultrasonic wave.
◦3.20.2017【Activity】COINS Newsletter Vol.3 was published.
◦3.28.2017【News】Dr. Kazunori Kataoka, Director General, iCONM appeared in 'Front-Line Medicine' of "Flood of appointments! Amazing doctors at special outpatient!!" on TBS.
◦3.29.2017【News】Articles related to the research of Professor Yoshihiro Muragaki, Faculty of Advanced Techno-Surgery, Institute ofAdvanced Biomedical Engineering and Science, Tokyo Women's Medical
University (COINS Theme 5) were appeared in Nikkei online and p.11 in
Nikkei Morning paper. The title is "Anticancer agent × ultrasound clinicalstudy”.

◦5.31.2017【Award】Mr. Sotaro Kuroyanagi, D1, Tokyo Institute of Technology (COINS Theme5), Mr. Naoto Nakamura, M2, The University ofTokyo (COINS Theme1) and Mr. Naoto Yoshinaga, M2, The University ofTokyo (COINS Theme1) receive Poster Awards from 66th SPSJ Annual
Meeting.
◦6.1.2017【Award】Dr. Kanjiro Miyata, Visiting Research Scientist (Associate Professor, The University of Tokyo) received The Nucleic Acids
Therapeutics Society of Japan (NatsJ) Award for Young Scientists.
◦6.2.2017【Activity】The 8th COINS General meeting was held. (p. 14 inthis issue)◦6.14.2017【Activity】Mr. Yoichi Ito, Chief, The Science and Technology
Policy Bureau of Ministry of Education, Culture, Sports, Science andTechnology (MEXT) and 7 others visited iCONM and COINS.
◦6.26.2017【News】Angewandte Chemie International Edition (Publishedby German Chemical Society) carries an article about selection of Prof.
Kazunori Kataoka, Director General of iCONM, to foreign member ofUnited States National Academy of Engineering. The title is“News: New
Members and Foreign Members of the National Academy of Engineering”.
◦6.26.2017【Activity】The iCONM information delivery system was ready.
The information of events of COINS or/and iCONM and related projects(seminars, symposium etc.) were sent by email. Please register on line via
COINS or iCONM homepage.
◦6.29.2017【Award】Mr. Naoto Nakamura (Trainee of iCONM, The University of Tokyo, Cabral Lab.) received Poster Awards from the 70th Annual Meeting of Society for Free Radical Research Japan.

◦4.7.2017【News】Article related to research of Prof. Takahiro Ochiya,

NanoSky VOL.04 DECEMBER 2017| 15

Editor’s NoteThe“in-body hospitals”that COINS seeks is a future visionof medical care that enables the support of health without
mental and physical burden. The key to achieving this is thecreation of“smart nanomachines”that circulate in the body 24hours a day to detect, diagnose and treat disease autonomously.
In the present issue, Theme 2 significantly handles thetechnical development of nanomachines to allow them to run
through the body.
Our bodies have various barrier systems to protect us fromexternal enemies and foreign bodies and sustain homeostasis.
Among these biological barriers, the most difficult one for
substances to pass is the blood-brain barrier (BBB) in the brain.
So, in Theme 2, treatments effective for cranial nervous systemdiseases are being developed under the mission of“deliverdrugs into the brain beyond the BBB”and venture companies
h ave b e e n e s t a b lis h e d i n o rd e r to p ro c e e d to s o cia l
implementation. For details, see the Talk about Theme 2 (p. 2)
and Research topics 1 (p. 8).
In Theme 2, the research and development of a novel nucleic
acid drug “hetero -duplex oligonucleotide” has also been
advanced. As hetero-duplex oligonucleotide has a higher
therapeutic effect than previous antisense nucleic acids andsiRNA, it is expected to be applied to treatment for cranial
nervous system diseases by being mounted in the nanomachine.
For details, see Researcher’s interview (p. 6) and Research
topics 2 (p. 10).
It is said that innovative drug discovery requires a period aslong as several dozen years. Where and how human resources
for the future are fostered is an issue. In the iCONM Roundtable talk (p. 12), we asked the future researchers engaging inresearch at the Innovation Center of NanoMedicine (iCONM) to
talk casually about activities and human resource development
in iCONM. You may see the cheerful and positive young
researchers.
Dr. Kazunori Kataoka, Research Leader of COINS, wasappointed as a foreign associate of the U.S. National Academyof Engineering. Being selected as an associate is the greatest
honor in the field of engineering. This is a result of theappreciation of his life-long performance. Congratulations! In
addition, iCONM is holding COINS seminars, inviting Professor
Mark E. Davis, California Institute of Technology and othereminent researchers as speakers (topics p. 14). For the detailsof the seminars, sign up at Information or Information Provision
pages on the COINS website.
The subject in the next issue is“the development of medical
care-machine combination device for single day treatment ofcancer”in Theme 5 and will be published in March 2018. I
hope you look forward to this.
Finally, we are most grateful to those who were willing tocooperate in the publication of this newsletter despite their busy
schedules.
Chief Editor: Takashi Sugimoto

4

Edited by NanoSky Editorial Board (Takashi SUGIMOTO, Yasutaka
ANRAKU, Hiroya KUWAHARA, Shigehito OSAWA, Yuki MOCHIDA)
Writer： Ayumi KOJIMA
Camera: Aki TANAKA
Design: Studio L Co., Ltd.
Copyright: KAWASAKI INSTITUTE OF INDUSTRIAL PROMOTION

Vol.

Published by Center of Open Innovation Network for Smart Health (COINS),
Innovation Center of NanoMedicine (iCONM),
KAWASAKI INSTITUTE OF INDUSTRIAL PROMOTION,
3-25-14, Tonomachi, Kawasaki-ku, Kawasaki City, Kanagawa Pref. JAPANTEL: +81 44 589 5785 / FAX: +81 44 589 5789
http://coins.kawasaki-net.ne.jp/