Newsletter Volume 38, Number 1, 2023

Comments from the Award Winners


On receiving the Best Poster Award

Research Pharmacokinetics Laboratory, Takeda Pharmaceutical Company Limited
Miyu Nakayama

 We are pleased to announce that we received the Best Poster Award at the 37th Annual Meeting of the Japanese Society of Pharmacokinetics for our presentation entitled “State-of-the-art light-sheet microscopic imaging of a whole-brain with tissue clearing technique: Comprehensive I received the Best Poster Award for the presentation entitled “State-of-the-art light-sheet microscopic imaging of a whole-brain with tissue clearing technique: Comprehensive analysis of brain distribution for antisense oligonucleotides. I am honored to receive such a prestigious award. I would like to express my sincere gratitude to the selection committee members and all the people involved in the Japanese Society of Pharmacokinetics and Pharmacodynamics.

 Intrathecal (IT) administration of antisense oligonucleotide (ASO) is commonly used in clinical practice for the treatment of central nervous system diseases. In studies using small animals such as rodents, intracerebroventricular (ICV) administration is sometimes used because IT administration is technically difficult. In general, the intracerebroventricular distribution of ASO after IT and ICV administration is evaluated by three-dimensional imaging using positron emission tomography or cryo-fluorescence tomography, or two-dimensional imaging on tissue sections using confocal microscopy. However, their distribution in the brain and excretion mechanisms, as well as their species differences, have not been fully elucidated due to technical problems such as insufficient spatial resolution and limited observation area. Recently, whole brain imaging at the single cell level has become possible due to the remarkable progress of light-sheet fluorescence microscopy and tissue transparency techniques. However, there has been no application to the brain distribution of ASO. In this study, we aimed to construct a whole-brain drug distribution evaluation platform with high spatial resolution using these technologies, and to clarify the intracerebral distribution, excretion mechanism, and species differences of ASOs.

 After a specified period of time, brains were harvested, transparency was applied, and three-dimensional imaging of immunostained cerebral blood vessels and fluorescent nucleic acids was performed using a light-sheet microscope. As a result, we succeeded in visualizing the cerebrovascular network and ASO localization in the whole brain, and revealed the following three new findings. (1) IT- and ICV-infused ASOs are distributed in the brain along the cerebrospinal fluid flow in the periarterial space by the glymphatic system. (2) The brain distribution pattern described in (1) is conserved between rodents and primates across species. The intramural peri-arterial drainage pathway may be involved in the elimination of ASO, since ASO administered into the brain parenchyma is rapidly distributed into the surrounding peri-arterial space, whereas ASO distribution was not observed in the peri-arterial space. These are the mechanisms of ASO distribution in the brain. These findings provide new insights into the mechanism of ASO distribution in the brain and may be useful for future ASO drug discovery.

 In this study, we succeeded in establishing an evaluation platform for drug distribution in the whole brain. Compared to conventional methods, this platform is superior in that it can comprehensively evaluate drug distribution in tissues with high spatial resolution. This platform can be applied to the evaluation of drug distribution in treatment modalities other than ASO, and will be widely used in future drug distribution research.

 Finally, we would like to take this opportunity to express our sincere gratitude to Misato Mori, Hiroshi Watanabe, Yuko Haidani, Ayaka Kusanagi, Hideki Hirabayashi, Akihiko Goto, Shunsuke Yamamoto, and Takeda Pharmaceutical Company Limited Pharmacokinetics Research Laboratories, who conducted the research with us, and for their guidance and support.