Faculty of Pharmaceutical Sciences
Validation of therapeutic strategies using mitochondrial drug delivery systems
Yuma Yamada1,2* and Hideyoshi Harashima112Fac. of Pharm. Sci., Hokkaido Univ., Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, JapanJST Fusion Oriented REsearch for disruptive Science and Technology (FOREST) Program, Japan
E-mail: u-ma@pharm.hokudai.ac.jp

It is now well accepted thatmitochondrial dysfunctions are
implicated in a variety of diseases,
includingneurodegenerativediseases, cancer and a variety ofinherited mitochondrial diseases.
Because of this, mitochondria
represent a promising therapeutic
drug target, and mitochondrial therapy would be expected to be useful for the treatment of suchdiseases. To achieve such an innovative therapy, it will be necessary to deliver therapeutic agents tothe interior of mitochondria. A number of mitochondrial drug delivery systems (DDS) have beenreported during the past decade, but only a limited number of these are actually available inmitochondrial therapy. This is because these strategies face many problems including cellinternalization, limitations in the size and the physicochemical properties of the cargos, modificationof a functional device, and the denaturation of the cargoes. We recently reported on the developmentof a MITO-Porter, a liposome-based carrier that can be used to introduce macromolecular cargos into
mitochondria via membrane fusion (Y. Yamada et al, Biochim Biophys Acta 1778: 423-432 (2008), Y.
Yamada et al, Adv. Drug. Deliv. Rev. 154-155:187-209 (2020)). We are hopeful that this MITO-Portercan be used to deliver a wide variety of carrier-encapsulated molecules to mitochondria. Based on ourprogress to date regarding the use of the MITO-Porter for mitochondrial DDS, we are currently in theprocess of expanding collaborative research targeting mitochondria with researchers and cliniciansfrom various fields. In this presentation, we summarize the current state of mitochondrial DDS
focusing on our research and show some examples of the use of mitochondrial DDS for regulating
mitochondrial function. These studies include the fields of mitochondrial gene therapy, with a focus
on mitochondrial RNA therapy in mitochondrial diseased cells using a MITO-Porter. These recent
studies demonstrated that the MITO-Porter system could be useful for the delivery of all three typesof RNA encoded by mtDNA: tRNA (E. Kawamura et al, Mol. Ther. – Nucleic Acids 20: 687-698(2020)), mRNA (Y. Yamada et al, Sci. Rep. 10: 7511 (2020)) and rRNA (Y. Yamada et al,Mitochondrion 55: 134-144 (2020)). We are currently in the process of studying mitochondrial DDS
that are directed toward the development of mitochondrial nano medicines. We hope that these studies
will open new research areas in mitochondrial DDS and will have a significant impact on the medicaland life sciences.
Yuma YAMADA is an Associate Professor in the Faculty of Pharmaceutical Sciences,
Hokkaido University and a Pharmacist in the Department of Pharmacy, Hokkaido
University Hospital. He received his B.S., M.S. and Ph.D. degrees from Hokkaido
University in 2003, 05 and 08, respectively. After serving as an Instructor in the Facultyof Pharmaceutical Sciences, Hokkaido University in 2007, he was promoted to the rankof Assistant Professor and Associate Professor in 2009 and 16, respectively. His main
research interest is the development of mitochondrial DDS, nanoparticle packaging forvarious cargos (protein, nucleic acids, etc.), gene and cell therapy and nano design ofpharmaceutics for organelle targeting.