DataVXACS Applied Materials & InterfacesPaper
journal article·2022-09-14

Multifunctional Therapeutic Cyclodextrin-Appended Dendrimer Complex for Treatment of Systemic and Localized Amyloidosis

Masamichi Inoue, Taishi Higashi, Yuya Hayashi, Risako Onodera, Kazuya Fujisawa, Toru Taharabaru, Ryoma Yokoyama, Kenta Ouchi, Yohei Misumi, Mitsuharu Ueda, Yasuteru Inoue, Mineyuki Mizuguchi, Takashi Saito, Takaomi C. Saido, Yukio Ando, Hidetoshi Arima, Keiichi Motoyama, Hirofumi Jono

ACS Applied Materials & Interfaces· Volume 14· Issue 36
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Source abstract

Abstract

Amyloidosis pathologically proceeds via production of amyloidogenic proteins by organs, formation of protein aggregates through structural changes, and their deposition on tissues. A growing body of evidence demonstrates that amyloidosis generally develops through three critical pathological steps: (1) production of amyloid precursor proteins, (2) amyloid formation, and (3) amyloid deposition. However, no clinically effective therapy that is capable of targeting each pathological step of amyloidosis independently is currently available. Here, we combined therapeutic effects and developed a short hairpin RNA expression vector (shRNA) complex with a cyclodextrin-appended cationic dendrimer (CDE) as a novel multitarget therapeutic drug that is capable of simultaneously suppressing these three steps. We evaluated its therapeutic effects on systemic transthyretin (ATTR) amyloidosis and Alzheimer’s disease (AD) as localized amyloidosis, by targeting TTR and amyloid β, respectively. CDE/shRNA exhibited RNAi effects to suppress amyloid protein production and also achieved both inhibition of amyloid formation and disruption of existing amyloid fibrils. The multitarget therapeutic effects of CDE/shRNA were confirmed by evaluating TTR deposition reduction in early- and late-onset human ATTR amyloidosis model rats and amyloid β deposition reduction in AppNL-G-F/NL-G-F AD model mice. Thus, the CDE/shRNA complex exhibits multifunctional therapeutic efficacy and may reveal novel strategies for establishing curative treatments for both systemic and localized amyloidosis.
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Research context

Materials processing

OpenAlex topics: Ocular Surface and Contact Lens

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan

Program for Leading Graduate Schools “Health Life Science: Interdisciplinary and Glocal Oriented (HIGO) Program”, Kumamoto University, Kumamoto 862-0973, Japan

Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan

Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan

Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan

Department of Amyloidosis Research, Nagasaki International University, 2825-7 Huis Ten Bosch-machi, Sasebo-shi, Nagasaki 859-3298, Japan

Laboratory of Evidence-Based Pharmacotherapy, Daiichi University of Pharmacy, 22-1 Tamagawa-machi, Minami-ku, Fukuoka 815-8511 Japan

Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

Funding

Daiichi-Sankyo · Japan Society for the Promotion of Science

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