Inability of α-cyclodextrins to accommodate cholesterol potentially underlies their lack of efficacy and ototoxicity in Niemann-Pick disease type C treatment
Abstract Niemann-Pick disease type C (NPC) is a life-threatening neurodegenerative disease caused by impaired intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for treating NPC, but its ototoxicity rem...
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Nature Portfolio
2025-08-01
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| Online Access: | https://doi.org/10.1038/s41598-025-15599-0 |
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| author | Yusei Yamada Mayuko Tanaka Yusei Ikeda Yuki Kondo Toru Takeo Naomi Nakagata Toru Miwa Hiroki Takeda Yorihisa Orita Keiichi Motoyama Taishi Higashi Hidetoshi Arima Takahiro Seki Yuki Kurauchi Hiroshi Katsuki Katsumi Higaki Kotaro Matsusaka Kentaro Minami Naoki Yoshikawa Ryuji Ikeda Muneaki Matsuo Tetsumi Irie Yoichi Ishitsuka |
| author_facet | Yusei Yamada Mayuko Tanaka Yusei Ikeda Yuki Kondo Toru Takeo Naomi Nakagata Toru Miwa Hiroki Takeda Yorihisa Orita Keiichi Motoyama Taishi Higashi Hidetoshi Arima Takahiro Seki Yuki Kurauchi Hiroshi Katsuki Katsumi Higaki Kotaro Matsusaka Kentaro Minami Naoki Yoshikawa Ryuji Ikeda Muneaki Matsuo Tetsumi Irie Yoichi Ishitsuka |
| author_sort | Yusei Yamada |
| collection | DOAJ |
| description | Abstract Niemann-Pick disease type C (NPC) is a life-threatening neurodegenerative disease caused by impaired intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for treating NPC, but its ototoxicity remains problematic. We previously reported that β- and γ-forms of cyclodextrin (CD) derivatives with various substituents capable of accommodating/solubilizing unesterified cholesterol (UC) exerted more pronounced therapeutic and ototoxic effects when administered intracerebroventricularly than subcutaneously for NPC treatment. However, the impact of substituent variations on these effects is unconfirmed for cyclic hexasaccharides, α-CD derivatives. Here, we investigated these effects for α-CD derivatives with various replaced substituents from the perspective of their interaction with UC. Even when administered intracerebroventricularly, a representative α-CD derivative had no impact on survival in NPC model mice. The normalization of intracellular cholesterol trafficking in NPC model cells and the auditory dysfunction in wild-type mice, both caused by HP-β-CD, were not seen for the α-CD derivatives, regardless of their substituent variations. Solubility and molecular simulation analyses showed negligible UC-solubilizing ability of α-CD derivatives because of their insufficient capacity to accommodate the UC molecule, rather than their substituent variations. These results underscore the importance of UC accommodation by CD for both efficacy and ototoxicity in NPC treatment. |
| format | Article |
| id | doaj-art-6ece602c89b34360a2ea2a02c6eeacfb |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-6ece602c89b34360a2ea2a02c6eeacfb2025-08-24T11:31:05ZengNature PortfolioScientific Reports2045-23222025-08-0115111010.1038/s41598-025-15599-0Inability of α-cyclodextrins to accommodate cholesterol potentially underlies their lack of efficacy and ototoxicity in Niemann-Pick disease type C treatmentYusei Yamada0Mayuko Tanaka1Yusei Ikeda2Yuki Kondo3Toru Takeo4Naomi Nakagata5Toru Miwa6Hiroki Takeda7Yorihisa Orita8Keiichi Motoyama9Taishi Higashi10Hidetoshi Arima11Takahiro Seki12Yuki Kurauchi13Hiroshi Katsuki14Katsumi Higaki15Kotaro Matsusaka16Kentaro Minami17Naoki Yoshikawa18Ryuji Ikeda19Muneaki Matsuo20Tetsumi Irie21Yoichi Ishitsuka22Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto UniversityDepartment of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto UniversityDepartment of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto UniversityDepartment of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto UniversityDivision of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto UniversityDivision of Reproductive Biotechnology and Innovation, Center for Animal Resources and Development (CARD), Institute of Resource Development and Analysis, Kumamoto UniversityDepartment of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto UniversityDepartment of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kumamoto UniversityDepartment of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kumamoto UniversityDepartment of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto UniversityDepartment of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto UniversityCenter for Advanced Pharmaceutical Data Research, School of Pharmacy, Daiichi University of PharmacyDepartment of Pharmacology, Faculty of Pharmaceutical Sciences, Himeji Dokkyo UniversityDepartment of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto UniversityDepartment of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto UniversityResearch Initiative Center, Organization for Research Initiative and Promotion, Tottori UniversityDepartment of Pharmacy, University of Miyazaki HospitalDepartment of Pharmacy, University of Miyazaki HospitalDepartment of Pharmacy, University of Miyazaki HospitalDepartment of Pharmacy, University of Miyazaki HospitalDepartment of Pediatrics, Faculty of Medicine, Saga UniversityDepartment of Pharmaceutical Packaging Technology, Faculty of Life Sciences, Kumamoto UniversityDepartment of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto UniversityAbstract Niemann-Pick disease type C (NPC) is a life-threatening neurodegenerative disease caused by impaired intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for treating NPC, but its ototoxicity remains problematic. We previously reported that β- and γ-forms of cyclodextrin (CD) derivatives with various substituents capable of accommodating/solubilizing unesterified cholesterol (UC) exerted more pronounced therapeutic and ototoxic effects when administered intracerebroventricularly than subcutaneously for NPC treatment. However, the impact of substituent variations on these effects is unconfirmed for cyclic hexasaccharides, α-CD derivatives. Here, we investigated these effects for α-CD derivatives with various replaced substituents from the perspective of their interaction with UC. Even when administered intracerebroventricularly, a representative α-CD derivative had no impact on survival in NPC model mice. The normalization of intracellular cholesterol trafficking in NPC model cells and the auditory dysfunction in wild-type mice, both caused by HP-β-CD, were not seen for the α-CD derivatives, regardless of their substituent variations. Solubility and molecular simulation analyses showed negligible UC-solubilizing ability of α-CD derivatives because of their insufficient capacity to accommodate the UC molecule, rather than their substituent variations. These results underscore the importance of UC accommodation by CD for both efficacy and ototoxicity in NPC treatment.https://doi.org/10.1038/s41598-025-15599-0Niemann-Pick disease type CCholesterolCyclodextrinMolecular dockingIntracerebroventricular administrationOtotoxicity |
| spellingShingle | Yusei Yamada Mayuko Tanaka Yusei Ikeda Yuki Kondo Toru Takeo Naomi Nakagata Toru Miwa Hiroki Takeda Yorihisa Orita Keiichi Motoyama Taishi Higashi Hidetoshi Arima Takahiro Seki Yuki Kurauchi Hiroshi Katsuki Katsumi Higaki Kotaro Matsusaka Kentaro Minami Naoki Yoshikawa Ryuji Ikeda Muneaki Matsuo Tetsumi Irie Yoichi Ishitsuka Inability of α-cyclodextrins to accommodate cholesterol potentially underlies their lack of efficacy and ototoxicity in Niemann-Pick disease type C treatment Scientific Reports Niemann-Pick disease type C Cholesterol Cyclodextrin Molecular docking Intracerebroventricular administration Ototoxicity |
| title | Inability of α-cyclodextrins to accommodate cholesterol potentially underlies their lack of efficacy and ototoxicity in Niemann-Pick disease type C treatment |
| title_full | Inability of α-cyclodextrins to accommodate cholesterol potentially underlies their lack of efficacy and ototoxicity in Niemann-Pick disease type C treatment |
| title_fullStr | Inability of α-cyclodextrins to accommodate cholesterol potentially underlies their lack of efficacy and ototoxicity in Niemann-Pick disease type C treatment |
| title_full_unstemmed | Inability of α-cyclodextrins to accommodate cholesterol potentially underlies their lack of efficacy and ototoxicity in Niemann-Pick disease type C treatment |
| title_short | Inability of α-cyclodextrins to accommodate cholesterol potentially underlies their lack of efficacy and ototoxicity in Niemann-Pick disease type C treatment |
| title_sort | inability of α cyclodextrins to accommodate cholesterol potentially underlies their lack of efficacy and ototoxicity in niemann pick disease type c treatment |
| topic | Niemann-Pick disease type C Cholesterol Cyclodextrin Molecular docking Intracerebroventricular administration Ototoxicity |
| url | https://doi.org/10.1038/s41598-025-15599-0 |
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