Posted by HP-β-CD is currently under clinical investigation for treating Niemann-Pick disease type C (NPC), but its ototoxicity remains problematic. It was previously reported that β- and γ-CD based 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, i.e. α-CD derivatives. Here, these effects were investigated for α-CD derivatives with various replaced substituents from the perspective of their interaction with UC. Even when administered intracerebroventricularly, representative α-CD derivatives 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.
Yamada Y, Tanaka M, Ikeda Y, Kondo Y, Takeo T, Nakagata N, Miwa T, Takeda H, Orita Y, Motoyama K, Higashi T, Arima H, Seki T, Kurauchi Y, Katsuki H, Higaki K, Matsusaka K, Minami K, Yoshikawa N, Ikeda R, Matsuo M, Irie T, Ishitsuka Y. Inability of α-cyclodextrins to accommodate cholesterol potentially underlies their lack of efficacy and ototoxicity in Niemann-Pick disease type C treatment. Sci Rep. 2025 Aug 22;15(1):30857. https://doi.org/10.1038/s41598-025-15599-0.
Yamada et al. (2025) confirmed the lack of ototoxicity with HPaCD, but still treated small groups (“n = 4 for each group”) of “mice once at 4 weeks of age” only with a single HPaCD dose of up to 60 mg/kg (5 g per 83 kg). In the current phase 3 trial, children are treated every for 96 weeks with 2 g/kg HPbCD every other week. Maybe the study with HPaCD should be repeated with a higher (still safe) dose of HPaCD given over a longer time to larger groups of animals until more definite conclusions can be drawn.