Niemann-Pick type C is a sever lysosomal storage disease, commonly refereed as ‘children’s Alzheimer’. There is no cure for it yet, however there are a few compounds that try to ameliorate the symptoms. One of them is the 2-hydroxypropyl-beta-cyclodextrin, which is approved as an orphan drug by the FDA, and there are ongoing clinical trials with this drug.
Unfortunately, this field has been quite unexplored regarding to structure-activity relationships…yet.
Two recent articles explore the role of modified cyclodextrins in NPC.
The common elements in the investigated molecules are as follows:
- -single isomer cyclodextrins
- -mono substituted at position 6 with maltosyl moiety
However, one is beta- the other one is gamma-CD derivative.
In the first article (1) the effect of 6-O-α-maltosyl-β cyclodextrin (6MaBCD) on lipid metabolism in Npc1-deficient Chinese hamster ovary cells is investigated. It is revealed that 6MaBDD could correct abnormal lipid metabolism in Npc1-KO cells by inducing the synthesis of esterified cholesterols via translocation of lysosomal unesterified cholesterol and increased long-chain fatty acid levels.
The second article (2) is the first to report that this gamma derivative (G2γCD) solubilizes a small amount of unesterified cholesterol and exerts a potential therapeutic effect against NPC manifestations without obvious hearing loss, the most concerning dose-limiting toxicity of HP-β-CD therapy in clinical development. Although the cavity of γCD is not the most ideal for inclusion of cholesterol, but surprisingly earlier also HPγCD was found to effectively reduce unesterfied cholesterol level without showing ototoxicity (3).
There is still much to discover, but for me it is quite interesting that two different articles investigate the role of maltosyl-appended cyclodextrin derivatives in NPC, especially that they are different in cavity size.
- Yasuyo Okada, Sayako Kuroiwa, Ayaka Noi, Ayaka Tanaka, Junichi Nishikawa, Yuki Kondo, Yoichi Ishitsuka, Tetsumi Irie, Katsumi Higaki, Muneaki Matsuo, Atsushi Ichikawa (2022) Effects of 6-O-α-maltosyl-β cyclodextrin on lipid metabolism in Npc1-deficient Chinese hamster ovary cells. Molecular Genetics and Metabolism, 137, 239-248 https://doi.org/10.1016/j.ymgme.2022.09.007
- Yusei Yamada, Toru Miwa, Masaki Nakashima, Aina Shirakawa, Akira Ishii, Nanami Namba, Yuki Kondo, Toru Takeo, Naomi Nakagata, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Yuki Kurauchi, Takahiro Seki, Hiroshi Katsuki, Yasuyo Okada, Atsushi Ichikawa, Katsumi Higaki, Ken Hayashi, Kentaro Minami, Naoki Yoshikawa, Ryuji Ikeda, Yoshihide Ishikawa, Tomohito Kajii, Kyoko Tachii, Hiroki Takeda, Yorihisa Orita, Muneaki Matsuo, Tetsumi Irie, Yoichi Ishitsuka (2022) Fine-tuned cholesterol solubilizer, mono-6-O-α-D-maltosyl-γ-cyclodextrin, ameliorates experimental Niemann–Pick disease type C without hearing loss. Biomedicine & Pharmacotherapy 155, 113698. https://doi.org/10.1016/j.biopha.2022.113698
- Davidson, C.D., Fishman, Y.I., Puskás, I., Szemán, J., Sohajda, T., McCauliff, L.A., Sikora, J., Storch, J., Vanier, M.T., Szente, L., Walkley, S.U., Dobrenis, K. (2016) Efficacy and ototoxicity of different cyclodextrins in Niemann-Pick C disease. Annals of Clinical and Translational Neurology 3(5), 366-380. https://doi.org/10.1002/acn3.306