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Background and Objectives: Niemann-Pick type C (NPC) is a rare lysosomal storage disease characterized by hepatosplenomegaly and progressive neurological deterioration due to abnormal intracellular cholesterol transport. Cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HPBCD) is an effective treatment for NPC; however, few reports have shown its long-term efficacy and safety. To demonstrate long-term efficacy and safety of intrathecal HPBCD (IT-HPBCD) treatment for NPC, we herein reports five patients with NPC treated using IT-HPBCD for 4-11 years., Cases and Results: Patients' ages at the onset ranged from 1.5 to 20 years. Notably, all patients showed rapid disease progression despite treatment with miglustat before IT-HPBCD treatment. Similarly, some patients showed transient improvement; however, all patients' conditions stabilized after long-term IT-HPBCD therapy. Mild-to-moderate hearing loss was observed in three patients. Furthermore, long-term treatment with IT-HPBCD may suppress neurological deterioration in patients with NPC; however, patients still experience some disease progression., Conclusions: Long-term treatment with IT-HPBCD may suppress neurological deterioration in patients with NPC; however, the treatment outcome is dependent on the neurological status at the time of diagnosis, and disease progression is not completely inhibited. Awareness of the disease and newborn screening is needed for earlier disease detection. In addition, further optimization of the treatment protocol and additional treatments are needed to improve patient outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disorder caused by abnormal intracellular cholesterol trafficking. Cyclodextrins (CDs), the most promising therapeutic candidates for NPC, but with concerns about ototoxicity, are cyclic oligosaccharides with dual functions of unesterified cholesterol (UC) shuttle and sink that catalytically enhance the bidirectional flux and net efflux of UC, respectively, between the cell membrane and the extracellular acceptors. However, the properties of CDs that regulate these functions and how they could be used to improve treatments for NPC are unclear., Methods: We estimated CD-UC complexation for nine CD derivatives derived from native α-, β-, and γ-CD with different cavity sizes, using solubility and molecular docking analyses. The stoichiometry and complexation ability of the resulting complexes were investigated in relation to the therapeutic effectiveness and toxicity of each CD derivative in NPC experimental models., Findings: We found that shuttle and sink activities of CDs are dependent on cavity size-dependent stoichiometry and substituent-associated stability of CD-UC complexation. The ability of CD derivatives to form 1:1 and 2:1 complexes with UC were correlated with their ability to normalize intracellular cholesterol trafficking serving as shuttle and with their cytotoxicity associated with cellular UC efflux acting as sink, respectively, in NPC model cells. Notably, the ability of CD derivatives to form an inclusion complex with UC was responsible for not only efficacy but ototoxicity, while a representative derivative without this ability negligibly affected auditory function, underscoring its preventability., Conclusions: Our findings highlight the importance of strategies for optimizing the molecular structure of CDs to overcome this functional dilemma in the treatment of NPC., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Cyclodextrin (CD), a cyclic oligosaccharide, is a pharmaceutical additive that improves the solubility of hydrophobic compounds. Recent research has focused on the potential active pharmaceutical abilities of CD. Lysosomal storage diseases are inherited metabolic diseases characterized by lysosomal dysfunction and abnormal lipid storage. Niemann-Pick disease type C (NPC) is caused by mutations in cholesterol transporter genes (NPC1, NPC2) and is characterized by cholesterol accumulation in lysosomes. A biocompatible cholesterol solubilizer 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was recently used in NPC patients for compassionate use and in clinical trials. HP-β-CD is an attractive drug candidate for NPC; however, its adverse effects, such as ototoxicity, should be solved. In this review, we discuss the current use of HP-β-CD in basic and clinical research and discuss alternative CD derivatives that may outperform HP-β-CD, which should be considered for clinical use. The potential of CD therapy for the treatment of other lysosomal storage diseases is also discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with disrupted intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is a cholesterol solubilizer that is being developed to treat NPC, but its ototoxicity and pulmonary toxicity remain important issues. We have characterized 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), a cyclic octasaccharide with a larger cavity than HP-β-CD, as a candidate drug to treat NPC. However, the molecular target of HP-γ-CD with respect to NPC and its potential for clinical application are still unclear., Experimental Approach: We investigated the mode of interaction between HP-γ-CD and cholesterol by phase-solubility analysis, proton NMR spectroscopy and molecular dynamics simulations. We then evaluated the therapeutic effects of HP-γ-CD compared with HP-β-CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted., Key Results: HP-γ-CD solely formed a 1:1 inclusion complex with cholesterol with an affinity similar to that of HP-β-CD. In vitro, HP-γ-CD and HP-β-CD amelioration of NPC-related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP-β-CD shifted to the highly soluble 2:1 complex whereas that of HP-γ-CD maintained solely the 1:1 complex. The constant lower cholesterol solubilizing ability of HP-γ-CD conferred it with significantly reduced toxicity compared with HP-β-CD, but equal efficacy in treating a mouse model of NPC., Conclusions and Implications: HP-γ-CD can serve as a fine-tuned cholesterol solubilizer for the treatment of NPC with a wider safety margin than HP-β-CD in terms of ototoxicity and pulmonary toxicity., (© 2021 The British Pharmacological Society.)

Abstract: Niemann–Pick Type C disease (NPC) is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration. Currently, there are no effective treatments for NPC, although miglustat has shown some effectiveness in stabilizing neurological status in juvenile-onset NPC patients. Recent studies have demonstrated the efficacy of hydroxypropyl-β-cyclodextrin (HPB-CD) in NPC mice. Herein, we describe the effects of HPB-CD in two patients with NPC. The two patients received HPB-CD infusions twice (Patient 2) or thrice (Patient 1) weekly, starting with a dose of 80mg/kg per dose that was increased gradually to 2g/kg per dose (Patient 2) or 2.5g/kg per dose (Patient 1). Although HPB-CD did not improve the neurological deficits in either patient, it was partially effective in improving hepatosplenomegaly and central nervous system dysfunction, especially during the first 6months of treatment. No adverse effects were observed over the course of treatment, although Patient 1 exhibited transient cloudiness of the lungs with fever after 2years. For more effective treatment of NPC patients with HPB-CD, it is necessary to improve drug delivery into the central nervous system. [Copyright &y& Elsevier]

Niemann-Pick disease Type C (NPC) is a lysosomal storage disorder caused by mutation of the NPC1 / NPC2 genes, which ultimately results in the accumulation of unesterified cholesterol (UEC) in lysosomes, thereby inducing symptoms such as progressive neurodegeneration and hepatosplenomegaly. This study determines the effects of 6- O -α-maltosyl-β cyclodextrin (Mal-βCD) on lipid levels and synthesis in Npc1 -deficient (Npc1-KO cells) and vehicle CHO cells. Compared to vehicle cells, Npc1-KO cells exhibited high level of UEC, and low levels of esterified cholesterols (ECs) and long-chain fatty acids (LCFAs). The difference in lipid levels between Npc1-KO and CHO cells was largely ameliorated by Mal-βCD administration. Moreover, the effects of Mal-βCD were reproduced in the lysosomes prepared from Npc1-KO cells. Stable isotope tracer analysis with extracellular addition of D4-deuterated palmitic acid (D4-PA) to Npc1-KO cells increased the synthesis of D4-deuterated LCFAs (D4-LCFAs) and D4-deuterated ECs (D4-ECs) in a Mal-βCD-dependent manner. Simultaneous addition of D6-deuterated UEC (D6-UEC) and D4-PA promoted the Mal-βCD-dependent synthesis of D6-/D4-ECs, consisting of D6-UEC and D4-PA, D4-deuterated stearic acid, or D4-deuterated myristic acid, in Npc1-KO cells. These results suggest that Mal-βCD helps to maintain normal lipid metabolism by restoring balance among UEC, ECs, and LCFAs through acting on behalf of NPC1 in Npc1-KO cells and may therefore be useful in designing effective therapies for NPC. • 6- O -α-Maltosyl-β cyclodextrin (Mal-βCD) acts on behalf of NPC1 in Npc1 -deficient cells. • Mal-βCD improved lipid balance in Npc1 -deficient cells. • Mal-βCD reduced cellular/lysosomal unesterified cholesterol in Npc1 -deficient cells. • Mal-βCD increased esterified cholesterol and long-chain fatty acid in Npc1 -deficient cells. [ABSTRACT FROM AUTHOR]

This study was conducted to evaluate the attenuating potential of 2-hydroxypropyl-β-cyclodextrin (HPBCD) against Niemann-Pick Type C (NPC) disease, as well as the physical and chemical properties, particularly the cholesterol-solubilizing ability, in an NPC disease model in vitro. As parameters of NPC abnormalities, intracellular free and esterified cholesterol levels and lysosome volume were measured in Npc1 null Chinese hamster ovary cells. HPBCD showed dose-dependent effects against dysfunctional intracellular cholesterol trafficking, such as the accumulation and shortage of free and esterified cholesterols, respectively, in Npc1 null cells. However, the effectiveness was gradually offset by exposure to ≥ 8 mM HPBCD. The same effect was also observed for increasing lysosome volume in Npc1 null cells. The degree of substitution of the hydroxypropyl group had little influence on the attenuating effects of HPBCD against the NPC abnormalities, at least in the range between 2.8 and 7.4. Next, we compared the effects of other hydroxyalkylated β-cyclodextrin derivatives with different cholesterol-solubilizing abilities, such as 2-hydroxyethyl-β-cyclodextrin (HEBCD) and 2-hydroxybutyl-β-cyclodextrin (HBBCD). The cholesterol solubilizing potential, attenuating effects against NPC abnormalities and cytotoxicity induction were HBBCD ≫ HPBCD > HEBCD, HBBCD = HPBCD > HEBCD and HBBCD ≫ HPBCD = HEBCD, respectively. HPBCD may be superior in terms of safety and efficacy in Npc1 null cells compared with HEBCD and HBBCD. The results of this study will provide a rationale for the optimization of HPBCD therapy for NPC disease. [ABSTRACT FROM AUTHOR]