Efficacy and ototoxicity of different cyclodextrins in Niemann–Pick C disease

Abstract

ObjectiveNiemann–Pick type C (NPC) disease is a fatal, neurodegenerative, lysosomal storage disorder characterized by intracellular accumulation of unesterified cholesterol (UC) and other lipids. While its mechanism of action remains unresolved, administration of 2‐hydroxypropyl‐β‐cyclodextrin (HPβCD) has provided the greatest disease amelioration in animal models but is ototoxic. We evaluated other cyclodextrins (CDs) for treatment outcome and chemical interaction with disease‐relevant substrates that could pertain to mechanism.MethodsNPC disease mice treated for 2 weeks with nine different CDs were evaluated for UC, and GM2 and GM3 ganglioside accumulation using immunohisto/cytochemical and biochemical assays. Auditory brainstem responses were determined in wild‐type mice administered CDs. CD complexation with UC, gangliosides, and other lipids was quantified.ResultsFour HPβCDs varying in degrees of substitution, including one currently in clinical trial, showed equivalent storage reduction, while other CDs showed significant differences in relative ototoxicity and efficacy, with reductions similar for the brain and liver. Importantly, HPγCD and two sulfobutylether‐CDs showed efficacy with reduced ototoxicity. Complexation studies showed: incomplete correlation between CD efficacy and UC solubilization; an inverse correlation for ganglioside complexation; substantial interaction with several relevant lipids; and association between undesirable increases of UC storage in Kupffer cells and UC solubilization.InterpretationCDs other than HPβCD identified here may provide disease amelioration without ototoxicity and merit long‐term treatment studies. While direct interactions of CD‐UC are thought central to the mechanism of correction, the data show that this does not strictly correlate with complexation ability and suggest interactions with other NPC disease‐relevant substrates should be considered.

Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice

“…In Npc1 −/− mice the drugs reduced concentrations of cholesterol and other lipids including the glycosphingolipids GM2 and GM3 in brain, liver, and other organs [12,16,23,24]. We here hypothesize that by using the respective drugs in wild-type mice, concentrations of cholesterol and other lipids were decreased below normal level, interfering with normal cellular or membrane functions.…”

“…We here hypothesize that by using the respective drugs in wild-type mice, concentrations of cholesterol and other lipids were decreased below normal level, interfering with normal cellular or membrane functions. Interestingly, Davidson and others showed that therapeutically efficacious doses of HPβCD in wild-type mice and also cats led to ototoxicity, possibly by lipid depletion of the delicate hair cells [16,17,18]. Moreover, in Npc1 −/− CHO cells Tanaka et al [25] found a high tolerability against HPβCD toxicity compared with wild-type CHO cells and discussed this phenomenon with respect to cholesterol-solubilizing activity of cyclodextrin without giving an explanation for the precise molecular mechanism.…”

“…Moreover, it seemed important to evaluate the consequences of therapeutically used drugs in wild-type animals in order to study specific negative effects or to show that no side effects occurred. Interestingly, HPβCD was shown to have no effect on visual evoked potential response in wild-type mice [15], whereas others reported severe ototoxicity of exactly this drug in mice and cats [16,17,18]. …”

Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases

“…Even though universally used in drug formulations and considered safe [20], HPβCD has displayed effective ototoxicity as reported in the feline model of NPC1 disease in which cochlear outer hair cells were affected by HPβCD treatment [66]. Therefore, investigations about developing safer alternates to HPβCD in modifying its degree of substitution are currently occurring as well as an ongoing clinical trial to evaluate their efficacy in NPC1 treatment avoiding at the same time the side-effect of hearing loss [67].…”

Supramolecular Pharmaceutical Sciences: A Novel Concept Combining Pharmaceutical Sciences and Supramolecular Chemistry with a Focus on Cyclodextrin-Based Supermolecules

“…Recently, various bioactivities of CyDs have been demonstrated, and CyDs have been used as active pharmaceutical ingredients (APIs) against Niemann-Pick disease type C (NPC), [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] leukemia, 77) hyperlipidemia, 78) Alzheimer's disease, [79][80][81][82][83][84] cerebral ischemic injury, 85) atherosclerosis, 86) diabetic kidney disease, 87) chronic renal failure, 88) AIDS, 89,90) influenza, 91) peripheral artery disease, 92) sterility, [93][94][95] solid cancers, [96][97][98][99][100][101] bacterial growth, 102) α-synucleinopathy, 103) GM1-gangliosidosis, 104) septic shock, [105][106][107] hypervitaminosis, 108) and transthyretin-related familial amyloidotic polyneuropathy (FAP) …”