title: Efficacy and ototoxicity of different cyclodextrins in Niemann-Pick C disease.
abstract: Niemann-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.
  
  
  
  NPC 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.
  
  
  
  Four 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.
  
  
  
  CDs 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.
authors.affiliation: Dominick P. Purpura Department of Neuroscience Rose F. Kennedy Center Intellectual and Developmental Disabilities Research Center Albert Einstein College of Medicine Bronx New York 10461.
authors.forename: Cristin D
authors.initials: CD
authors.lastname: Davidson
authors.affiliation: Dominick P. Purpura Department of Neuroscience Rose F. Kennedy Center Intellectual and Developmental Disabilities Research Center Albert Einstein College of Medicine Bronx New York 10461.
authors.forename: Yonatan I
authors.initials: YI
authors.lastname: Fishman
authors.affiliation: CycloLab Cyclodextrin Research & Development Laboratory Ltd. Budapest H-1097 Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Puskás
authors.affiliation: CycloLab Cyclodextrin Research & Development Laboratory Ltd. Budapest H-1097 Hungary.
authors.forename: Julianna
authors.initials: J
authors.lastname: Szemán
authors.affiliation: CycloLab Cyclodextrin Research & Development Laboratory Ltd. Budapest H-1097 Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Sohajda
authors.affiliation: Department of Nutritional Sciences and Rutgers Center for Lipid Research Rutgers University New Brunswick New Jersey 08901.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: McCauliff
authors.affiliation: Dominick P. Purpura Department of Neuroscience Rose F. Kennedy Center Intellectual and Developmental Disabilities Research Center Albert Einstein College of Medicine Bronx New York 10461; Institute of Inherited Metabolic Disorders First Faculty of Medicine Charles University in Prague and General University Hospital in Prague Prague Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Sikora
authors.affiliation: Department of Nutritional Sciences and Rutgers Center for Lipid Research Rutgers University New Brunswick New Jersey 08901.
authors.forename: Judith
authors.initials: J
authors.lastname: Storch
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unit 820; EA4611 Lyon-1 University Lyon France.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Vanier
authors.affiliation: CycloLab Cyclodextrin Research & Development Laboratory Ltd. Budapest H-1097 Hungary.
authors.forename: Lajos
authors.initials: L
authors.lastname: Szente
authors.affiliation: Dominick P. Purpura Department of Neuroscience Rose F. Kennedy Center Intellectual and Developmental Disabilities Research Center Albert Einstein College of Medicine Bronx New York 10461.
authors.forename: Steven U
authors.initials: SU
authors.lastname: Walkley
authors.affiliation: Dominick P. Purpura Department of Neuroscience Rose F. Kennedy Center Intellectual and Developmental Disabilities Research Center Albert Einstein College of Medicine Bronx New York 10461.
authors.forename: Kostantin
authors.initials: K
authors.lastname: Dobrenis