Abstract
2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) is a promising experimental therapy for Niemann-Pick type C disease that improved intracellular cholesterol transport, substantially reduced neurodegeneration and hepatic disease, and increased lifespan in npc1 mice. On the basis of favorable treatment outcome in mice, HPbetaCD is being evaluated as a therapy in children with Niemann-Pick type C (NPC) disease. We evaluated the efficacy of HPbetaCD in the feline model of NPC disease and recognized a dose-dependent increase in hearing threshold associated with therapy as determined by brain stem auditory evoked response (BAER) testing. To further assess the effect of HPbetaCD on hearing threshold, normal cats were administered the drug s.c. at either 4000 mg/kg or 8000 mg/kg body weight, or intrathecally at a dose of 4000 mg/kg brain weight. HPbetaCD caused a significant increase in hearing threshold following one dose of 8000 mg/kg s.c. or 120 mg intrathecally, and the effect was maintained for at least 12 weeks. Repeated weekly s.c. administration of 4000 mg/kg HPbetaCD resulted in a similar increase in hearing threshold. These studies are the first to describe a specific negative effect of HPbetaCD on the auditory system and suggest the need for auditory testing in patients receiving similar doses of HPbetaCD.