Abstract
BACKGROUND: Intrathecal 2-hydoxypropyl-β-cyclodextrin has been found to mobilize cholesterol, extend life, reduce cerebellar pathology, and delay onset of ataxia in the mouse and cat models of Niemann-Pick disease, type C1, a clinically variable progressive and ultimately fatal neurodegenerative storage disorder characterized by endolysosomal accumulation of unesterified cholesterol. OBJECTIVE: In this study, the long-term effects of intrathecal 2-hydoxypropyl-β-cyclodextrin treatment for 2.5 to three years in humans with Niemann-Pick disease, type C, were evaluated. METHODS: Three patients with Niemann-Pick disease, type C, in different stages of progression and displaying varying disease manifestations were treated with intrathecal 2-hydoxypropyl-β-cyclodextrin (VTS-270) delivered by lumbar puncture infusion through an intermediate-size patient population investigational new drug application for expanded access. Disease progression was monitored with the Niemann-Pick disease, type C, Neurological Severity Scale and numerous objective measures of function in five neurological domains typically impacted by the disease: cognitive/language, gait/balance, fine motor, swallowing, and eye movement. RESULTS: No worsening in any domain except eye movements (vertical pursuit gain) was seen for any of the three patients, and in the other domains, improved scores on measures were seen over time for one or more patients. The Niemann-Pick disease type C (NPC) Neurological Severity Scale (NSS) showed stable to slightly improved ratings. CONCLUSIONS: These trajectories are not consistent with the typical trajectory of the disease and suggest that intrathecal 2-hydoxypropyl-β-cyclodextrin has stabilized the disease over an extended period of time, supporting the current phase 2/3 controlled registration trial with VTS-270.