Intrathecal 2-hydroxypropyl-beta-cyclodextrin in a single patient with Niemann–Pick C1

• Published in: Molecular genetics and metabolism Vol. 116; no. 1-2; pp. 75 - 79
• Main Authors: Maarup, Timothy J., Chen, Agnes H., Porter, Forbes D., Farhat, Nicole Y., Ory, Daniel S., Sidhu, Rohini, Jiang, Xuntian, Dickson, Patricia I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2015
• Subjects: 2-Hydroxypropyl-beta-cyclodextrin; beta-Cyclodextrins - administration & dosage; beta-Cyclodextrins - adverse effects; beta-Cyclodextrins - therapeutic use; Biomarkers - blood; Child; Cyclodextrin; Disease Progression; Excipients - administration & dosage; Excipients - adverse effects; Excipients - therapeutic use; Eye Movements; Hearing - drug effects; Hearing Loss; Humans; Hydroxycholesterols - blood; Injections, Spinal; Male; Niemann-Pick Disease, Type C - drug therapy; Niemann-Pick Disease, Type C - metabolism; Niemann-Pick Disease, Type C - physiopathology; Niemann–Pick C; Ototoxicity; Therapeutic; Therapeutic; Cyclodextrin; Niemann–Pick C; Ototoxicity
• ISSN: 1096-7192; 1096-7206; 1096-7206
• DOI: 10.1016/j.ymgme.2015.07.001

Niemann–Pick C, type 1 (NPC1) is a progressive autosomal recessive neurologic disease caused by defective intracellular cholesterol and lipid trafficking. There are currently no United States Food and Drug Administration approved treatments for NPC1. We undertook a study evaluating the safety, efficacy, and biomarker response of intrathecal 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in a 12-year old subject with mildly symptomatic NPC. The subject received 200mg intrathecal HP-β-CD administered biweekly via lumbar puncture. To date the subject has received 27 intrathecal HP-β-CD injections. Intrathecal HP-β-CD has been generally safe and well tolerated in this subject. There has been an improvement in vertical gaze. The subject has developed subclinical hearing loss at high frequency that is likely HP-β-CD related. Plasma 24-(S)-hydroxycholesterol, a pharmacodynamic biomarker for cholesterol redistribution in the central nervous system, was significantly increased in response to each of the first 5 drug administrations. Further dosing as well as dose escalations are needed to more completely ascertain the safety and efficacy of intrathecal HP-β-CD. •We administered intrathecal HP-β-CD to a 12year old male with Niemann–Pick C, type 1.•The subject developed high frequency hearing loss while being treated with HP-β-CD.•Plasma 24-(S)-hydroxycholesterol increased following administration of HP-β-CD.•Further dosages are needed to evaluate the safety and efficacy of this therapy.