title: Intrathecal 2-hydroxypropyl-beta-cyclodextrin in a single patient with Niemann-Pick C1.
abstract: 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.
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA. Electronic address: tmaarup@labiomed.org.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Maarup
authors.affiliation: Department of Pediatrics, Division of Neurology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Agnes H
authors.initials: AH
authors.lastname: Chen
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, Bethesda, MD, USA.
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.affiliation: Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, Bethesda, MD, USA.
authors.forename: Nicole Y
authors.initials: NY
authors.lastname: Farhat
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Rohini
authors.initials: R
authors.lastname: Sidhu
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Xuntian
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Dickson
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D015415:Biomarkers / Q000097:blood; D002648:Child; D018450:Disease Progression; D005079:Excipients / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005133:Eye Movements; D006309:Hearing / Q000187:drug effects; D034381:Hearing Loss; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood; D007278:Injections, Spinal; D008297:Male; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D005079:Excipients; D006888:Hydroxycholesterols; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C044563:24-hydroxycholesterol
keywords: Cyclodextrin; Niemann–Pick C; Ototoxicity; Therapeutic