Table 1.

Animal studies of different HPβCD products in the NPC1 setting.

Citation	Route of Administration	HPβCD Dose, Frequency, and Duration	Key BBB Penetration Findings	Key NPC1 Safety/Efficacy Findings
NPC1-/- Mouse Model
Camargo, 2001a	Intraperitoneal	100 or 500 mg/kg, three times weekly	No significant penetration	Small delay of onset of neurological symptoms (~20%); lowered unesterified cholesterol
Davidson, 2009b	Subcutaneous, intraperitoneal	4000 mg/kg every other day Short term: 2 weeks Chronic: to end-stage disease	Not assessed	Short term: Little to no accumulation of cholesterol or gangliosides; autophagosome marker expression similar to wild type Chronic: Delayed onset of ataxic gait and tremor; increased lifespan; reduced accumulation of cholesterol and glycosphingolipid; reduced markers of neurodegeneration; autophagosome marker expression similar to wild type Safety: Concerns raised about possible pulmonary complications with long-term high-dose subcutaneous treatment
Liu, 2009c	Subcutaneous	4000 mg/kg single injection	Not assessed	Reduced total body cholesterol burden and macrophage activation; improved liver function, Purkinje cell survival; increased lifespan
Aqul, 2011d	Subcutaneous; intracerebroventricular infusion	Subcutaneous: 4000 mg/kg every 7 days from day 7 until day 49 Intracerebro-ventricular: 23 mg/kg per day from day 21 until day 49 (along with subcutaneous administration)	Not assessed	Subcutaneous: Some slowing of neuro-degeneration; increased lifespan Intracerebroventricular: Histology indistinguishable from control mice; all animals remained clinically well HPβCD far more effective when administered directly to the brain
Ramirez, 2011e	Subcutaneous	4000 mg/kg (single dose)	Not assessed directly	HPβCD dose achieving 50% inhibition of unesterified cholesterol synthesis was 2-fold higher in the brain vs the liver
Pontikis, 2013f	Intraperitoneal	10 μCi (single dose)	No significant penetration	Not assessed
Lopez, 2014g	Subcutaneous	4000 mg/kg weekly	Not assessed directly	In adult (49 days old) mice, HPβCD reduced cholesterol in liver and spleen but not brain by 77 days, with only marginal increase in lifespan
NPC1 Cat Model
Vite, 2015h	Subcutaneous; intrathecal	Subcutaneous: 1000, 4000, or 8000 mg/kg every 7 days Intrathecal: 3.8, 7.5, 15, 30, 60, or 120 mg every 14 days	No significant penetration	Subcutaneous: Improved hepatic disease; increased body weight; decreased hepatic cholesterol, sphingomyelin, neutral glycolipids, free sphingosine, and ganglioside storage; improved Purkinje cell survival and increased mean survival time from 21 weeks in untreated cats to 35 weeks at 8000 mg/kg Intrathecal: Delayed cerebellar dysfunction; reduced Purkinje cell loss; normalized cholesterol and sphingolipid levels in the brain; reduced storage of gangliosides; slowed disease progression at 24 weeks of age; at doses ≥30 mg, all cats were still living at the end of the 76-week study period and exhibited only mild to moderate ataxia Safety: Increase in hearing threshold/ototoxicity; subcutaneous doses high enough to reduce neurological disease resulted in pulmonary toxicity

BBB, blood-brain barrier; CNS, central nervous system; HPβCD, 2-hydroxypropyl-β-cyclodextrin; NA, not available; NPC1, Niemann-Pick disease Type C1; TDS, total degrees of substitution.

^a[16].

^b[17].

^c[18].

^d[19].

^e[8].

^f[7].

^g[21].

^h[20].