Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease

Vite, Charles H.; Bagel, Jessica H.; Swain, Gary P.; Prociuk, Maria; Sikora, Tracey; Stein, Veronika M.; O’Donnell, Patricia; Ruane, Therese; Ward, Sarah; Crooks, Alexandra; Li, Su; Mauldin, Elizabeth A.; Stellar, Susan; Meulder, Marc De; Kao, Mark; Ory, Daniel S.; Davidson, Cristin; Vanier, Marie T.; Walkley, Steven U.

doi:10.1126/scitranslmed.3010101

Cited by 181 publications

(226 citation statements)

References 75 publications

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“…There is still controversy over whether the IV route contributes in NPD-C therapy. Preclinical reports showed effectiveness in the peripheral manifestations of the disease in organs [20,25], including the liver, the spleen, and, to a lesser extent, the lungs. However, the influence of HP-β-CD in CNS after IV infusion remains in humans unknown.…”

Section: Experience In Humans: First Experiences Of Compassionate Usementioning

confidence: 99%

“…However, any patients showed renal toxicity with HP-β-CD therapy [32]. This was the first route employed, but later a change to IT route was requested due to the discovery that HP-β-CD not cross the BBB and only a little quantity is able to enter to the brain [21,24,25,30].…”

Section: Experience In Humans: Potential Toxicities Of the Different mentioning

confidence: 99%

“…In cats receiving intracisternal HP-β-CD, a significant elevation in the auditory threshold was also observed. [25].…”

Section: Animal Studiesmentioning

confidence: 99%

“…The orphan drug brand Trappsol ® Cyclo™ was approved specifically for treating NPD-C. New findings suggested that the passage of HP-β-CD across the BBB was limited [21,24,25,30], and physicians who treated the first patients reported slight benefit with IV route [26]. The FDA approved the request for IT delivery of HP-β-CD in September 2010 [31].…”

Section: Experience In Humans: First Experiences Of Compassionate Usementioning

confidence: 99%

“…When different reports in animals demonstrated that HP-β-CD administered intravenously cross in very little proportion the BBB [21,24,25,30], this route was changed or combined with IT/ICV administration of the same drug. Theoretically, IT and ICV routes deliver directly the drug in the central nervous system (CNS), the area mainly affected in NPD-C, especially in the neurological symptoms.…”

Section: Experience In Humans: First Experiences Of Compassionate Usementioning

confidence: 99%

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Use of 2-Hydroxypropyl-Beta-Cyclodextrin for Niemann-Pick Type C Disease

Megías‐Vericat¹,

Company-Albir²,

García-Robles³

et al. 2018

Cyclodextrin - A Versatile Ingredient

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Niemann-Pick disease type C (NPD-C) is a rare neurodegenerative disorder characterized by a lysosomal storage disorder. Treatment has been supportive and symptomatic. In animal studies, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) showed a significant decrease in cerebellar damage, neurological progression, and higher lifespan. Based on these results, HP-β-CD has been tested in NPD-C patients for last 8 years. The first compassionate uses of intravenous HP-β-CD obtained a limited improvement in neurological symptoms, probably associated to the non-permeation of the blood-brain barrier. The change or combination with intrathecal administrations of HP-β-CD achieved higher benefits, especially improvement or stabilization of NPD-C progression. Biomarkers of neurological cholesterol homeostasis are being investigated in order to quantify the response of HP-β-CD treatment. The results of a clinical trial recently published have reproduced the slowing of NPD-C progression in 14 patients treated with a dose-escalation protocol of HP-β-CD intrathecal monthly infusions, with respect to a historical comparison cohort. The safety profile of this therapy is acceptable, being the loss of hearing as the most frequent adverse event. However, some severe toxicities have been reported in relation with HP-β-CD, including chemical meningitis and fever. The short experience with HP-β-CD suggested that it could be effective in the management of NPD-C.

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Section: Experience In Humans: First Experiences Of Compassionate Usementioning

confidence: 99%

Section: Experience In Humans: Potential Toxicities Of the Different mentioning

confidence: 99%

“…In cats receiving intracisternal HP-β-CD, a significant elevation in the auditory threshold was also observed. [25].…”

Section: Animal Studiesmentioning

confidence: 99%

Section: Experience In Humans: First Experiences Of Compassionate Usementioning

confidence: 99%

Section: Experience In Humans: First Experiences Of Compassionate Usementioning

confidence: 99%

See 3 more Smart Citations

Use of 2-Hydroxypropyl-Beta-Cyclodextrin for Niemann-Pick Type C Disease

Megías‐Vericat¹,

Company-Albir²,

García-Robles³

et al. 2018

Cyclodextrin - A Versatile Ingredient

View full text Add to dashboard Cite

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Efficacy and ototoxicity of different cyclodextrins in Niemann–Pick C disease

Davidson

Fishman

Puskás

et al. 2016

Ann Clin Transl Neurol

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ObjectiveNiemann–Pick type C (NPC) disease is a fatal, neurodegenerative, lysosomal storage disorder characterized by intracellular accumulation of unesterified cholesterol (UC) and other lipids. While its mechanism of action remains unresolved, administration of 2‐hydroxypropyl‐β‐cyclodextrin (HPβCD) has provided the greatest disease amelioration in animal models but is ototoxic. We evaluated other cyclodextrins (CDs) for treatment outcome and chemical interaction with disease‐relevant substrates that could pertain to mechanism.MethodsNPC disease mice treated for 2 weeks with nine different CDs were evaluated for UC, and GM2 and GM3 ganglioside accumulation using immunohisto/cytochemical and biochemical assays. Auditory brainstem responses were determined in wild‐type mice administered CDs. CD complexation with UC, gangliosides, and other lipids was quantified.ResultsFour HPβCDs varying in degrees of substitution, including one currently in clinical trial, showed equivalent storage reduction, while other CDs showed significant differences in relative ototoxicity and efficacy, with reductions similar for the brain and liver. Importantly, HPγCD and two sulfobutylether‐CDs showed efficacy with reduced ototoxicity. Complexation studies showed: incomplete correlation between CD efficacy and UC solubilization; an inverse correlation for ganglioside complexation; substantial interaction with several relevant lipids; and association between undesirable increases of UC storage in Kupffer cells and UC solubilization.InterpretationCDs other than HPβCD identified here may provide disease amelioration without ototoxicity and merit long‐term treatment studies. While direct interactions of CD‐UC are thought central to the mechanism of correction, the data show that this does not strictly correlate with complexation ability and suggest interactions with other NPC disease‐relevant substrates should be considered.

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Hepatocellular carcinoma as a complication of Niemann‐Pick disease type C1

Rodriguez-Gil

Bianconi

Farhat

et al. 2021

American J of Med Genetics Pt A

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Niemann-Pick disease type C (NPC) is a rare and fatal lysosomal storage disorder characterized by neurodegeneration and hepatic involvement. Mutations in either NPC1 or NPC2, two genes encoding lysosomal proteins, lead to an intracellular accumulation of unesterified cholesterol and sphingolipids in late endosomes/lysosomes. Early cholestatic disease is considered a hallmark of patients with early disease onset.This can potentially result in liver failure shortly after birth or subclinical hepatic inflammation. Previous reports suggest an association between NPC and hepatocellular carcinoma, a cancer that is rare during childhood. We present a 12-year-old male with a known diagnosis of NPC1 disease who was found to have a stage III hepatocellular carcinoma, underwent surgical resection with adjuvant chemotherapy, and subsequently died from metastatic disease. This report provides evidence of an increased risk of hepatocellular carcinoma in NPC patients, suggesting a need for screening in this patient population.

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Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease

Cited by 181 publications

References 75 publications

Use of 2-Hydroxypropyl-Beta-Cyclodextrin for Niemann-Pick Type C Disease

Use of 2-Hydroxypropyl-Beta-Cyclodextrin for Niemann-Pick Type C Disease

Efficacy and ototoxicity of different cyclodextrins in Niemann–Pick C disease

Hepatocellular carcinoma as a complication of Niemann‐Pick disease type C1

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