Intrathecal cyclodextrin in the treatment of Niemann-Pick disease type C

Santed, Maria Roch; Poy, M. J. Cabañas; Riera, M. del Toro; Ramírez, Carlos Santos; Polo, Aurora; Bautista, Susana Clemente

doi:10.1136/ejhpharm-2016-001067

Cited by 4 publications

(5 citation statements)

References 6 publications

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“…Brain imaging in NPC is usually nonspecific early in the disease and is often reported as cerebellar and cerebral atrophy at later stages of progression. In the EIF cohort reviewed here we found that brain atrophy and white matter signal abnormalities were the most frequent changes reported [ 42 , 49 , 50 , 51 ] consistent with other studies [ 82 ].…”

Section: Discussionsupporting

confidence: 91%

“…Neuroimaging data was available in 10/81 patients and only one of them was reported as normal [ 51 ]. Cerebral atrophy was mentioned in nine patients [ 42 , 46 , 49 , 50 ]. Deep white matter signal abnormalities were seen in six patients [ 42 , 49 ].…”

Section: Resultsmentioning

confidence: 99%

“…Cerebral atrophy was mentioned in nine patients [42,46,49,50]. Deep white matter signal abnormalities were seen in six patients [42,49].…”

Section: Neuroimaging Findingsmentioning

confidence: 97%

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Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

Yılmaz

Baruteau

Rahim

et al. 2020

IJMS

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Niemann Pick disease type C (NPC) is a neurovisceral disorder due to mutations in NPC1 or NPC2. This review focuses on poorly characterized clinical and molecular features of early infantile form of NPC (EIF) and identified 89 cases caused by NPC1 (NPC1) and 16 by NPC2 (NPC2) mutations. Extra-neuronal features were common; visceromegaly reported in 80/89 NPC1 and in 15/16 NPC2, prolonged jaundice in 30/89 NPC1 and 7/16 NPC2. Early lung involvement was present in 12/16 NPC2 cases. Median age of neurological onset was 12 (0–24) and 7.5 (0–24) months in NPC1 and NPC2 groups, respectively. Developmental delay and hypotonia were the commonest first detected neurological symptoms reported in 39/89 and 18/89 NPC1, and in 8/16 and 10/16 NPC2, respectively. Additional neurological symptoms included vertical supranuclear gaze palsy, dysarthria, cataplexy, dysphagia, seizures, dystonia, and spasticity. The following mutations in homozygous state conferred EIF: deletion of exon 1+promoter, c.3578_3591 + 9del, c.385delT, p.C63fsX75, IVS21-2delATGC, c. 2740T>A (p.C914S), c.3584G>T (p.G1195V), c.3478-6T>A, c.960_961dup (p.A321Gfs*16) in NPC1 and c.434T>A (p.V145E), c.199T>C (p.S67P), c.133C>T (p.Q45X), c.141C>A (p.C47X) in NPC2. This comprehensive analysis of the EIF type of NPC will benefit clinical patient management, genetic counselling, and assist design of novel therapy trials.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

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Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

Yılmaz

Baruteau

Rahim

et al. 2020

IJMS

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“…Recent evidence has proposed hydroxypropyl-β-cyclodextrin (HPβCD) as a new line of treatment for NPC disease, as it could minimize neurological damage, reduce symptoms, and delay progression [ 97 , 98 ]. The therapeutic efficacy of HPβCD was discovered casually, following its use as an excipient to administer allopregnanolone in an NPC1 mouse model [ 99 ].…”

Section: Therapeutic Approaches Used To Counteract Cognitive Deficitsmentioning

confidence: 99%

Neurodegeneration in Niemann–Pick Type C Disease: An Updated Review on Pharmacological and Non-Pharmacological Approaches to Counteract Brain and Cognitive Impairment

Cariati

Masuelli

Bei

et al. 2021

IJMS

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Niemann–Pick type C (NPC) disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol in the late endo-lysosomal system of cells. Progressive neurological deterioration and the onset of symptoms, such as ataxia, seizures, cognitive decline, and severe dementia, are pathognomonic features of the disease. In addition, different pathological similarities, including degeneration of hippocampal and cortical neurons, hyperphosphorylated tau, and neurofibrillary tangle formation, have been identified between NPC disease and other neurodegenerative pathologies. However, the underlying pathophysiological mechanisms are not yet well understood, and even a real cure to counteract neurodegeneration has not been identified. Therefore, the combination of current pharmacological therapies, represented by miglustat and cyclodextrin, and non-pharmacological approaches, such as physical exercise and appropriate diet, could represent a strategy to improve the quality of life of NPC patients. Based on this evidence, in our review we focused on the neurodegenerative aspects of NPC disease, summarizing the current knowledge on the molecular and biochemical mechanisms responsible for cognitive impairment, and suggesting physical exercise and nutritional treatments as additional non-pharmacologic approaches to reduce the progression and neurodegenerative course of NPC disease.

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“…The most relevant toxicities were intermittent fever and a suspicion of chemical meningitis [32,46]. A recently published article described the IT therapy of a young NPD-C girl of 22 months [47]. The dosage of HP-β-CD was 175-325 mg every 2 weeks for 20 months.…”

Section: Experience In Humans: Efficacy Of the Intrathecal Administramentioning

confidence: 99%

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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Intrathecal cyclodextrin in the treatment of Niemann-Pick disease type C

Cited by 4 publications

References 6 publications

Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

Neurodegeneration in Niemann–Pick Type C Disease: An Updated Review on Pharmacological and Non-Pharmacological Approaches to Counteract Brain and Cognitive Impairment

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

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