Current advancements in therapy for Niemann-Pick disease: progress and pitfalls

Bremova-Ertl, Tatiana; Schneider, Susanne A.

doi:10.1080/14656566.2023.2215386

Cited by 4 publications

(6 citation statements)

References 133 publications

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“…For children under 12 years of age, the dosage should be adjusted based on body surface area. The efficacy of miglustat lies in its mechanism of action: once having crossed the blood-brain barrier, it is able to directly target the lipid storage in the central nervous system [89,90]. Patients with NPC under therapy showed a significantly lower level of oxyesterol (in particular, cholestane-3β,5α,6β-triol concentrations) compared to untreated patients [91].…”

Section: Disease-modifying Therapymentioning

confidence: 99%

“…The first randomized clinical trial demonstrating the efficacy of miglustat in NPD type C was conducted in 2007 [92]. After that, several longitudinal cohort studies (lasting from 2 to 8 years) indicated a disease stabilization in terms of neurological involvement [90]. In these studies, it was observed that there was a greater efficacy in patients with juvenile and adult-onset phenotypes than those with infantile-onset (<6 years) forms [50].…”

Section: Disease-modifying Therapymentioning

confidence: 99%

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The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

Tirelli,

Rondinone,

Italia

et al. 2024

Biomolecules

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Niemann–Pick Disease (NPD) is a rare autosomal recessive disease belonging to lysosomal storage disorders. Three types of NPD have been described: NPD type A, B, and C. NPD type A and B are caused by mutations in the gene SMPD1 coding for sphingomyelin phosphodiesterase 1, with a consequent lack of acid sphingomyelinase activity. These diseases have been thus classified as acid sphingomyelinase deficiencies (ASMDs). NPD type C is a neurologic disorder due to mutations in the genes NPC1 or NPC2, causing a defect of cholesterol trafficking and esterification. Although all three types of NPD can manifest with pulmonary involvement, lung disease occurs more frequently in NPD type B, typically with interstitial lung disease, recurrent pulmonary infections, and respiratory failure. In this sense, bronchoscopy with broncho-alveolar lavage or biopsy together with high-resolution computed tomography are fundamental diagnostic tools. Although several efforts have been made to find an effective therapy for NPD, to date, only limited therapeutic options are available. Enzyme replacement therapy with Olipudase α is the first and only approved disease-modifying therapy for patients with ASMD. A lung transplant and hematopoietic stem cell transplantation are also described for ASMD in the literature. The only approved disease-modifying therapy in NPD type C is miglustat, a substrate-reduction treatment. The aim of this review was to delineate a state of the art on the genetic basis and lung involvement in NPD, focusing on clinical manifestations, radiologic and histopathologic characteristics of the disease, and available therapeutic options, with a gaze on future therapeutic strategies.

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Section: Disease-modifying Therapymentioning

confidence: 99%

Section: Disease-modifying Therapymentioning

confidence: 99%

The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

Tirelli,

Rondinone,

Italia

et al. 2024

Biomolecules

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“…NPC disease is highly heterogeneous, comprising systemic, neurological, and psychiatric signs [ 79 ]. Early- and late-infantile forms of NPC are present with severe hepatosplenomegaly, cataplexy, epilepsy, and a regress of already-gained neurological skills.…”

Section: Lysosomal Storage Diseasesmentioning

confidence: 99%

“…Other substances are in development for NPC, such as chaperone-treatment with arimoclomol [ 92 ], AZ-3102 [ 79 ], efavirenz [ 93 ] or cyclodextrin [ 94 ], and are at different development stages. A phase 2, 12-week study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral AZ-3102 in patients with NPC or GM2 gangliosidosis (see above) has just been initiated (NCT05758922).…”

Section: Lysosomal Storage Diseasesmentioning

confidence: 99%

Inborn Errors of Metabolism with Ataxia: Current and Future Treatment Options

Bremova-Ertl,

Hofmann,

Stucki

et al. 2023

Cells

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A number of hereditary ataxias are caused by inborn errors of metabolism (IEM), most of which are highly heterogeneous in their clinical presentation. Prompt diagnosis is important because disease-specific therapies may be available. In this review, we offer a comprehensive overview of metabolic ataxias summarized by disease, highlighting novel clinical trials and emerging therapies with a particular emphasis on first-in-human gene therapies. We present disease-specific treatments if they exist and review the current evidence for symptomatic treatments of these highly heterogeneous diseases (where cerebellar ataxia is part of their phenotype) that aim to improve the disease burden and enhance quality of life. In general, a multimodal and holistic approach to the treatment of cerebellar ataxia, irrespective of etiology, is necessary to offer the best medical care. Physical therapy and speech and occupational therapy are obligatory. Genetic counseling is essential for making informed decisions about family planning.

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“…The drug, which is approved for NPCD in many countries, but not in the US, slows down disease progression in NPC1-deficient mice (Zervas et al, 2001b), cats (Stein et al, 2012), and patients (Patterson et al, 2020; Patterson et al, 2007; Pineda et al, 2018; Solomon et al, 2022) except for those presenting early infantile disease onset (Freihuber et al, 2023). Within the last decade, numerous therapeutic approaches have been tested, but only few have entered clinical studies, and none has been approved (Bremova-Ertl and Schneider, 2023; Cariati et al, 2021; Heras et al, 2023; Pfrieger, 2023; Sitarska et al, 2021). Therefore, there is a strong need to develop new therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Reversal of pathologic changes in fibroblasts from Niemann-Pick type C disease patients by inhibition of bromodomain and extraterminal proteins

Parente,

Barthelemy,

Tonini

et al. 2023

Preprint

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Niemann-Pick type C disease (NPCD) is a lysosomal disorder whith patients presenting highly variable onset, neurovisceral symptoms and life spans due to defective lipid homeostasis. At present, therapeutic options are limited to palliative and disease-modifying drugs, and there is a continued need for new approaches. Here, we explored bromodomain and extraterminal (BET) proteins as new drug target for NPCD using patient-derived fibroblasts. Treatment of cells with JQ1, a prototype BET inhibitor, enhanced the level of NPC1 protein and increased its presence in lysosomes, diminished lysosomal expansion and cholesterol accumulation and induced extracellular release of lysosomal components in a time- and dose-dependent manner. The reversal of pathologic changes in an established cell model suggest inhibition of BET protein as new therapeutic approach for NPCD.

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Current advancements in therapy for Niemann-Pick disease: progress and pitfalls

Cited by 4 publications

References 133 publications

The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

Inborn Errors of Metabolism with Ataxia: Current and Future Treatment Options

Reversal of pathologic changes in fibroblasts from Niemann-Pick type C disease patients by inhibition of bromodomain and extraterminal proteins

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