Efficacy and safety of arimoclomol in <scp>Niemann‐Pick</scp> disease type C: Results from a double‐blind, randomised, placebo‐controlled, multinational phase 2/3 trial of a novel treatment

Mengel, Karl Eugen; Patterson, Marc C.; Riol, Rosalia Maria Da; Toro, Mireia del; Deodato, Federica; Gautschi, Matthias; Grünewald, Stéphanie; Grønborg, Sabine; Harmatz, Paul; Héron, Bénédicte; Maier, Esther M.; Roubertie, Agathe; Santra, Saikat; Tylki‐Szymańska, Anna; Day, Simon; Andreasen, Anne Katrine; Geist, Marie Aavang; Petersen, Nikolaj H.T.; Ingemann, Linda; Hansen, Thomas; Blaettler, Thomas; Kirkegaard, Tove; Dali, Christine í

doi:10.1002/jimd.12428

Cited by 38 publications

(35 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Even with access to next‐generation sequencing, difficulties in establishing a diagnosis of NPC often arise, for example when trying to decipher identified variants of unknown significance. Hence, the development of robust disease‐specific markers for diagnosis, accurate disease monitoring, and assessment of efficacy of emerging novel, targeted therapies 5 is crucial.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, early detection is paramount for patients with disorders affecting the developing brain or resulting in neurodegeneration in order to achieve the best clinical outcomes 3 . This is more pertinent in the current era of personalized medicine, where an ever‐increasing number of novel, targeted, and disease‐specific therapeutic approaches are becoming available for neurological diseases that in the past were considered untreatable 4–6 …”

mentioning

confidence: 99%

See 1 more Smart Citation

Niemann–Pick type C disease as proof‐of‐concept for intelligent biomarker panel selection in neurometabolic disorders

Papandreou

Doykov

Śpiewak

et al. 2022

Develop Med Child Neuro

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Niemann–Pick type C disease as proof‐of‐concept for intelligent biomarker panel selection in neurometabolic disorders

Papandreou

Doykov

Śpiewak

et al. 2022

Develop Med Child Neuro

View full text Add to dashboard Cite

show abstract

“…Accordingly, efforts have been made to identify drug candidates that lead to upregulation of NPC1 variant expression, thereby increasing the NPC1 functional capacity. This resulted, among others, in the identification of ryanodine receptor antagonists [31], histone deacetylase inhibitors (HDACi, [32,33]) and arimoclomol [34,35] to modulate the NPC1 folding environment.…”

Section: Discussionmentioning

confidence: 99%

Assessment of FDA-Approved Drugs as a Therapeutic Approach for Niemann-Pick Disease Type C1 Using Patient-Specific iPSC-Based Model Systems

Völkner

Pantoom

Liedtke

et al. 2022

Cells

View full text Add to dashboard Cite

Niemann-Pick type C1 (NP-C1) is a fatal, progressive neurodegenerative disease caused by mutations in the NPC1 gene. Mutations of NPC1 can result in a misfolded protein that is subsequently marked for proteasomal degradation. Such loss-of-function mutations lead to cholesterol accumulation in late endosomes and lysosomes. Pharmacological chaperones (PCs) are described to protect misfolded proteins from proteasomal degradation and are being discussed as a treatment strategy for NP-C1. Here, we used a combinatorial approach of high-throughput in silico screening of FDA-approved drugs and in vitro biochemical assays to identify potential PCs. The effects of the hit compounds identified by molecular docking were compared in vitro with 25-hydroxycholesterol (25-HC), which is known to act as a PC for NP-C1. We analyzed cholesterol accumulation, NPC1 protein content, and lysosomal localization in patient-specific fibroblasts, as well as in neural differentiated and hepatocyte-like cells derived from patient-specific induced pluripotent stem cells (iPSCs). One compound, namely abiraterone acetate, showed comparable results to 25-HC and restored NPC1 protein level, corrected the intracellular localization of NPC1, and consequently decreased cholesterol accumulation in NPC1-mutated fibroblasts and iPSC-derived neural differentiated and hepatocyte-like cells. The discovered PC altered not only the pathophysiological phenotype of cells carrying the I1061T mutation— known to be responsive to treatment with PCs—but an effect was also observed in cells carrying other NPC1 missense mutations. Therefore, we hypothesize that the PCs studied here may serve as an effective treatment strategy for a large group of NP-C1 patients.

show abstract

“…Various strategies are currently being studied to overcome this caveat, and recently, the intraventricular administration of ERT has been shown to be effective in neuronal ceroid lipofuscinosis type 2 22. Depending on the neurometabolic disease, increasing the enzyme activity may be possible through other strategies than ERT: (1) the administration of a high-dose vitamin or an enzymatic cofactor , such as vitamin B6 (pyridoxine) in certain forms of classic homocystinuria (cystathionine beta-synthase deficiency)23; (2) the administration of a molecule with a chaperone effect that will limit enzyme degradation, like migalastat in Fabry disease or arimoclomol in Niemann-Pick C disease (that increases heat shock protein expression)24 25; (3) haematopoietic stem cell transplant of cells expressing a normal activity of the deficient enzyme, whether allogenous (classically used in X-ALD, Krabbe disease and metachromatic leucodystrophy)26–28 or ex vivo genetically modified autologous stem cells expressing the deficient enzyme in a supraphysiological manner (recent trials have demonstrated the efficacy of this latter strategy in children with X-ALD and metachromatic leucodystrophy)29 30; and (4) liver and/or kidney transplant with restricted indications in organic acidurias and UCDs. Without directly acting on enzyme activity, some treatments similarly aim to support the deficient metabolic function: this mainly concerns defects of energy metabolism (Glut1 deficiency, PDC deficiency and mitochondrial beta-oxidation disorders) for which specific ketogenic diets can restore energy production, bypassing the altered energetic pathway.…”

Section: Key Concepts In Neurometabolic Diseasesmentioning

confidence: 99%

Diagnostic approach in adult-onset neurometabolic diseases

Fernández‐Eulate

Carreau²,

Benoist

et al. 2022

J Neurol Neurosurg Psychiatry

View full text Add to dashboard Cite

Neurometabolic diseases are a group of individually rare but numerous and heterogeneous genetic diseases best known to paediatricians. The more recently reported adult forms may present with phenotypes strikingly different from paediatric ones and may mimic other more common neurological disorders in adults. Furthermore, unlike most neurogenetic diseases, many neurometabolic diseases are treatable, with both conservative and more recent innovative therapeutics. However, the phenotypical complexity of this group of diseases and the growing number of specialised biochemical tools account for a significant diagnostic delay and underdiagnosis. We reviewed all series and case reports of patients with a confirmed neurometabolic disease and a neurological onset after the age of 10 years, with a focus on the 36 treatable ones, and classified these diseases according to their most relevant clinical manifestations. The biochemical diagnostic approach of neurometabolic diseases lays on the use of numerous tests studying a set of metabolites, an enzymatic activity or the function of a given pathway; and therapeutic options aim to restore the enzyme activity or metabolic function, limit the accumulation of toxic substrates or substitute the deficient products. A quick diagnosis of a treatable neurometabolic disease can have a major impact on patients, leading to the stabilisation of the disease and cease of repeated diagnostic investigations, and allowing for familial screening. For the aforementioned, in addition to an exhaustive and clinically meaningful review of these diseases, we propose a simplified diagnostic approach for the neurologist with the aim to help determine when to suspect a neurometabolic disease and how to proceed in a rational manner. We also discuss the place of next-generation sequencing technologies in the diagnostic process, for which deep phenotyping of patients (both clinical and biochemical) is necessary for improving their diagnostic yield.

show abstract

Efficacy and safety of arimoclomol in Niemann‐Pick disease type C: Results from a double‐blind, randomised, placebo‐controlled, multinational phase 2/3 trial of a novel treatment

Cited by 38 publications

References 44 publications

Niemann–Pick type C disease as proof‐of‐concept for intelligent biomarker panel selection in neurometabolic disorders

Niemann–Pick type C disease as proof‐of‐concept for intelligent biomarker panel selection in neurometabolic disorders

Assessment of FDA-Approved Drugs as a Therapeutic Approach for Niemann-Pick Disease Type C1 Using Patient-Specific iPSC-Based Model Systems

Diagnostic approach in adult-onset neurometabolic diseases

Contact Info

Product

Resources

About