scholarly journals Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice

2018 ◽  
Vol 25 (24) ◽  
pp. 2783-2796 ◽  
Author(s):  
Annalisa Marcuzzi ◽  
Claudia Loganes ◽  
Claudio Celeghini ◽  
Giulio Kleiner
Keyword(s):  
Mevalonate Pathway ◽  
Clinical Symptoms ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Similar Action ◽  
Cellular Models ◽  
Inflammatory Stimuli

Background: Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome. <p> Objective: Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints’ conditions and their quality of life. <p> Methods: MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block. <p> Results: A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile. <p> Conclusions: Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases.

scholarly journals Real-Life Indications of Interleukin-1 Blocking Agents in Hereditary Recurrent Fevers: Data From the JIRcohort and a Literature Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Caroline Vinit ◽  
Sophie Georgin-Lavialle ◽  
Aikaterini Theodoropoulou ◽  
Catherine Barbier ◽  
Alexandre Belot ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Literature Review ◽  
Disease Activity ◽  
Severe Disease ◽  
Interleukin 1 ◽  
Real Life ◽  
Treat To Target ◽  
Mevalonate Kinase Deficiency ◽  
Combining Data

BackgroundInterleukin (IL)-1 inhibitors represent the main treatment in patients with colchicine-resistant/intolerant familial Mediterranean fever (crFMF), mevalonate kinase deficiency (MKD), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). However, the reasons for the use of IL-1 inhibitors in these diseases are still not completely clarified.ObjectiveIdentify real-life situations that led to initiating anakinra or canakinumab treatment in hereditary recurrent fevers (HRFs), combining data from an international registry and an up-to-date literature review.Patients and MethodsData were extracted from the JIRcohort, in which clinical information (demographic data, treatment, disease activity, and quality of life) on patients with FMF, MKD, and TRAPS was retrospectively collected. A literature search was conducted using Medline, EMBASE, and Cochrane databases.ResultsComplete data of 93 patients with HRF (53.8% FMF, 31.2% MKD, and 15.1% TRAPS) were analyzed. Data from both the registry and the literature review confirmed that the main reasons for use of IL-1 blockers were the following: failure of previous treatment (n = 57, 61.3% and n = 964, 75.3%, respectively), persistence of disease activity with frequent attacks (n = 44, 47.3% and n = 1,023, 79.9%) and/or uncontrolled inflammatory syndrome (n = 46, 49.5% and n = 398, 31.1%), severe disease complication or associated comorbidities (n = 38, 40.9% and n = 390, 30.4%), and worsening of patients’ quality of life (n = 36, 38.7% and n = 100, 7,8%). No reasons were specified for 12 (16.4%) JIRcohort patients and 154 (12%) patients in the literature.ConclusionIn the absence of standardized indications for IL-1 inhibitors in crFMF, MKD, and TRAPS, these results could serve as a basis for developing a treat-to-target strategy that would help clinicians codify the therapeutic escalation with IL-1 inhibitors.

Mevalonate Kinase Deficiency: Disclosing the Role of Mevalonate Pathway Modulation in Inflammation

2012 ◽  
Vol 18 (35) ◽  
pp. 5746-5752 ◽  
Author(s):  
Annalisa Marcuzzi ◽  
Sergio Crovella ◽  
Lorenzo Monasta ◽  
Liza Vecchi Brumatti ◽  
Marco Gattorno ◽  
...  
Keyword(s):  
Mevalonate Pathway ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase

scholarly journals Tocilizumab for the Treatment of Mevalonate Kinase Deficiency

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Nadia K. Rafiq ◽  
Helen Lachmann ◽  
Frodi Joensen ◽  
Troels Herlin ◽  
Paul A. Brogan
Keyword(s):  
Autoinflammatory Disease ◽  
Energy Levels ◽  
Poor Quality ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Recessive Mutations ◽  
Limited Experience ◽  
Life Threatening ◽  
Important Addition

Mevalonate kinase deficiency (MKD) is a severe autoinflammatory disease caused by recessive mutations in MVK resulting in reduced function of the enzyme mevalonate kinase, involved in the cholesterol/isoprenoid pathway. MKD presents with periodic episodes of severe systemic inflammation, poor quality of life, and life-threatening sequelae if inadequately treated. We report the case of a 12-year-old girl with MKD and severe autoinflammation that was resistant to IL-1 and TNF-αblockade. In view of this, she commenced intravenous tocilizumab (8 mg/kg every 2 weeks), a humanised monoclonal antibody targeting the IL-6 receptor (IL-6R) that binds to membrane and soluble IL-6R, inhibiting IL-6-mediated signaling. She reported immediate cessation of fever and marked improvement in her energy levels following the first infusion; after the fifth dose, she was in complete clinical and serological remission, now sustained for 24 months. This is one of the first reported cases of a child with MKD treated successfully with tocilizumab and adds to the very limited experience of this treatment for MKD. IL-6 blockade could therefore be an important addition to the armamentarium for the treatment of this rare monogenic autoinflammatory disease.

scholarly journals Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

2017 ◽  
Vol 41 (4) ◽  
pp. 1649-1660 ◽  
Author(s):  
Paola Maura Tricarico ◽  
Alessandra Romeo ◽  
Rossella Gratton ◽  
Sergio Crovella ◽  
Fulvio Celsi
Keyword(s):  
Cell Death ◽  
Mevalonate Pathway ◽  
Cell Model ◽  
Neuroblastoma Cell ◽  
Neuronal Cell ◽  
Autophagic Flux ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Protein Prenylation ◽  
Prenylated Proteins

Background/Aims: Mevalonate Kinase Deficiency (MKD), is a hereditary disease due to mutations in mevalonate kinase gene (MVK). MKD has heterogeneous clinical phenotypes: the correlation between MVK mutations and MKD clinical phenotype is still to be fully elucidated. Deficiency of prenylated proteins has been hypothesized as possible MKD pathogenic mechanism. Based on this hypothesis and considering that neurologic impairment characterizes Mevalonic Aciduria (MA), the most severe form of MKD, we studied the effects of I268T and N301T MVK mutations on protein prenylation, autophagy and programmed cell death in SH-SY5Y neuroblastoma cell lines. Methods: SH-SY5Y cells were transiently transfected, with the pCMV-6 plasmid containing MVK wild type and the two mutated sequences. Protein prenylation levels were evaluated using GFP-RhoA-F to assess farnesylation, and GFP-RhoA to evaluate geranylgeranylation; autophagy was measured by evaluating LC3 and p62 protein levels, while Annexin V-FITC and Propidium Iodide staining allowed apoptosis detection. Results: MVK mutants’ over-expression causes decreased levels of farnesylation and geranylgeranylation, and also increased LC3 lipidation in SH-SY5Y, with concomitant p62 accumulation. Treatment with bafilomycin A1 (an inhibitor of vacuolar H+-ATPase, a late autophagy inhibitor) further increase LC3-II and p62 levels, suggesting that degradation of autophagolysosome could be impaired. SH-SY5Y, with both MVK mutants, showed apoptosis increase; the presence of N301T associated with augmented cell death. Conclusions: We hypothesize that mevalonate pathway impairment causes alteration of farnesylation and geranylgeranylation proteins and alteration of the autophagic flux; these changes can induce apoptosis, possibly more relevant in the presence of N301T mutation.

Efficacy of Continuous Interleukin 1 Blockade in Mevalonate Kinase Deficiency: A Multicenter Retrospective Study in 13 Adult Patients and Literature Review

2018 ◽  
Vol 45 (3) ◽  
pp. 425-429 ◽  
Author(s):  
Samuel Deshayes ◽  
Sophie Georgin-Lavialle ◽  
Arnaud Hot ◽  
Cécile-Audrey Durel ◽  
Eric Hachulla ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Literature Review ◽  
Partial Remission ◽  
Interleukin 1 ◽  
Adult Patients ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Data Support ◽  
Therapeutic Outcomes

Objective.To report efficacy and tolerance of interleukin 1 blockade in adult patients with mevalonate kinase deficiency (MKD).Methods.We retrospectively collected data on 13 patients with MKD who had received anakinra (n = 10) and canakinumab (n = 7).Results.Anakinra resulted in complete or partial remission in 3/10 and 5/10 patients, respectively, and no efficacy in 2/10, but a switch to canakinumab led to partial remission. Canakinumab resulted in complete or partial remission in 3/7 and 4/7 patients, respectively.Conclusion.These data support frequent partial responses, showing a better response with canakinumab. The genotype and therapeutic outcomes correlation should help in the personalization of treatment.

scholarly journals Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency

Rheumatology ◽  
2012 ◽  
Vol 51 (10) ◽  
pp. 1855-1859 ◽  
Author(s):  
C. Galeotti ◽  
U. Meinzer ◽  
P. Quartier ◽  
L. Rossi-Semerano ◽  
B. Bader-Meunier ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase

Mevalonate Kinase Deficiency: A Cause of Severe Very-Early-Onset Inflammatory Bowel Disease

2021 ◽  
Author(s):  
Brigitte Bader-Meunier ◽  
Andreia Luís Martins ◽  
Fabienne Charbit-Henrion ◽  
Ulrich Meinzer ◽  
Alexandre Belot ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Early Onset ◽  
Interleukin 1 ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Peritoneal Adhesions ◽  
History Of ◽  
Inflammatory Bowel ◽  
Chronic Fever

Abstract Mevalonate kinase deficiency should be considered in patients with severe very-early-onset inflammatory bowel disease (IBD), especially in patients with a history of recurrent or chronic fever, peritoneal adhesions, and atypical IBD pathology. Anti-interleukin-1 therapy may be efficacious in these patients with monogenic very-early-onset IBD.

scholarly journals Monogenic auto-inflammatory diseases in children and adults: what a rheumatologist should know

2019 ◽  
Vol 57 (2) ◽  
pp. 125-132 ◽  
Author(s):  
S. O. Salugina ◽  
E. S. Fedorov ◽  
E. M. Agafonova
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Molecular Genetic ◽  
Disease Onset ◽  
Organ Damage ◽  
Genetic Characteristics ◽  
Current State ◽  
Principles Of Treatment ◽  
Satisfactory Quality

The article presents information on the current state of the problem of autoinflammatory diseases (AID) in rheumatology, reflects the clinical and demographic, laboratory and molecular genetic characteristics of the main monogenic AID (mAID), the most common in real clinical practice. Approaches to the diagnosis and differential diagnosis of these conditions are presented. The variants of classification and diagnostic criteria of the most studied mAID are discussed. The principles of treatment with an emphasis on the use of targeted therapy with interleukin 1 (IL1) inhibitors are shown. The clinical examples demonstrate the variants of late diagnosis of the mAID in adult patients with the disease onset in childhood. Different variants of multi-organ damage are considered. Effectiveness of therapy with IL1β inhibitor kanakinumab is demonstrated. Even in such cases it provided the possibility of significant symptoms regression and restoration of a satisfactory quality of life.

scholarly journals Intranasal glucocorticosteroids for the complex treatment of patients with chronic diseases of the nose and paranasal sinuses

2020 ◽  
pp. 66-70
Author(s):  
P. A. Kochetkov ◽  
V. A. Svistushkin ◽  
E. S. Shchennikova
Keyword(s):  
Quality Of Life ◽  
Chronic Rhinosinusitis ◽  
Paranasal Sinuses ◽  
Clinical Symptoms ◽  
Inflammatory Diseases ◽  
Mometasone Furoate ◽  
Acute Rhinosinusitis ◽  
Airway Pathology ◽  
Nose And Paranasal Sinuses

Intriduction. Chronic rhinitis and rhinosinusitis noticeably deteriorate the patients’ quality of life and lead to the accompanying upper airway pathology development. The main purpose of treatment of this group of patients is to decrease severity of symptoms and the second one to prevent complications. The optimal therapy will help patients to maintain their lifestyle. Intranasal glucocorticosteroids are first-line drugs to treat acute rhinosinusitis or exacerbations of chronic rhinosinusitis in adults (including the elderly) and adolescents aged 12 years and older as an auxiliary therapeutic agent if treated by antibiotics, and to treat acute rhinosinusitis with mild to moderate symptoms without signs of severe bacterial infection. In the number of trials, mometasone furoate effectiveness in regard to decreasing of prominent symptoms with no side effects development has been shown.Objective: this article reviews available data on the effectiveness of intranasal corticosteroids – mometasone furoate – in the treatment of different forms of chronic inflammatory diseases of the nose and paranasal sinuses.Methods: information for this review was identified through a RISC and MEDLINE databases applying key words.Conclusions: based on the available data, treatment of chronic rhinosinusites and rhinitis should be initiated by conservative therapy. Summarizing information from the available literature we can conclude that treatment by mometasone furoate improve quality of life decreasing clinical symptoms of chronic rhinosinusitis and rhinitis.

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