%0 Journal Article %J Curr Med Chem %D 2018 %T Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice. %A Marcuzzi, Annalisa %A Loganes, Claudia %A Celeghini, Claudio %A Kleiner, Giulio %K Acyl Coenzyme A %K Cholesterol %K Drug Repositioning %K Farnesyl-Diphosphate Farnesyltransferase %K Humans %K Hypercholesterolemia %K Mevalonate Kinase Deficiency %K Oxazepines %K Phosphotransferases (Alcohol Group Acceptor) %K Piperidines %X

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.

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.

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.

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.

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.

%B Curr Med Chem %V 25 %P 2783-2796 %8 2018 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/28901277?dopt=Abstract %R 10.2174/0929867324666170911161417 %0 Journal Article %J Mol Med Rep %D 2015 %T Alendronate, a double-edged sword acting in the mevalonate pathway. %A Tricarico, Paola Maura %A Girardelli, Martina %A Kleiner, Giulio %A Knowles, Alessandra %A Valencic, Erica %A Crovella, Sergio %A Marcuzzi, Annalisa %X

Aminobisphosphonate aledronate is a compound commonly used clinically for the treatment of osteoporosis and other bone diseases, as a result of it preventing bone resorption. However, in previous years it has also been used to obtain cellular and animal models of a rare genetic disorder termed Mevalonate Kinase Deficiency (MKD). MKD is caused by mutations affecting the mevalonate kinase enzyme, in the cholesterol pathway and alendronate can be used to biochemically mimic the genetic defect as it inhibits farnesyl pyrophosphate synthase in the same pathway. Despite evidence in favor of the inhibition exerted on the mevalonate pathway, there is at least one clinical case of MKD in which alendronate improved not only skeletal and bone fractures, as expected, but also MKD clinical features. Based on this finding, the present study assessed the anti‑inflammatory properties of this aminobisphosphonate in vitro. No anti‑inflammatory effects of alendronate were observed in the in vitro experiments. Since MKD lacks specific treatments, these results may assist scientists and physicians in making the decision as to the most suitable choice of therapeutic compounds for this neglected disease.

%B Mol Med Rep %V 12 %P 4238-42 %8 2015 Sep %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26096667?dopt=Abstract %R 10.3892/mmr.2015.3957 %0 Journal Article %J Apoptosis %D 2015 %T Microglia activation and interaction with neuronal cells in a biochemical model of mevalonate kinase deficiency. %A Tricarico, Paola Maura %A Piscianz, Elisa %A Monasta, Lorenzo %A Kleiner, Giulio %A Crovella, Sergio %A Marcuzzi, Annalisa %X

Mevalonate kinase deficiency is a rare disease whose worst manifestation, characterised by severe neurologic impairment, is called mevalonic aciduria. The progressive neuronal loss associated to cell death can be studied in vitro with a simplified model based on a biochemical block of the mevalonate pathway and a subsequent inflammatory trigger. The aim of this study was to evaluate the effect of the mevalonate blocking on glial cells (BV-2) and the following effects on neuronal cells (SH-SY5Y) when the two populations were cultured together. To better understand the cross-talk between glial and neuronal cells, as it happens in vivo, BV-2 and SH-SY5Y were co-cultured in different experimental settings (alone, transwell, direct contact); the effect of mevalonate pathway biochemical block by Lovastatin, followed by LPS inflammatory trigger, were evaluated by analysing programmed cell death and mitochondrial membrane potential, cytokines' release and cells' morphology modifications. In this experimental condition, glial cells underwent an evident activation, confirmed by elevated pro-inflammatory cytokines release, typical of these disorders, and a modification in morphology. Moreover, the activation induced an increase in apoptosis. When glial cells were co-cultured with neurons, their activation caused an increase of programmed cell death also in neuronal cells, but only if the two populations were cultured in direct contact. Our findings, being aware of the limitations related to the cell models used, represent a preliminary step towards understanding the pathological and neuroinflammatory mechanisms occurring in mevalonate kinase diseases. Contact co-culture between neuronal and microglial cells seems to be a good model to study mevalonic aciduria in vitro, and to contribute to the identification of potential drugs able to block microglial activation for this orphan disease. In fact, in such a pathological condition, we demonstrated that microglial cells are activated and contribute to neuronal cell death. We can thus hypothesise that the use of microglial activation blockers could prevent this additional neuronal death.

%B Apoptosis %V 20 %P 1048-55 %8 2015 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/26003816?dopt=Abstract %R 10.1007/s10495-015-1139-8 %0 Journal Article %J Exp Ther Med %D 2015 %T Pediatric patients with inflammatory bowel disease exhibit increased serum levels of proinflammatory cytokines and chemokines, but decreased circulating levels of macrophage inhibitory protein-1β, interleukin-2 and interleukin-17. %A Kleiner, Giulio %A Zanin, Valentina %A Monasta, Lorenzo %A Crovella, Sergio %A Caruso, Lorenzo %A Milani, Daniela %A Marcuzzi, Annalisa %X

Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory condition of the gastrointestinal tract. Although the causative events that lead to the onset of IBD are yet to be fully elucidated, deregulation of immune and inflammatory mechanisms are hypothesized to significantly contribute to this disorder. Since the onset of IBD is often during infancy, in the present study, the serum values of a large panel of cytokines and chemokines in pediatric patients (<18 years; n=26) were compared with age-matched controls (n=37). While elevations in the serum level of several proinflammatory and immune regulating cytokines were confirmed, such as interleukin (IL)-1β, IL-5, IL-7, interferon (IFN)-γ-inducible protein-10, IL-16, cutaneous T-cell-attracting chemokine, leukemia inhibitory factor, monokine induced by γ-IFN, IFN-α2 and IFN-γ, notably decreased levels of IL-2, IL-17 and macrophage inhibitory protein-1β were also observed. Therefore, while a number of proinflammatory cytokines exhibit increased levels in IBD patients, pediatric IBD patients may also exhibit certain aspects of a reduced immunological response.

%B Exp Ther Med %V 9 %P 2047-2052 %8 2015 Jun %G ENG %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/26136934?dopt=Abstract %R 10.3892/etm.2015.2370 %0 Journal Article %J Int J Mol Sci %D 2014 %T Block of the mevalonate pathway triggers oxidative and inflammatory molecular mechanisms modulated by exogenous isoprenoid compounds. %A Tricarico, Paola Maura %A Kleiner, Giulio %A Valencic, Erica %A Campisciano, Giuseppina %A Girardelli, Martina %A Crovella, Sergio %A Knowles, Alessandra %A Marcuzzi, Annalisa %K Animals %K Apoptosis %K Carotenoids %K Carrier Proteins %K Cell Line %K Cytokines %K Diterpenes %K Humans %K Mevalonate Kinase Deficiency %K Mevalonic Acid %K Mice %K Mitochondria %K Nitric Oxide %K Phytol %K Terpenes %X

Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines' release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD.

%B Int J Mol Sci %V 15 %P 6843-56 %8 2014 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24758928?dopt=Abstract %R 10.3390/ijms15046843 %0 Journal Article %J Gut %D 2014 %T Mevalonate kinase deficiency and IBD: shared genetic background. %A Bianco, Anna Monica %A Girardelli, Martina %A Vozzi, Diego %A Crovella, Sergio %A Kleiner, Giulio %A Marcuzzi, Annalisa %K Genetic Predisposition to Disease %K Humans %K Inflammatory Bowel Diseases %B Gut %V 63 %P 1367-8 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24531851?dopt=Abstract %R 10.1136/gutjnl-2013-306555 %0 Journal Article %J Amyloid %D 2012 %T Serum amyloid A and cholesterol: a pivotal role on inflammation. %A Tricarico, Paola Maura %A Marcuzzi, Annalisa %A Zanin, Valentina %A Kleiner, Giulio %A Bianco, Anna Monica %A Crovella, Sergio %K Animals %K Humans %K Serum Amyloid A Protein %B Amyloid %V 19 %P 163-4; author reply 165-6 %8 2012 Sep %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22624603?dopt=Abstract %R 10.3109/13506129.2012.689266