Mario Negri Institute for Pharmacological Research

Bergamo, Italy

Mario Negri Institute for Pharmacological Research

Bergamo, Italy

The Mario Negri Institute for Pharmacological Research is a nonprofit research institute dedicated to clinical and biomedical research. It was made possible by a special bequest of Milan philanthropist it:Mario Negri . It was founded in 1961 although it started working in Milan from 1st Feb 1963. There are branches of the institute in Bergamo, Ranica , and at Santa Maria Imbaro, near Chieti.Founder and director from 1961 is prof. it:Silvio Garattini. Wikipedia.

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News Article | April 26, 2017
Site: www.eurekalert.org

Amsterdam, The Netherlands, April 26, 2017 - The use of animals in biomedical research has long been the focus of campaigns by animal rights activists. Two leading scientists writing in the European Journal of Internal Medicine give their expert view of the importance of animal testing to medical progress and present ways it could be further improved to yield more useful clinical results. "It cannot be stressed enough that animal studies have led to the production of drugs that have affected the epidemiology of human pathology, contributing to prolonging life. There is no magic formula at present to predict - at the preclinical level - the therapeutic value of a drug for people with a disease. Preclinical studies are needed in order to formulate hypotheses that justify clinical trials. Without these preliminary in vitro and in vivo studies in selected animal species, it would be unethical to test still unproven chemicals in humans," explains Silvio Garattini, MD, Founder and Director of the Mario Negri Institute for Pharmacological Research, Milan, Italy. His co-author, Giuliano Grignaschi, PhD, head of the Animal Care Unit at the Mario Negri Institute and vice president of the Basel Declaration Society in Switzerland, which promotes information about animal testing, adds that "the pressure of public opinion, particularly of organized groups of 'animalists,' obliges preclinical and clinical scientists to come out of their 'ivory tower' to explain the complexity of translating research results from animals to man." Vaccines against poliomyelitis, meningitis, and rotaviruses are excellent examples in which animal testing, and the translation from animals to man, have proved effective, as are a number of antibiotics and the recent agents against HIV and hepatitis C viruses. However, the authors acknowledge that at the other extreme, there have been poor correlations between results in animals and man in several diseases such as stroke, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease, and they summarize several analyses that have set out to understand why results in animals and man differ in these cases. The authors present four ways in which animal experiments could be improved in order to increase their probability of predicting useful clinical results. First, studies need to be intensified and techniques developed to improve and reduce the use of animals following the 3R rule (Replace, Reduce, and Refine). These guiding principles underpin the humane use of animals in scientific research and any researcher planning to use animals in their research must first show why there is no alternative and what will be done to minimize numbers and suffering, Second, rules developed to improve clinical trials should be incorporated into animal testing to minimize bias. Third, research is needed to improve the translation of animal research to patients, they argue, pointing out that the National Institutes of Health (NIH) in the U.S. has recently launched a program to train preclinical scientists to plan their experimental trials better by applying the same rules as for clinical trials. "There is, however, a pressing need for responsibility in the scientific community, not only among scientists, but also in the editorial boards of journals and funding bodies to focus more on the quality of articles and research proposals dealing with animal investigation," they note. Fourth, once bias has been taken care of, difficulties remain for each specific demand for therapy - symptomatic, preventive, or curative - of finding the animal species that best mimics the human condition. Animals with specific pathology such as diabetes, high cholesterol, and hypertension have helped scientists develop antidiabetic, hypocholesterolemic, and antihypertensive drugs, which have been effective in man and are widely used. More studies are needed in aged animals to mimic the condition of elderly people with co-morbidities that require several drugs. Different chemical mediators may be important tools for discovering new drugs once they have been found to exert similar effects in a given animal species and man. "Limitations to the use of animals, particularly other than rodents, are an obstacle to obtaining a wider spectrum of activity across species which may help in deciding when a treatment is suitable for patients," says Dr Grignaschi. "Nevertheless, there is room for substantial improvement in the protocols of animal tests to boost their credibility and reproducibility. "For the time being, animal models remain the best alternative given the limited usefulness of computer and in vitro models, and their use must continue, considering that patients cannot just wait for better tests to cure their suffering," concludes Prof. Garattini.


Esperite's (Euronext: ESP) biotech subsidiary The Cell Factory develops extracellular vesicles (EVs) biologic drug (CF-MEV-117) for treatment of drug-resistant epilepsy in children. The consortium sponsored by The Cell Factory have achieved an important milestone in the CF-MEV-117 drug development confirming an anti-inflammatory and immunosuppressive activity of the CF-MEV-117 in a dose response manner. Full results will be presented during the International Society for Extracellular Vesicles (ISEV) meeting in Toronto, Canada from 18-21 May, 2017. The Cell Factory, a company of Esperite Group in collaboration with Bambino Gesù Children's Hospital in Rome, Mario Negri Institute for Pharmacological Research in Milan and Women's and Children's Health Department of the University of Padua are developing the EVs drug candidate (CF-MEV-117) for treatment of drug resistant epilepsy in children. The consortium is investigating the immunomodulatory properties of EVs derived from MSCs in several in vitro and in vivo models. It has been demonstrated by independent research groups that inhibitory effects of MSCs on human leukocytes was mediated by secreted EVs. Subsequently, it was demonstrated by our partners that MSC-derived EVs were responsible for inhibition of B-cell proliferation and differentiation and activation of T-cell apoptosis (Budoni et al., 2013; Del Fattore et al., 2015). These results have been recently confirmed with the CF-MEV-117 drug candidate manufactured by The Cell Factory. Preclinical and clinical study demonstrate that brain inflammation could be responsible for severe epileptic seizures. Pro-inflammatory molecules secreted by the stimulated glial cells are responsible for a status epilepticus. Therefore, immunomodulatory and anti-inflammatory treatment focused on astrocytes and microglia cells are reducing or eliminating symptoms of epilepsy and can prevent a relapse of the disease in the future. The project is investigating anti-inflammatory and anti-epileptic effect of the CF-MEV-117 drug candidate in both an acute phase of epilepsy and preventing development of a chronic disease. In addition, we expect that CF-MEV-117 will demonstrate much broader therapeutic effect in neurology influencing neural cells apoptosis, neurons hyperexcitability, and neurogenesis process leading to faster brain regeneration. This will allow using the MSC-derived EVs in treatment of unmet medical needs e.g. stroke, TBI, spinal cord injury. EVs stability and small size are the key advantages allowing their immediate use in acute injuries and the drug penetration through the blood brain barrier. CF-MEV-117 is produced using a proprietary technology developed by The Cell Factory for a large-scale production of ultra-pure EVs, using fully defined, serum-free, xeno-free culture media with no use of animal-derived components and human platelet lysates at any stage of the production process. Production is performed in a closed and scalable stirring bioreactors including a downstream processing based on the integrated sequential filtration system. EVs are continuously secreting by expanded MSCs allowing multiple harvests during one production cycle. This approach significantly reduces the contamination risk, production time, staff, GMP labs use and the cost of goods. Effectively the production of the single EVs dose is now up to 10 times cheaper when comparing to the allogenic MSCs dose equivalent. CF-MEV-117 product is sterilised by filtration during production process what is not possible for any cell therapy products (ATMPs). CF-MEV-117 product has very high batch-to-batch reproducibility. Product analysis is performed using broad range of state-of-the-art techniques i.e. NTA, immunophenotyping, proteomics, among others. Several surface markers have been analysed for CF-MEV-117 product including the tetraspanin transmembrane proteins characteristic for EVs (CD9+, CD63+ and CD81+). Interestingly, CF-MEV-117 EVs do not express HLA-ABC and HLA-DRPQ what increases the drug's safety in human use. The consortium is fully focused on demonstration of the CF-MEV-117 product's anti-inflammatory and immunosuppressive activity and its mode of action. For that purpose T-cells and B-cells have been isolated from human peripheral blood and the cells were stimulated using anti-CD3/CD28 and CpG, respectively. CF-MEV-117 product has increased the activated T reg proliferation and effectively the T reg / T eff ration. In addition, reduction of the activated B cells proliferation and plasma cell differentiation have been observed in response to CF-MEV-117. This confirms previous results obtained using the research-grade EVs. It is worth stressing that the experiments were performed in parallel with the MSCs used for the CF-MEV-117 production. The results have confirmed the same anti-inflammatory effect of the MSCs and the MSC-derived EVs (CF-MEV-117) on stimulated human leukocytes. The CF-MEV-117 drug's effect was observed in a dose responsive manner. The next step is confirmation of the CF-MEV-117 in in vivo models before the clinical translation. EVs including exosomes are nanometre-size, natural biological particles secreted by different types of cells in vivo and in vitro. They contain proteins, growth factors, mRNA and other molecules responsible for the therapeutic effect of MSCs. In addition, EVs have several advantages over allogenic MSCs e.g.: up to 10-times lower production costs, no risk of uncontrolled proliferation and differentiation, lower risk of immune response and easy and safe delivery into different tissues and organs in vivo. High stability allows for easy transport and storage of the "ready-to-use" products. The Cell Factory is developing MSC-EVs drug candidate (CF-MEV-117) for treatment of untreatable-yet acute and chronic drug-resistant epilepsy. Epilepsy carries significant detrimental effects on the quality of life and can lead to a secondary brain damage. The disease can have different etiology, including stroke, brain trauma, and neuro-inflammation. Epilepsy is one of the most common brain diseases affecting about 1 in 100 children under 17-year old according to CDC. Severity of the seizures is variable and the antiepileptic drugs are effective only in about 2/3 of the patients. CDC estimated annual costs related to epilepsy exceeds 15 billion USD in the United States alone. It is expected that EVs products will be effective in treatment of other neuroinflammatory-related injuries of central nervous system. Moreover, EVs will be able to target an acute diseases i.e. TBI, brain stroke, spinal cord injury, more effectively when comparing to allogenic MSCs, due to the EV's stability and easier administration at shorter time what is critical for successful therapy. Diseases of central nervous system are among most devastating for patients and their relatives. Neurological disorders are generating a significant additional cost related to hospitalisation, rehabilitation, often eliminate the patients and their relatives from a job market. CDC estimated that annual costs related to epilepsy exceeds 15 billion USD in the United States alone with 50 million patients worldwide (WHO). Cost related to brain stroke in the United States is estimated to 34 billion USD per year (CDA), with 15 million new patients worldwide each year (WHO). Cumulative cost related to traumatic brain injury (TBI) and spinal cost injury in the United States is over 80 billion USD per year (CDA and AANS), with up to 0.5 million new incidents of spinal cord injury and 10 million of TBI per year (WHO). Most of these diseases have no effective therapy yet. The consortium led by Esperite's The Cell Factory is gathering the leading teams in paediatric regenerative medicine, neurology, gastroenterology, immunology and EVs science. The CF-MEV-107 product is developing in collaboration with Professor Maurizio Muraca's team at the Department of Women's and Children's Health at the University of Padova in Italy. The CF-MEV-117 product is developing in collaboration with Professor Federico Vigevano and Dr Alessandra Fierabracci team at Bambino Gesù Children's Hospital in Rome, Italy and with Dr. Annamaria Vezzani at Mario Negri Institute in Milan, Italy. Frederic Amar, CEO: "The Cell Factory is focused on development, clinical translation and commercialization of the advanced extracellular vesicles (EVs) biologic drugs and autologous stem cell therapies. The Cell Factory goal is to master the development and production of extracellular vesicles drugs in treatment of different indications." ESPERITE Group, listed at Euronext Amsterdam and Paris, is a leading international company in regenerative and predictive medicine established in 2000. The Cell Factory is a biotech company, a subsidy of the Esperite group, developing highest quality therapeutic tools for affordable regenerative medicine. The Cell Factory led by Dr. Marcin Jurga is focused on development, clinical translation and commercialization of the advanced extracellular vesicles (EVs) biologic drugs and autologous stem cell therapies. The Cell Factory goal is to become a leader in development and production of extracellular vesicles drugs in treatment of different indications i.e. graft versus host disease (GvHD) after solid organ and cell transplantations, arthritis, multiple sclerosis, cystic fibrosis, stroke, traumatic brain and spinal cord injury, newborn encephalopathy, and type 1 diabetes among others. The Cell Factory focuses on development of the selected EVs drug candidates from a TRL 4 (non-GLP POC) until TRL 6-7 (Clinical phase II). The Cell Factory is looking for partners and investors who are interested in a rapidly growing, disruptive technology of EVs biological drugs. We are looking for different collaboration models including out-licencing, technology transfer and joint venture product development and dilutive investments. The Cell Factory owns the full rights of a broad international patent family enabling MSC-derived extracellular vesicles (EVs) use in treatment of autoimmune, chronic and acute inflammatory diseases. The patents have been already granted in Europe and recently in China. The Cell Factory is developing the EVs biologic drug products for multiple indications in immunology, neurology and gastroenterology. The leading products are CF-MEV-107 for treatment of Crohn's disease (drug resistant perianal fistulae) and CF-MEV-117 for treatment of drug resistant epilepsy in children. The CF-MEV-107 product is ready for clinical translation and the consortium of leading academic and clinical teams sponsored by The Cell Factory is preparing the CF-MEV-107 product for first in man clinical translation in 2017. To learn more about ESPERITE Group, or to book an interview with CEO Frederic Amar: +31 575 548 998 - ir@esperite.com or visit the websites at www.esperite.com, www.cell-factory.com, www.cryo-save.com and www.genoma.com.


Devinsky O.,New York University | Vezzani A.,Mario Negri Institute for Pharmacological Research | Najjar S.,New York University | De Lanerolle N.C.,Yale University | Rogawski M.A.,University of California at Davis
Trends in Neurosciences | Year: 2013

Epilepsy is characterized by recurrent spontaneous seizures due to hyperexcitability and hypersynchrony of brain neurons. Current theories of pathophysiology stress neuronal dysfunction and damage, and aberrant connections as relevant factors. Most antiepileptic drugs target neuronal mechanisms. However, nearly one-third of patients have seizures that are refractory to available medications; a deeper understanding of mechanisms may be required to conceive more effective therapies. Recent studies point to a significant contribution by non-neuronal cells, the glia - especially astrocytes and microglia - in the pathophysiology of epilepsy. This review critically evaluates the role of glia-induced hyperexcitability and inflammation in epilepsy. © 2012 Elsevier Ltd.


Vezzani A.,Mario Negri Institute for Pharmacological Research | Friedman A.,Ben - Gurion University of the Negev | Dingledine R.J.,Emory University
Neuropharmacology | Year: 2013

One compelling challenge in the therapy of epilepsy is to develop anti-epileptogenic drugs with an impact on the disease progression. The search for novel targets has focused recently on brain inflammation since this phenomenon appears to be an integral part of the diseased hyperexcitable brain tissue from which spontaneous and recurrent seizures originate. Although the contribution of specific proinflammatory pathways to the mechanism of ictogenesis in epileptic tissue has been demonstrated in experimental models, the role of these pathways in epileptogenesis is still under evaluation. We review the evidence conceptually supporting the involvement of brain inflammation and the associated blood-brain barrier damage in epileptogenesis, and describe the available pharmacological evidence where post-injury intervention with anti-inflammatory drugs has been attempted. Our review will focus on three main inflammatory pathways, namely the IL-1 receptor/Toll-like receptor signaling, COX-2 and the TGF-β signaling. The mechanisms underlying neuronal-glia network dysfunctions induced by brain inflammation are also discussed, highlighting novel neuromodulatory effects of classical inflammatory mediators such as cytokines and prostaglandins. The increase in knowledge about a role of inflammation in disease progression, may prompt the use of specific anti-inflammatory drugs for developing disease-modifying treatments. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. © 2012 Elsevier Ltd. All rights reserved.


Vezzani A.,Mario Negri Institute for Pharmacological Research | Viviani B.,University of Milan
Neuropharmacology | Year: 2015

Abstract Increasing evidence underlines that prototypical inflammatory cytokines (IL-1β, TNF-α and IL-6) either synthesized in the central (CNS) or peripheral nervous system (PNS) by resident cells, or imported by immune blood cells, are involved in several pathophysiological functions, including an unexpected impact on synaptic transmission and neuronal excitability. This review describes these unconventional neuromodulatory properties of cytokines, that are distinct from their classical action as effector molecules of the immune system. In addition to the role of cytokines in brain physiology, we report evidence that dysregulation of their biosynthesis and cellular release, or alterations in receptor-mediated intracellular pathways in target cells, leads to neuronal cell dysfunction and modifications in neuronal network excitability. As a consequence, targeting of these cytokines, and related signalling molecules, is considered a novel option for the development of therapies in various CNS or PNS disorders associated with an inflammatory component. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. © 2014 Elsevier Ltd.


Iori V.,Mario Negri Institute for Pharmacological Research | Frigerio F.,Mario Negri Institute for Pharmacological Research | Vezzani A.,Mario Negri Institute for Pharmacological Research
Current Opinion in Pharmacology | Year: 2016

A complex set of inflammatory molecules and their receptors has been described in epileptogenic foci in different forms of pharmacoresistant epilepsies. By activating receptor-mediated pathways in neurons, these molecules have profound neuromodulatory effects that are distinct from their canonical activation of immune functions. Importantly, the neuromodulatory actions of some inflammatory molecules contribute to hyperexcitability in neural networks that underlie seizures. This review summarizes recent findings related to the role of cytokines (IL-1beta and TNF-alpha) and danger signals (HMGB1) in decreasing seizure threshold, thereby contributing to seizure generation and the associated neuropathology. We will discuss preclinical studies suggesting that pharmacological inhibition of specific inflammatory signals may be useful to treat drug-resistant seizures in human epilepsy, and possibly arrest epileptogenesis in individuals at risk of developing the disease. © 2015 Elsevier Ltd.


Romagnani P.,University of Florence | Remuzzi G.,Mario Negri Institute for Pharmacological Research
Trends in Endocrinology and Metabolism | Year: 2013

Chronic kidney disease represents a major health problem worldwide. Although the kidney has the ability to repopulate structures that have sustained some degree of injury, the mechanisms underlying its regenerative capacity have been unclear. Recent evidence now supports the existence of a renal progenitor system able to replace podocytes and tubular cells, localized within the urinary pole of Bowman's capsule and along the tubule. Altered growth or differentiation of renal progenitors has been reported in several renal disorders including diabetic nephropathy. Pharmacological modulation of renal progenitor growth or differentiation can enhance kidney regeneration, suggesting that treatments aimed at reversing kidney injury are possible. Renal progenitors may represent a novel target in diabetic nephropathy and other kidney disorders. © 2012 Elsevier Ltd.


Zito E.,Mario Negri Institute for Pharmacological Research
Free Radical Biology and Medicine | Year: 2015

Oxidative protein folding in the endoplasmic reticulum (ER) is an essential function of eukaryotic cells that requires the relaying of electrons between the proteinaceous components of the pathway. During this process, protein disulfide isomerase (PDI) chaperones oxidatively fold their client proteins before endoplasmic reticulum oxireductin 1 (ERO1) oxidase transfers electrons from the reduced PDI to the terminal acceptor, which is usually molecular oxygen and is subsequently reduced to H2O2. ERO1 function is essential for disulfide bond formation in yeast, whereas in mammals its function is compensated for by alternative pathways. ERO1 activity is allosterically and transcriptionally regulated by the ER unfolded protein response (UPR). The ER stress-induced upregulation of ERO1 and other genes contributes to a cell's ability to cope with ER stress as a result of an adaptive homeostatic response, but the stress persists if a "maladaptive UPR" fails to reestablish ER homeostasis. As the oxidative activity of ERO1 is related to the production of H2O2 and consequently burdens cells with potentially toxic reactive oxygen species, deregulated ERO1 activity is likely to impair cell fitness under certain conditions of severe ER stress and may therefore lead to a change from an adaptive to a maladaptive UPR. This review summarizes the evidence of the double-edged sword activity of ERO1 by highlighting its role as a protein disulfide oxidase and H2O2 producer. © 2015 Elsevier Inc. All rights reserved.


Beghi E.,Mario Negri Institute for Pharmacological Research
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration | Year: 2013

Since the observation of several deaths from amyotrophic lateral sclerosis (ALS) among Italian professional soccer players, an association between ALS and soccer has been postulated, supported by high rates of morbidity and mortality risks in large cohorts of professionals. Several factors may explain this. A history of repeated (head) injuries is reported more frequently by ALS patients than by individuals with other clinical conditions. An association between exercise and ALS has also been suggested, but results in animals and humans are conflicting. Some clinical and experimental observations suggest a relation between ALS and use of substances such as non-steroidal anti-inflammatory agents, and dietary supplements including branched-chain amino acids. Although Italian soccer players may be at higher risk of ALS than players in other countries, and higher than expected disease frequency seems soccer-specific, increased attention by the Italian lay press is an explanation that cannot be excluded. However, growing evidence points to the possibility that soccer players with ALS are susceptible individuals who develop the disease in response to combinations of environmental factors. Only cohort and case-control studies carried out with the same design in different European countries can provide a definite answer to this suspected but still unconfirmed association. © 2013 Informa Healthcare.


Vezzani A.,Mario Negri Institute for Pharmacological Research
Epilepsy Currents | Year: 2014

The possibility that inflammatory processes in the brain contribute to the etiopathogenesis of seizures and the establishment of a chronic epileptic focus is increasingly recognized as a result of supportive evidence in experimental models and in the clinical setting. Prototypical inflammatory cytokines (such as IL-1beta) and "danger signals" (such as HMGB1 and S100beta) are overexpressed in human and experimental epileptogenic tissue, prominently by glia. Neurons and endothelial cells of the blood-brain barrier contribute to inflammatory processes. All these cell types also express receptors for inflammatory mediators, suggesting that inflammatory molecules in the brain exert both autocrine and paracrine activation of intracellular signaling cascades; thus, they may act as soluble mediators of cell communication in diseased tissue. In experimental models, seizures also trigger brain inflammation in the absence of cell loss; in human epileptogenic tissue, the type of neuropathology associated with chronic seizures contributes to determine the type of cells expressing the inflammatory mediators, and the extent to which inflammation occurs. Inflammatory molecules, such as IL-1beta and HMGB1, have proconvulsant activity in various seizure models, most likely by decreasing seizure threshold via functional interactions with classical neurotransmitter systems. These findings reveal novel glioneuronal communications in epileptic tissue that highlight potential new targets for therapeutic intervention.

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