Padua, Italy
Padua, Italy

The University of Padua is a premier Italian university located in the city of Padua, Italy. The University of Padua was founded in 1222 as a school of law and was one of the most prominent universities in early modern Europe. It is among the earliest universities of the world and the second oldest in Italy. The University of Padua is one of Italy’s leading universities and ranks in the first position in all the recent ranking of Italian large universities. In 2010 the university had approximately 65,000 students and in 2009 was ranked "best university" among Italian institutions of higher education with more than 40,000 students. Wikipedia.


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RATIONALE:: Critical limb ischemia (CLI) is a life-threatening complication of peripheral arterial disease (PAD). In patients who are ineligible for revascularization procedures, there are few therapeutic alternatives, leading to amputations and death. OBJECTIVE:: To provide a systematic review of the literature and a meta-analysis of studies evaluating safety and efficacy of autologous cell therapy for intractable PAD/CLI. METHODS AND RESULTS:: We retrieved 19 randomized controlled trials (RCTs; 837 patients), 7 non-randomized trials (338 patients), and 41 non-controlled studies (1,177 patients). The primary outcome was major amputation. Heterogeneity was high and publication bias could not be excluded. Despite these limitations, the primary analysis (all RCTs) showed that cell therapy reduced the risk of amputation by 37%, improved amputation-free survival by 18% and improved wound healing by 59%, without affecting mortality. Cell therapy significantly increased ABI, TcO2, and reduced rest pain. The secondary analysis (all controlled trials; n=1,175 patients) shows there may be potential to avoid approximately 1 amputation/year for every 2 patients successfully treated. The tertiary analysis (all studies; n=2,332 patients) precisely estimated the changes in ABI, TcO2, rest pain, and walking capacity after cell therapy. Intra-muscular implantation appeared more effective than intra-arterial infusion, and mobilized peripheral blood mononuclear cells (MNCs) may outperform bone marrow-MNCs and mesenchymal stem cells. Amputation rate was improved more in trials wherein the prevalence of diabetes was high. Cell therapy was not associated with severe adverse events. Remarkably, efficacy of cell therapy on all end-points was no longer significant in placebo-controlled RCTs and disappeared in RCTs with a low risk of bias. CONCLUSIONS:: Although this meta-analysis highlights the need for more high quality placebo-controlled trials, equipoise may no longer be guaranteed, because autologous cell therapy has the potential to modify the natural history of intractable CLI. © 2017 American Heart Association, Inc.


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.


Grant
Agency: European Commission | Branch: H2020 | Program: ERA-NET-Cofund | Phase: SC5-15-2015 | Award Amount: 52.36M | Year: 2016

In the last decade a significant number of projects and programmes in different domains of environmental monitoring and Earth observation have generated a substantial amount of data and knowledge on different aspects related to environmental quality and sustainability. Big data generated by in-situ or satellite platforms are being collected and archived with a plethora of systems and instruments making difficult the sharing of data and knowledge to stakeholders and policy makers for supporting key economic and societal sectors. The overarching goal of ERA-PLANET is to strengthen the European Research Area in the domain of Earth Observation in coherence with the European participation to Group on Earth Observation (GEO) and the Copernicus. The expected impact is to strengthen the European leadership within the forthcoming GEO 2015-2025 Work Plan. ERA-PLANET will reinforce the interface with user communities, whose needs the Global Earth Observation System of Systems (GEOSS) intends to address. It will provide more accurate, comprehensive and authoritative information to policy and decision-makers in key societal benefit areas, such as Smart cities and Resilient societies; Resource efficiency and Environmental management; Global changes and Environmental treaties; Polar areas and Natural resources. ERA-PLANET will provide advanced decision support tools and technologies aimed to better monitor our global environment and share the information and knowledge in different domain of Earth Observation.


Grant
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: FETOPEN-01-2016-2017 | Award Amount: 3.98M | Year: 2017

SUMCASTEC explores radically new approach for cancer stem cells (CSCs) real time isolation (i.e. within minutes vs current 40 days) and neutralization. A novel micro-optofluidic lab-on-chip (LOC) platform will be developed through a joint and iterative effort by biologists, clinicians and engineers. For the first time, a single LOC will be capable of delivering ultra-wide broadband radiation to compare cell spectral signatures, image subcellular features, and hence modulate CSCs microenvironment conditions with unprecedented space and time resolution. It will be driven to isolate CSCs from heterogeneous differentiated and stem cell populations, and force CSCs differentiation, ultimately inducing sensitivity to anticancer treatments. Extensive in vitro and in vivo testing along with biophysical modelling will validate the approach and establish the proof-of-principle within the project life-time, while laying the groundwork for further development of future electrosurgical tools that will be capable CSCs neutralization in tissue. This will not only establish a new line of treatment for brain cancers such as Glioblastoma Multiforme and Medulloblastoma, whose initiation and recurrence were linked to CSCs, and that claim tremendous human and economic tolls, worldwide; it will also push the current boundaries of microbiological analysis by enabling microenvironment characterization/manipulation and real-time ionic channels monitoring without cytotoxic patch-clamping or electron microscopy. By investing in efforts such as SUMCASTECs, Europe will stand at the forefront of global biomedical innovation and push through a similar miniaturization trend as the one that propelled mobile communications, yet with much deeper societal impact. All the required competences are gathered within this consortium. The ambitious objectives of the project are planned over 42 months with a requested grant of 3 978 517,5 .


Grant
Agency: European Commission | Branch: H2020 | Program: SGA-RIA | Phase: FETFLAGSHIP | Award Amount: 89.00M | Year: 2016

This project is the second in the series of EC-financed parts of the Graphene Flagship. The Graphene Flagship is a 10 year research and innovation endeavour with a total project cost of 1,000,000,000 euros, funded jointly by the European Commission and member states and associated countries. The first part of the Flagship was a 30-month Collaborative Project, Coordination and Support Action (CP-CSA) under the 7th framework program (2013-2016), while this and the following parts are implemented as Core Projects under the Horizon 2020 framework. The mission of the Graphene Flagship is to take graphene and related layered materials from a state of raw potential to a point where they can revolutionise multiple industries. This will bring a new dimension to future technology a faster, thinner, stronger, flexible, and broadband revolution. Our program will put Europe firmly at the heart of the process, with a manifold return on the EU investment, both in terms of technological innovation and economic growth. To realise this vision, we have brought together a larger European consortium with about 150 partners in 23 countries. The partners represent academia, research institutes and industries, which work closely together in 15 technical work packages and five supporting work packages covering the entire value chain from materials to components and systems. As time progresses, the centre of gravity of the Flagship moves towards applications, which is reflected in the increasing importance of the higher - system - levels of the value chain. In this first core project the main focus is on components and initial system level tasks. The first core project is divided into 4 divisions, which in turn comprise 3 to 5 work packages on related topics. A fifth, external division acts as a link to the parts of the Flagship that are funded by the member states and associated countries, or by other funding sources. This creates a collaborative framework for the entire Flagship.


Grant
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: SC1-PM-09-2016 | Award Amount: 6.00M | Year: 2017

Liver cirrhosis is a very common chronic disease and one of the leading causes of death in European. Moreover, cirrhosis has a marked impact in patients quality of life and represents a major burden for health systems. Treatment of cirrhosis is currently based on symptomatic management of complications and has not changed substantially in the last 20 years. There is an unmet need for therapies that target the pathobiology of cirrhosis. The objective of LIVERHOPE project is to evaluate a novel therapeutic strategy for patients with cirrhosis based on a combination of rifaximin and simvastatin, targeting the main pathophysiological mechanisms of disease progression , namely the impairment in the gut-liver axis and the persistent hepatic and systemic inflammatory response. This dual therapeutic approach is supported by preclinical data showing excellent and very promising results. We will perform two randomized double-blind trials to investigate safety, tolerability and efficacy of combination of simvastatin plus rifaximin in patients with decompensated cirrhosis in 5 EU countries (285 patients will be enrolled in two trials in DE, ES, FR, IT, UK). The expected impact is to halt progression to acute-on-chronic liver failure, the main cause of death, to decrease complications of the disease, to reduce hospital readmissions, to improve cost-effectiveness of therapy. Our final aim is to improve patients quality-of-life and increase survival as patients care is the core of LIVERHOPE. Within the project we will also investigate biomarkers of response to treatment and disease progression that can be useful in clinical practice for improving the treatment of patients. We will invest our effort also in communication and dissemination activities for increasing awareness about chronic liver diseases in European countries so that preventive measures can be established to decrease the burden of cirrhosis and reduce social stigmatization of patients with chronic liver diseases.


Grant
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: NMBP-02-2016 | Award Amount: 7.69M | Year: 2017

The main objective of this proposal is to develop reliable GaN-based power devices and systems for high and medium power electronics targeting industrial and automotive applications and bringing the GaN power devices another step towards the wide usability in the energy saving environment to further tap the full potential which this new material brings along. This proposal addresses two subjects, one of which is medium power (till 10kW) GaN-on-Si based lateral HEMT structures, with special focus on high reliability, which is still a major blocking item to allow wide-spread market adoption. Hence, the impact of the GaN material quality, in combination with the device layout in view of long-term reliability will be addressed. The project aims an in-depth reliability study and qualification strategy development whereby the study of the impact of dislocations and other structural disturbances inside the materials on the long term device reliability will be specifically addressed. In addition, this proposal aims to demonstrate new device concepts with increased robustness and reliability, which will be realized, evaluated and tested thoroughly. This will demonstrate how it is possible to overcome the known limitations of the GaN on Silicon technology, like e.g. the vertical leakage, trapping phenomena and/or breakdown of lateral HEMTs. The current proposal also contains the development of novel device architecture (dual channel, substrate removal, e-mode), as well as the exploration of new material systems (Aluminum Nitride (Al-based) devices) which can also largely contribute to overcome drawbacks of the GaN on Si technology. The applicability of the novel GaN-on-Si concepts in form of an industrial inverter will be demonstrated finally, with the development of an innovative low inductance packaging system for power devices, making full benefits of the fast switching capability of GaN-based power devices.


Urciuolo A.,University of Padua
Nature communications | Year: 2013

Adult muscle stem cells, or satellite cells have essential roles in homeostasis and regeneration of skeletal muscles. Satellite cells are located within a niche that includes myofibers and extracellular matrix. The function of specific extracellular matrix molecules in regulating SCs is poorly understood. Here, we show that the extracellular matrix protein collagen VI is a key component of the satellite cell niche. Lack of collagen VI in Col6a1(-/-) mice causes impaired muscle regeneration and reduced satellite cell self-renewal capability after injury. Collagen VI null muscles display significant decrease of stiffness, which is able to compromise the in vitro and in vivo activity of wild-type satellite cells. When collagen VI is reinstated in vivo by grafting wild-type fibroblasts, the biomechanical properties of Col6a1(-/-) muscles are ameliorated and satellite cell defects rescued. Our findings establish a critical role for an extracellular matrix molecule in satellite cell self-renewal and open new venues for therapies of collagen VI-related muscle diseases.


The assessment of mitochondrial respiratory chain (RC) enzymatic activities is essential for investigating mitochondrial function in several situations, including mitochondrial disorders, diabetes, cancer, aging and neurodegeneration, as well as for many toxicological assays. Muscle is the most commonly analyzed tissue because of its high metabolic rates and accessibility, although other tissues and cultured cell lines can be used. We describe a step-by-step protocol for a simple and reliable assessment of the RC enzymatic function (complexes I-IV) for minute quantities of muscle, cultured cells and isolated mitochondria from a variety of species and tissues, by using a single-wavelength spectrophotometer. An efficient tissue disruption and the choice for each assay of specific buffers, substrates, adjuvants and detergents in a narrow concentration range allow maximal sensitivity, specificity and linearity of the kinetics. This protocol can be completed in 3 h.


Collini E.,University of Padua
Chemical Society Reviews | Year: 2013

One of the most surprising and significant advances in the study of the photosynthetic light-harvesting process is the discovery that the electronic energy transfer might involve long-lived electronic coherences, under physiologically relevant conditions. This means that the transfer of energy among different chromophores does not follow the expected classical incoherent hopping mechanism, but that quantum-mechanical laws can steer the migration of energy. The implications of such a quantum transport regime, although currently under debate, might have a tremendous impact on our way of thinking about natural and artificial light-harvesting. Central to these discoveries has been the development of new ultrafast spectroscopic techniques, in particular two-dimensional electronic spectroscopy, which is now the primary tool to obtain clear and definitive experimental proof of such effects. This review aims to provide an overview of the experimental techniques developed with the purpose of attaining a more detailed picture of the coherent and incoherent quantum dynamics relevant to energy transfer processes, not limited to the two-dimensional electronic spectroscopy. With the idea of summarizing the experimental and theoretical basic notions necessary to introduce the field, the connection between experimental observables and coherence dynamics will be analysed in detail for each technique, highlighting how electronic coherences could be manifested in different experimental signatures. Similarities and differences among coherent signals as well as advantages and disadvantages of each approach will be critically discussed. Current opinions and debated issues will be emphasised and some possible future directions to address still open questions will be suggested. © 2013 The Royal Society of Chemistry.

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