AVANTEA srl

Cremona, Italy

AVANTEA srl

Cremona, Italy

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Grant
Agency: European Commission | Branch: H2020 | Program: ERC-ADG | Phase: ERC-ADG-2014 | Award Amount: 2.31M | Year: 2015

Sudden cardiac death (SCD) is a leading cause of death in western countries: coronary artery disease is the major cause of SCD in older subjects while inherited arrhythmogenic diseases are the leading cause of SCD in younger individuals. After 25 years dedicated to research of the molecular bases of heritable arrhythmias, the PI of this proposal now intends to pioneer gene therapy for prevention of SCD: a virtually unexplored field. The development of molecular therapies for rhythm disturbances is a high risk effort however, if successful, it will be highly rewarding. The PI has envisioned an ambitious and comprehensive project to target two severe inherited arrhythmogenic diseases: dominant catecholaminergic polymorphic ventricular tachycardia (CPVT) and Long QT syndrome type 8 (LQT8). The availability of a clinically relevant model is critical to ensure clinical translation of results: the team will exploit an existing CPVT model and will engineer a knock-in pig to model LQT8. The PI and her team will investigate innovative strategies of gene-delivery, gene-silencing and gene-editing to the heart comparing efficacy of different constructs and promoters. The team will also carefully engineer novel gene-therapy approaches to avoid the development of regional inhomogeneity in protein expression that may facilitate proarrhythmic events. Such a comprehensive approach will provide a most valuable core of knowledge on the comparative efficacy of a broad range of molecular strategies on the electrical milieu of the heart. It is expected that these results will not only benefit CPVT and LQT8 but rather they will foster development of gene therapy for other inherited and acquired arrhythmias.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2010.4.2-9-1 | Award Amount: 9.40M | Year: 2011

In the development of products for use by humans it is vital to identify compounds with toxic properties at an early stage of their development, to avoid spending time and resource on unsuitable and potentially unsafe candidate products. Human pluripotent stem cell lines offer a unique opportunity to develop a wide variety of human cell-based test systems because they may be expanded indefinitely and triggered to differentiate into any cell type. SCR&Tox aims at making use of these two attributes to provide in vitro assays for predicting toxicity of pharmaceutical compounds and cosmetic ingredients. The consortium has been designed to address all issues related with biological and technological resources to meet that goal. In order to demonstrate the value of pluripotent stem cells for toxicology, the consortium will focus on four complementary aspects: Relevance i.e. establishing and maintaining discrete cell phenotypes over long-term cultures; providing large versatility to adapt to assays of specific pathways. Efficiency for i) automated cell production and differentiation, ii) cell engineering for differentiation and selection iii) multi-parametric toxicology using functional genomic, proteomic and bioelectronics. Extension i.e. i) scalability through production of cells and technologies for industrial-scale assays, and ii) diversity of phenotypes (5 different tissues), and of genotypes (over 30 different donors). Normalization validation and demonstration of reproducibility and robustness of cell-based assays on industrial-scale platforms, to allow for secondary development in the pharmaceutical and cosmetic industry. SCR&Tox will be intricately associated to other consortia of the Alternative Testing call, sharing biological, technological and methodological resources. Proof of concept of the proposed pluripotent stem cell-based assays for toxicology will be provided on the basis of toxicity pathways and test compounds identified by other consortia.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-TP | Phase: KBBE.2012.1.3-04 | Award Amount: 3.91M | Year: 2013

Good fertility is essential for the sustainability of livestock production. Of all livestock sectors, fertility of dairy cattle is raising the greatest cause for concern. Cow fertility has declined, particularly in Holstein cattle, from 80% pregnancy to first service 20 years ago to less than 40% today. Poor fertility is one of the main reasons for early culling, such that modern dairy cows complete fewer than 3 lactations, on average. The FECUND project will address the metabolic and genetic causes of low reproductive success of dairy cows in an interdisciplinary approach that will integrate in vivo and in vitro studies, biology, physiology, -omics technologies and bioinformatics. FECUND will focus on the early phases of reproduction from oocyte development to implantation of the conceptus. Starting from biological materials produced from high and low genetic merit cattle and from cows under energy stress of early lactation vs dry cows and heifers, FECUND will study, independently, the effects of genetics and metabolic stress on reproductive physiology to identify factors and early markers associated with high and low developmental potential, and with positive mother-conceptus interaction during the early stages of reproduction. These data will be mined to reveal physiological pathways and key candidate genes controlling variations of fertility. The biological knowledge created on early reproductive events in vivo will be validated in vitro, and extended to create further knowledge on the effects of the local environment on oocyte and embryo programming at the epigenetic level. Validated information will be used to improve herd management, gene assisted and genomic selection and assisted reproductive technologies, from in vitro ooctye maturation to optimised embryo culture. Information on biomarkers, indicator traits and improvements in assisted reproduction will be translated to applications that can be immediately implemented by SMEs.


Grant
Agency: European Commission | Branch: FP7 | Program: ERC-AG | Phase: ERC-AG-LS4 | Award Amount: 2.50M | Year: 2013

Mitochondria are the major source of ATP, synthesized by the mitochondrial respiratory chain (MRC) through the process of oxidative phosphorylation. ATP deficiency leads to cellular dysfunction and ultimately death. In mammals, 13 mitochondrial DNA (mtDNA)-encoded subunits interact with over 70 nuclear-encoded subunits to form four of the five MRC complexes. Many additional factors are essential for the regulation of MRC activity, and the maintenance and expression of mtDNA. As a result, genetic defects affecting either genome can compromise ATP synthesis and cause human disease. There is no effective treatment for mitochondrial disorders. Major hurdles to this achievement include (i) the still incomplete molecular definition of mitochondrial disease; (ii) the poorly understood function of many disease gene products, (iii) the difficulty to rationally manipulate the complex biochemical and genetic systems underpinning mitochondrial bioenergetics. The ultimate scope of MitCare is to develop effective therapy in mitochondrial medicine. MitCare will implement three Workpackages (WP). WP1 will test the effects of pharmacological stimulation of mitochondrial biogenesis in mouse disease models. WP2 will test the effects of Adeno-Associated Viral (AAV)- and lentiviral-mediated delivery of therapeutic genes, in mouse models and human mutant cells, respectively. Since the clinical features of human disorders often fail to be faithfully replicated in mice, WP3 will implement the creation of a mitochondrial disease model in the pig, whose proximity to humans is much closer than mice. The Surf1 gene, encoding an assembly factor of complex IV, will be disrupted by zincfinger nuclease technology in swine fibroblasts, which will then serve to clone a Surf1 knockout pig by somatic cell nuclear transfer. Mitopigs will be used to test the direct transferability of experimental treatments from suitable mammalian models to the clinics.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2012-ITN | Award Amount: 3.66M | Year: 2013

Scientific evidence clearly indicates that ageing and health in adult life is programmed by genetic and epigenetic mechanisms early in life. Developmental plasticity in response to the environment, including nutrient availability, of mammalian embryos indicates the capacity for newly emerging embryonic and extraembryonic cell lineages to initiate compensatory responses which may attune nutrient delivery to the needs of the developing fetus. EpiHealth will focus on these early events in several relevant models(diabetes, obesity and assisted reproductive technologies (ART)),using human samples, stem cell lines, animal models and data mining/bioinformatics tools to decipher some of the most important pathways and to offer options for early intervention to avoid adverse health effects. Main goal of the project is to improve health of the human population by understanding the mechanisms and pathways in early development, with special emphasis on epigenetic changes and developmentally relevant metabolic signalling, which create biological variation and have a long term effect on the health of individuals across the lifespan. Specific goals include: i)Identification of the main genetic pathways affecting the health of the developing embryos in a diabetic or obese maternal environment; ii) Identification of the main genetic and metabolic pathways affected and epigenomic and imprinting perturbations from mouse and human ART resulting in altered health of the progeny; iii)Discovery of the key genes and pathways affecting epigenetic and imprinting sensitivity in early stages of development in order to create intervention tools against epigenetic mis-programming; iv)Linking for the first time by bioinformatics tools the longevity related pathways and those susceptible to early epigenetic perturbations in order to explain how early events influence the health and lifespan of individuals; v)Studying the possibilities of early intervention by controlling the maternal environment.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.2.2.2-2 | Award Amount: 3.82M | Year: 2011

Scientific evidence clearly indicates that ageing and health in adult life is programmed by genetic and epigenetic mechanisms early in life. Developmental plasticity in response to the environment, including nutrient availability, of mammalian embryos indicates the capacity for newly emerging embryonic and extraembryonic cell lineages to initiate compensatory responses which may attune nutrient delivery to the needs of the developing fetus. EpiHealth will focus on these early events in several relevant models(diabetes, obesity and assisted reproductive technologies (ART)),using human samples, stem cell lines, animal models and data mining/bioinformatics tools to decipher some of the most important pathways and to offer options for early intervention to avoid adverse health effects. Main goal of the project is to improve health of the human population by understanding the mechanisms and pathways in early development, with special emphasis on epigenetic changes and developmentally relevant metabolic signalling, which create biological variation and have a long term effect on the health of individuals across the lifespan. Specific goals include: i)Identification of the main genetic pathways affecting the health of the developing embryos in a diabetic or obese maternal environment; ii) Identification of the main genetic and metabolic pathways affected and epigenomic and imprinting perturbations from mouse and human ART resulting in altered health of the progeny; iii)Discovery of the key genes and pathways affecting epigenetic and imprinting sensitivity in early stages of development in order to create intervention tools against epigenetic mis-programming; iv)Linking for the first time by bioinformatics tools the longevity related pathways and those susceptible to early epigenetic perturbations in order to explain how early events influence the health and lifespan of individuals; v)Studying the possibilities of early intervention by controlling the maternal environment.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.0-1 | Award Amount: 6.42M | Year: 2013

During the last five years, within the EU FP6 Integrated Project XENOME (LSHB-CT-2006-037377), we have convincingly demonstrated in primates that a complete control of induced type 1 diabetes is routinely obtained for 6/8 months after transplantation of subcutaneous alginate macroencapsulated porcine islets xenograft without the use of any immunosuppression. In order to improve the function of pig islets, we have produced with AVANTEA a transgenic pig expressing GLP-1 at the level of the pig islets. In fact, GLP1 is not only able to (i) increase the insulin gene expression and insulin biosynthesis, but also to (ii) induce the replication of islet cells and promotes islet-cell neogenesis and (iii) protect islets cells from apoptosis. GLP-1 has already demonstrated its in vivo potential to improve insulin secretion in subjects with impaired glucose tolerance and type 2 diabetes. The main objectives of this three-year project will therefore be (1) to evaluate in vitro the effect of GLP1 transgene expression in pig islets after hyperglycaemic challenge; (2) to continue to produce transgenic pigs specifically expressing GLP-1 in pig islets under insulin promoter, and (3) finally to test these modified pig islets in our well characterized pig-to-diabetic primates model in vivo. However, in order to use islets from newborn unmodified or transgenic pigs, we will also set up (4) the pig islets isolation and cell maturation technique for Neonates Pancreatic Pig Cluster cells since neonates pig islets have prolonged survival and would also render possible the use of Designed Pathogen Free (DPF) neonates pigs which will represent a key point to reach clinical studies. BIOT will be mainly involved in this part of the work which is in vitro purification, amplification of NPCCS. GCU and AVIDIN Ltd will together develop arrays and a set of molecular testing for pig cell pathogens. A pilot study for safety will be achived whether all the prerequisite are achieved within the third year.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.1.3-2 | Award Amount: 7.95M | Year: 2013

TRANSLINK is a project devoted to assessing the mid-to long-term risk factors and improve the outcome of animal (bovine/porcine)-derived Bioprosthetic Heart Valve (BHV) implants. 300,000 patients/year benefit from BHV, a major healthcare problem (second most frequent cardiac surgery). BHV clinical outcome suffers from late dysfunctions restricting their application to older recipients. Based on a retrospective (already computerised) and prospective cohort of approximately 3,000 BHV recipients and control patients from 3 large EU cardiac surgery groups, TRANSLINK aims primarily to establish the possible role of recipients immune response (IR) against BHV as a major cause to mid- to-long term clinical dysfunction. Precise molecular analysis of preimplantation BVH sugar moieties will be performed. Possible indirect side-effects on BHV endocarditis and host vessels inflammation are secondary end points. Serial and trans-sectional blood samples will be dispatched to a battery of highly specialised partner groups for testing anti-Gal, -Neu5Gc and -hyaluronic acid antibodies (Ig) using both validated and newly designed screening tools, glycan array patterns, and macrophages/NK responses. Data will be crossed with clinical outcome scores. Project design aims at delivering comprehensive recommendations in the time-frame of the grant. Fundamental basic science progress in the field of carbohydrate antigens is also expected. Furthermore, prevention (BHV from engineered animal source lacking major antigens) and treatment (bioabsorbants of deleterious Ig) oriented remedies as well as prospective biomarkers of longterm BHV deterioration will be set up by three first-class SMEs. TRANSLINK may strongly impact the treatment of heart valve diseases by improving morbid-mortality in patients with heart valves diseases and increasing the indication of BHV to younger patients.


Grant
Agency: European Commission | Branch: H2020 | Program: MSCA-RISE | Phase: MSCA-RISE-2016 | Award Amount: 841.50K | Year: 2017

The number of biobanks for diagnostic/clinical/biodiversity preservation purposes is increasing exponentially, representing an economic burden for the EU. Cryopreservation (Liquid Nitrogen LN) is the only cells/gametes long-term repository method. LN storage is expensive though, requires dedicated facilities, is hazardous, carries pathogens and has high carbon footprint. DRYNET objective is to set an inter-sectorial/multidisciplinary/international network between EU academic (5), SME (3), the EU pan-Biobank, and international partners (Japan/Thailand), with the aim of sharing knowhow & expertise to lay down the theoretical and early empirical basis for the dry storage of cells/germplasm. DRYNET merges the partners expertise, theoretical/ biophysical/ mathematical modelling, cellular/ molecular/ insect biology, embryology, mechanical engineering into a coherent approach towards dry storage of cells/germplasm. International/inter-sectorial secondments, with meeting/workshop/summer school will be primary tools to implement our strategy for biobanking. Outreaching activities will guarantee public awareness of the project. DRYNETs relies on water subtraction to induce a reversible block of metabolism, a survival strategy available in nature (anhydrobiosis). The work plan foresees the exploitation of natural xero-protectants (Late Embryogenesis Abundant proteins), loaded/expressed in gametes/cells, before drying. The best drying approaches, supported by theoretical/biophysical/math modelling, will be implemented by SMEs/academy partners. DRYNET will bring a simplification of currents practices, with cost and carbon footprint reduction, for the maintenance/shipping of biobanks. DRYNET will generate young scientists with transferable skills, ensuring career prospect in academia/industry. DRYNET strengthens the international/sectorial network between different disciplines, ensures long-term sustainability of the project, and boosts European competitiveness in biobanking.


The present invention concerns the field of high efficient integration and long-term transgene expression in specific genomic loci of transgenic animals, suitable for the generation of tools for biomedical research and biotechnological applications.

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