Meldolesi J.,Vita-Salute San Raffaele University
Pharmacological Research | Year: 2016
Cell adhesions are heterogeneous processes including two main forms, CAM and cell/matrix forms. Both these forms induce the interaction among cells and with the extracellular matrix, and the generation of intracellular signals. The signaling of the two adhesion forms include, at the cell surface, involvement of distinct integrins, necessary for intracellular cascade activation. I will focus on the cell/integrin form based on two specific integrins, α5β1 (the most important) and αvβ3, activated by the preferential binding of fibronectin, a unique extracellular matrix protein. Such binding induces local assembly of stratified adhesion complexes containing protein kinases, that trigger the intracellular signaling cascades (Akt, ERK and others); proteins that sustain mechanical processes; and proteins associated with the cytoskeleton. In view of its role in several diseases, from cancers to the eye macular-degeneration; from brain neurodegeneration to fibroses, the pharmacological interest for the cell/integrin adhesion has grown, and presumably will further grow in the near future. The agents identified and developed for therapy include antibodies, many peptides and chemical drugs against α5β1 integrin; drugs against fibronectin and metalloproteinases 2/9, responsible of the latter enzyme proteolysis; anti-kinase and anti-cascade drugs, some of which targeted to the activation of transcription factors and/or their transfer to the nucleus, with repression or activation of gene expression. A new perspective, based on the investigation of both animal models and human patients, includes factors active on the cell/matrix and CAM adhesions, considered separately or coordinately in distinct therapeutic approaches, integrated or not with classical chemotherapic treatments. © 2015 Elsevier Ltd. All rights reserved.
de Curtis I.,Vita-Salute San Raffaele University
Frontiers in Cellular Neuroscience | Year: 2014
Rac GTPases are regulators of the cytoskeleton that play an important role in several aspects of neuronal and brain development. Two distinct Rac GTPases are expressed in the developing nervous system, the widely expressed Rac1 and the neural-specific Rac3 proteins. Recent experimental evidence supports a central role of these two Rac proteins in the development of inhibitory GABAergic interneurons, important modulatory elements of the brain circuitry. The combined inactivation of the genes for the two Rac proteins has profound effects on distinct aspects of interneuron development, and has highlighted a synergistic contribution of the two proteins to the postmitotic maturation of specific populations of cortical and hippocampal interneurons. Rac function is modulated by different types of regulators, and can influence the activity of specific effectors. Some of these proteins have been associated to the development and maturation of interneurons. Cortical interneuron dysfunction is implicated in several neurological and psychiatric diseases characterized by cognitive impairment. Therefore the description of the cellular processes regulated by the Rac GTPases, and the identification of the molecular networks underlying these processes during interneuron development is relevant to the understanding of the role of GABAergic interneurons in cognitive functions. © 2014, Frontiers Research Foundation. All rights reserved.
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: ICT-24-2015 | Award Amount: 8.36M | Year: 2016
Due to an aging population and the spiralling cost of brain disease in Europe and beyond, EDEN2020 aims to develop the gold standard for one-stop diagnosis and minimally invasive treatment in neurosurgery. Supported by a clear business case, it will exploit the unique track record of leading research institutions and key industrial players in the field of surgical robotics to overcome the current technological barriers that stand in the way of real clinical impact. EDEN2020 will provide a step change in the modelling, planning and delivery of diagnostic sensors and therapies to the brain via flexible surgical access, with an initial focus on cancer therapy. It will engineer a family of steerable catheters for chronic disease management that can be robotically deployed and kept in situ for extended periods. The system will feature enhanced autonomy, surgeon cooperation, targeting proficiency and fault tolerance with a suite of technologies that are commensurate to the unique challenges of neurosurgery. Amongst these, the system will be able to sense and perceive intraoperative, continuously deforming, brain anatomy at unmatched accuracy, precision and update rates, and deploy a range of diagnostic optical sensors with the potential to revolutionise todays approach to brain disease management. By modelling and predicting drug diffusion within the brain with unprecedented fidelity, EDEN2020 will contribute to the wider clinical challenge of extending and enhancing the quality of life of cancer patients with the ability to plan therapies around delicate tissue structures and with unparalleled delivery accuracy. EDEN2020 is strengthened by a significant industrial presence, which is embedded within the entire R&D process to enforce best practices and maximise translation and the exploitation of project outputs. As it aspires to impact the state of the art and consolidate the position of European industrial robotics, it will directly support the Europe 2020 Strategy.
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.1.2-1 | Award Amount: 5.98M | Year: 2013
The purpose of the project INSERT is to provide clinically relevant stratification and improved personalized radio-chemo therapy for brain tumour patients using a specifically developed multi-modality imaging tool. The system will also be used for early assessment of treatment efficacy. The initial focus will be on patients with glioma but there is future potential to target a range of tumours in the head and neck region. The proposed system is based on the development of a novel SPECT (Single Photon Emission Computed Tomography) system, suitable for insertion in the bore of an existing MRI (Magnetic Resonance Imaging) system, a cost-effective solution for widespread application. The combined system will allow the simultaneous measurement of anatomical (MRI) and functional (SPECT & MRI) information and the evaluation of their correlation in space and time. The SPECT design will enable acquisition of fast dynamic studies, with possibility for simultaneous measurement using multiple radionuclides (emitting at different energies), a distinct advantage compared to positron emission tomography (PET). This property can allow in-vivo simultaneous visualisation of spectrally resolved molecular and biochemical tumour properties. The stationary SPECT system is based on recently developed innovative gamma-ray detectors made with Silicon Drift Photodetectors, technology that achieves high-spatial resolution and is compatible with MRI thanks to the use of a silicon photodetector instead of photomultiplier tubes. The multi-modality SPECT/MRI imaging here proposed will apply a fully translational, vertical integration of research and development from technology design through preclinical models to clinical validation.
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.2-1 | Award Amount: 7.84M | Year: 2013
The scope of the project is to generate a candidate drug targeting the inflammatory mediator High mobility group box 1 protein (HMGB1) to be used in treatment of stroke. The candidate drug will be validated in animal models, characterized and optimized for subsequent clinical development. Stroke remains a leading cause of death and disability throughout the world. Within EU, more than 500 000 persons die of stroke each year. Of those surviving stroke, 50% are left with physical or cognitive impairment and the total annual cost of stroke is estimated at Euro 27 billion. Stroke occurs as a consequence of hemorrhagic insult or artery occlusion due to underlying cardiovascular disease. Pivotal in beneficial treatment of stroke is instant intervention. Blood clot dissolution using recombinant tissue plasminogen activator is the only pharmacological treatment demonstrated to limit neurological damage in stroke, but is only effective for patients who present within 3 hours after stroke onset. Thus there is an unmet need for an efficacious therapy that can be administered within and beyond 3 hours to achieve neuroprotection. HMGB1, released during the cerebral ischemic event and the subsequent neuroinflammation, is a well-characterized mediator of inflammation. Beneficial effects of blocking HMGB1 is proven in preclinical stroke studies. The drug to be developed is an Affibody molecule binding to and neutralizing HMGB1. Affibody molecules are engineered proteins significantly smaller than antibodies and therefore having favorable biodistribution properties, and a history of being efficient and non-toxic in clinical trials. In this application, we describe a multidisciplinary research consortium with Europes leading scientists in HMGB1 research and in registry-based clinical trial and dissemination methodology. The consortium has unique potentials to bring a new treatment principle against cerebral stroke to clinical reality.
Agency: European Commission | Branch: H2020 | Program: IA | Phase: ICT-15-2014 | Award Amount: 6.08M | Year: 2015
The data generated in the health domain is coming from heterogeneous, multi-modal, multi-lingual, dynamic and fast evolving medical technologies. Today we are found in a big health landscape characterized by large volume, versatility and velocity (3Vs) which has led to the evolution of the informatics in the big biodata domain. AEGLE project will build an innovative ICT solution addressing the whole data value chain for health based on: cloud computing enabling dynamic resource allocation, HPC infrastructures for computational acceleration and advanced visualization techniques. AEGLE will: - Realize a multiparametric platform using algorithms for analysing big biodata including features such as volume properties, communication metrics and bottlenecks, estimation of related computational resources needed, handling data versatility and managing velocity - Address the systemic health big bio-data in terms of the 3V multidimensional space, using analytics based on PCA techniques - Demonstrate AEGLEs efficiency through the provision of aggregated services covering the 3V space of big bio-data. Specifically it will be evaluated in: a)big biostreams where the decision speed is critical and needs non-linear and multi-parametric estimators for clinical decision support within limited time, b)big-data from non-malignant diseases where the need for NGS and molecular data analytics requires the combination of cloud located resources, coupled with local demands for data and visualization, and finally c)big-data from chronic diseases including EHRs and medication, with needs for quantified estimates of important clinical parameters, semantics extraction and regulatory issues for integrated care - Bring together all related stakeholders, leading to integration with existing open databases, increasing the speed of AEGLE adaptation - Build a business ecosystem for the wider exploitation and targeting on cross-border production of custom multi-lingual solutions based on AEGLE.
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.0-1 | Award Amount: 7.88M | Year: 2013
Substantial evidence supports the therapeutic potential of ex vivo gene therapy based on Hematopoietic Stem Cell (HSC) or T lymphocytes to treat inherited diseases or cancer. Yet, the intrinsic limitations of current gene replacement approaches based on semi-randomly integrating vectors, and the occurrence in some clinical trials of severe adverse events related to gene transfer, prevent safe deployment and broad application of gene therapy. This project aims to overcome these limits by exploiting the results of an earlier highly successful integrated project (PERSIST), which demonstrated the potential of gene targeting technologies based on engineered nucleases to provide radical new solutions to these hurdles. By homology-driven repair of a nuclease-targeted dysfunctional gene, we will insert a functional copy downstream its own endogenous promoter in HSC, thus restoring both function and physiological expression control. For adoptive T-cell therapy, we will combine nuclease-mediated disruption of the endogenous TCR genes with transfer of tumor-specific TCR, thus editing T-cell specificity at the genetic level. We will develop these innovative approaches into robust, scalable and clinically ready processes for safe ex vivo genetic modification of hematopoietic cells, and apply them to the treatment of paradigmatic diseases that provide a favourable risk-benefit ratio for clinical testing. Because both HSC and T-cell based gene therapy strategies share methodological aspects and technological challenges, we will address them systematically by involving a SME which holds unique know-how and top-level expertise in vector manufacturing and HSC and T-cell processing, as already established for our previous and ongoing gene therapy trials. Our findings will lead to the design of new clinical trials to provide durable benefits or even a cure to patients suffering from severe and otherwise fatal diseases, and representing a template for broaden application in medicine.
Comi G.,Vita-Salute San Raffaele University
Multiple Sclerosis Journal | Year: 2013
The last 20 years have seen major progress in the treatment of relapsing-remitting multiple sclerosis (RRMS) using a variety of drugs targeting immune dysfunction. In contrast, all clinical trials of such agents in primary progressive multiple sclerosis (PPMS) have failed and there is limited evidence of their efficacy in secondary progressive disease. Evolving concepts of the complex interplay between inflammatory and neurodegenerative processes across the course of multiple sclerosis (MS) may explain this discrepancy. This paper will provide an up-to-date overview of the rationale and results of the published clinical trials that have sought to alter the trajectory of both primary and secondary MS, considering studies involving drugs with a primary immune target and also those aiming for neuroprotection. Future areas of study will be discussed, building on these results combined with the experience of treating RRMS and new concepts emerging from laboratory science and animal models. © 2013 The Author(s).
Perani D.,Vita-Salute San Raffaele University
Current Opinion in Neurology | Year: 2014
PURPOSE OF REVIEW: The availability of PET neuroimaging tools for the in-vivo assessment of metabolic dysfunction and amyloid burden in Alzheimer's disease has opened important methodological and practical issues in the diagnostic design and the conduct of new clinical trials. This review, addressing the different molecular information that the amyloid-PET and fluorodeoxyglucose-PET (FDG-PET) tools can provide, highlights their diverging paths in Alzheimer's disease and possible new perspectives in research and clinical applications. RECENT FINDINGS: Senile plaques and neurofibrillary tangles are prominent neuropathological hallmarks in Alzheimer's disease and are considered to be targets for therapeutic intervention and biomarkers for diagnostic in-vivo imaging agents. Alzheimer's disease is a slowly progressing disorder, in which pathophysiological abnormalities, detectable in vivo by PET biomarkers, precede clinical symptoms by many years to decades. The unitary view of Alzheimer's disease as a sequential pathological pathway, with beta-amyloid (Aβ) as the only initial and causal event (the 'amyloid cascade hypothesis'), is likely to be progressively replaced by a more complex picture, also on the basis of recent PET imaging findings showing that neuronal injury biomarkers and tau pathology can be independent of β-amyloid deposition. SUMMARY: The different molecular paths that PET in-vivo biomarkers can reveal in the timeframe of Alzheimer's disease progression reflect the events leading to deposition of Aβ and phosphorylated tau, neuronal injury and neurodegeneration, which can run in parallel instead of in a sequential manner. The amyloid and neuronal injury paths may diverge along the Alzheimer's disease cascade and bear separate relationships with Alzheimer's disease symptoms and clinical phenotypes. All these evidences are crucial for the diagnosis and the development of new drugs aimed at slowing or preventing dementia.© 2014 Wolters Kluwer Health.
Agency: European Commission | Branch: H2020 | Program: MSCA-IF-EF-ST | Phase: MSCA-IF-2015-EF | Award Amount: 180.28K | Year: 2016
This project will investigate the role of CYLD in Chronic Lymphocytic Leukaemia (CLL). CYLD is a deubiquinating enzyme acting as a tumour suppressor in numerous tumours. CLL is characterized by the accumulation of B-lymphocytes. It affects mostly the elder and has a high incidence rate in Europe. Recent data from CYLD knockout murine models indicate a link between CYLD and CLL, however the approach used for generation of these mice led to contrasting results. At the core of this interdisciplinary project is the generation of two transgenic murine with: i) targeted CYLD inactivation in B-lymphocytes, ii) targeted inactivation combined with a murine model of CLL. Targeted inactivation will be achieved using the Cre-Lox system, by crossing already available progenitor mice. The mice will be extensively characterized with an emphasis on B-lymphocytes development and pathophysiology. RNA-seq will be used to find differentially expressed genes in B-lymphocytes. Computational biology approaches will then be applied to identify the affected pathways, which will be evaluated against publicly available human CLL data, seeking wider consensus. CYLD targeted inactivation allows for the first time evaluation of CYLDs role in B-lymphocytes development and CLL ruling out the effect CYLD inactivation in other cells may have. This project will enable better understanding of the role of CYLD in B-lymphocytes biology and could unravel novel biomarkers and therapeutic targets. At the same time the applicant will train-through-research, master novel techniques and develop soft skills valuable for his future career. This project combines the applicants expertise in the generation and characterization of murine models with targeted CYLD inactivation with the hosts long track record in B-lymphocytes and CLL.It falls well within the EUs research agenda, which emphasizes interdisciplinary research leading to recognition of common disease mechanisms and identification of novel biomarkers.