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The NGF System and its interplay with endocannabinoid signalling, from peripheral sensory terminals to the brain: new targets for the development of next generation drugs for neuropathic pain

Bringing all the Partner groups together in this Consortium has a great added value, due to a strong integration, a high complementarity and a well recognized international leadership in each own’s field of activity.

  1. First, the Consortium brings together experts in two different areas, the NGF system and the EC system, both of which are crucially involved in the mechanisms of pain, and bringing together these two fields is a very original and innovative aspect of the Project, that will provide a quantum leap in the understanding of pain.
  2. Second, the Consortium incorporates Partners that have originated a large proportion of the therapeutic candidates currently under development in the chronic pain industry pipeline. The LEVI partner has been involved in the clinical development of Tanezumab, the antiNGF forerunner under development by Pfizer (Lane et al 2010), and has originated the new compound p75-Fc, a41 soluble form of the p75NTR receptor that acts as an NGF scavenger. The concept of the p75-Fc product was initially developed at Pfizer by Simon Westbrook, who then spun out the project from Pfizer, setting up the Levicept SME (LEVI). The Consortium is therefore at the very center of the industrial pipeline world-wide, in this very competitive therapeutic space.
  3. Moreover, the three reagents alfaD11 antiNGF, antiTrkA MNAC13 and p75-Fc are all available, in different forms, to the Consortium. The Consortium is therefore in the unique position of directly comparing in a side by side fashion the efficacy of the three approaches of neutralizing NGF activity in different NP models, as well as to evaluate in a comparative fashion their safety-related issues, and their potential liabilities. This represents a unique opportunity for the field, whose importance and relevance cannot be enough stressed, for a therapeutic field that is currently at the center of large attention.

The Paincage Consortium includes a series of excellence Universities and Centres, according to a number of different parameters and objective criteria, based also on the 2012 PCP ARWU ranking (Table B2.3c)

The Scuola Normale Superiore (SNS) in Pisa, a prestigious university centre for teaching and research, is based on a model which shaped European educational history. Founded by Napoleon in 1810 as a branch of the Ecole Normale Superieure Paris, it has been educating students and carrying out research for nearly two centuries. Three of the former students of the SNS, E. Fermi, C. Rubbia and G. Carducci, have been awarded the Nobel Prize. SNS keeps the highest teaching and academic standards. This is witnessed by the Shanghai Academic Ranking of the World Universities (ARWU) (http://www.shanghairanking.com/ARWU2012.html). Due to the small number of students and of faculty, the relevant ranking to be considered is the ranking normalized per number of students (PCP, Per Capita academic Performance). According to the PCP ranking, in 2012 SNS ranks at the 5th position world wide. SNS has a very strong track record of being awarded competitive international grants, including European grants (in particular ERC).

The European Brain Research Institute (EBRI) is the Research Institute founded in 2005 by Nobel Prize Awardee Rita Levi-Montalcini, entirely dedicated to the study of the brain. Although quite young, EBRI has altready established itself as a major attraction centre for brilliant young scientists from all over the world, specially targeting to attract as principal Investigators young scientists at their initial phase of independent scientific career. The current ISC is chaired by Moses Chao (the President of the US Society for Neurosciences) and includes scientists that have very made significant impact in modern neurosciences (Solomon Snyder, Lamberto Maffei, Graham Collingridge and others). Despite its young age, EBRI has already been able to secure a number of very competitive research grants, including an ERC grant, an FP7 project, two Alzheimers Association grants and two Young Investigator Alzheimer’s Association grants.

The Medical University of Vienna (MUW) is not only the largest medical organisation in Austria, it is also one of the most important top-level research institutions in Europe and provides Europe’s largest hospital, the AKH in Vienna, with all of its medical staff. With its long history and tradition, which covers 640 years, MUW has developed into a highly modern research institution and it is one of the most important centres for postgraduate training and the promotion of young researchers. The high standard of research is reflected in the considerable number of scientific published in the international specialist press.

King’s College London (KCL) is one of the top 25 universities in the world. A research-led university based in the heart of London, King’s has an outstanding reputation for providing world-class teaching and cutting-edge research. The Wolfson Centre for Age-Related Diseases is one of the most vibrant groupings of scientists at King’s College London with a research focus on neurodegeneration, pain, regeneration and clinical trials for vascular dementia and Alzheimer’s disease.

According to the Leiden Ranking 2011/2012 Aarhus University (AU) is ranked 51 of the 500 major universities worldwide, renowned for its strong international collaborations and strategic alliances. The University  has participated and is participating in several European projects under the subsequent RTD European Framework Programmes (I to VII) and other European Programmes / Actions, having experience in the development and management of more than 100 European Projects.

The University of Salamanca (USAL) participated in 53 community actions financed under the VI Framework Programme: Integrated Project, Network of Excellence, Specific Support Actions and Marie Curie Actions.

The Neuro Centre Magendie (INSERM) is a recently formed (2007) institute of INSERM dedicated to the study of the physiology and physiopathology of the central nervous system. It is one of the most recognized contemporary research centres of Neuroscience in Europe.

Following is a brief outline of the identity and area of excellence and leadership of each partner:

Partner Description What they bring to PAINCAGE
SNS University
  • leader in the field of NGF signalling, function, processing, in physiology and in pathology, particularly in the field of Alzheimer’s research (Capsoni et al., 2000), where SNS has made primary contributions;
  • originator of three NGF-based products in the industry pipeline;
  • deep knowledge of structural biology of NGF, proNGF (Coveceuszach et al., 2012) and its receptors as well as great experience in binding antibodies and intrabodies (Cattaneo and Biocca, 1999)

» More on SNS

EBRI Research Centre
  • founded by Nobel awardee Rita Levi-Montalcini, the NGF discoverer, has a world class expertise in the field of NGF;
  • deep expertise in NGF signaling in pain (Ugolini et al., 2007), pain in general (Marinelli et al, 2010; Vacca et al, 2012), the neurophysiology of TRPV1 at brain level (Marinelli et al., 2002, 2003, 2005) and the analysis of endocannabinoid-mediated synaptic modifications by patch electrophysiology (Marinelli et al., 2007, 2008, 2009);
  • cutting edge expertise in antibody technologies, including developing humanized recombinant Abs (Meli et al., 2009, Coveceuszach et al., 2011), and in functional genomics (D’Onofrio et al., 2009, 2011)

» More on EBRI

AU University
  • world expert in sortilin, providing the first evidence of proNGF receptor sortilin and its interaction with p75 and Trks (Nykjaer et al., 2004; Nykjaer and Willnow, 2012; Willnow et al., 2008);
  •  generated and characterized sortilin KO mice (Jansen et al, 2007)

» More on AU

MUW University
  • discovered many of the neuropeptide signaling systems and defined their role in NP (Wiesenfeld-Hallin et al., 2005);
  • expert in the developmental biology of endocannabinoid signaling (Berghuis et al., 2007), neuroanatomy, cell biology (Keimpema et al., 2010), sensory neuron development (Hjerling-Leffler et al., 2005), PLCβ inhibitors (Shi et al., 2008) and optogenetics (Cardin et al., 2009); demonstrated that NGF orchestrates EC signals via (Keimpema et al., 2013)

» More on MUW

LEVI Biotech
  • made significant advances in understanding the role played by soluble p75NTR in the homeostasis of the NGF system;
  • identified a novel mechanism by which the pathological (inflammatory algogen) function of NGF can be modulated safely, by the use of the extracellular binding domain of p75NTR coupled to Fc IgG, potentially a next-generation NGF-targeting analgesic compound 49

» More on LEVI

KCL University
  • a long standing pain expert, particularly in the fields of neurotrophinrelated mechanisms and of the glia’s role in pain, both being central themes to the PAINCAGE project;
  • showed that NGF up-regulates the expression and increases the release of pronociceptive peptides and BDNF from central terminals of primary afferent fibers in the spinal cord thereby contributing to central sensitization (Malcangio et al, 1997; Lever et al, 2001);
  • a world class expert in the structural biology of proteins relevant for neurological disorders, using a variety of diverse experimental biophysical and cell biology approaches, including NMR and structural bioinformatics;
  • ongoing collaborations with EBRI and SNS aimed at the structural determination of proNGF in solution by NMR (Paoletti et al., 2006, 2009), providing the basis for the planned work on solving the structure of NGFR100 and proNGFR100

» More on KCL

USAL University
  •  leader in the field of NGF-activated TrkA signalling, having discovered a novel signaling pathway involving TrkA ubiquitination;
  • generated ubiquitin ligase knock-in mice showing ubiquitination defect and an increased NGF- mediated signalling (Yu et al, 2011)

» More on USAL

GEN Biotech
  • technology-based SME in the field of genomics and Next-Generation Sequencing, with solid research-based grounds, having been started from scientists of the Italian National Research Council;
  • primary technology provider and an ideal partner for competitive scientific projects

» More on GEN

INSERM Research Centre
  • a well recognized leader in EC signalling, with particular regard to the generation of new transgenic models and with experience in mouse genetics, behavioral p pharmacology and energy metabolism;
  • generated global and conditional CB1R knock-outs (Marsicano et al., 2002), functionally characterized mitochondrial CB1Rs (mtCB1Rs; Bernard et al., 2012), and showed that endocannabinoids acting on glutamatergic transmission in the periaqueductal grey participate in producing analgesia upon electro-acupuncture (Hu et al., submitted);
  • generated and functionally characterized astroglial brain conditional CB1R KO mice showing that astrocytic CB1Rs promote glial-neuronal excitatory interaction (Han et al, 2012)

» More on INSERM