Overview

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

Objectives

The EU funded three years project PAINCAGE will pursue the following specific S&T objectives:

  • To understand the cognitive emotional and behavioral components of pain;
  • To identify, develop and validate new specific therapeutic targets for Neuropathic Pain and Osteoarthritis,
  • To identify neuronal and glial circuitries and processes modulating nociception and endogenous analgesia;
  • To develop a pipeline of second generation NGF-system-based compounds, for an improved control of Neuropathic Pain and Osteoarthritis;
  • To identify new markers from human samples for patient stratification;
  • To improve safety profile of pharmacological approaches for Neuropathic Pain and Osteoarthritis, currently undergoing clinical testing and targeting the NGF system.

Methodology

To achieve its aims, PAINCAGE will investigate

  1. the role of the individual components of the NGF and endocannabinoid systems in the regulation of Neuropathic Pain, including neuronal, inflammatory and neurotrophic mechanisms,
  2. the clinically proven or potential liabilities and safety concerns of targeting the NGF system for the treatment of Neuropathic Pain,
  3. the regulation of new targets by the NGF system and related signaling,
  4. the relationship between endocannabinoid and NGF signaling in healthy subjects and Neuropathic Pain patients.

Impact

Compared to current pain research, the PAINCAGE Project is the first to tackle the Neuropathic Pain (NP) and Osteoarthritis (OA) problem focusing on the proNGF/NGF-mediated signaling through their interaction with TrkA/p75NTR and sortilin receptors and on the interaction of the NGF system with another crucial player in the pain mechanisms, the Endocannabinoid system. A distinctive and innovative aspect of the PAINCAGE proposal is the analysis at different levels of the pain processing and perception cascade, from periphery to the central cortical areas, thereby studying also the emotional and cognitive aspects involved in NP. From a pharmacological perspective, these studies will lay solid foundations for the development of next-generation drugs targeting the NGF system and for new therapeutical designs, such as the association of (phyto/endo-) cannabinoidand NGF-derived drugs. From a clinical perspective, these studies will allow the identification and validation of new biomarkers to devise ad hoc, patient-selective treatments.

Scientific Methodology and Work Packages

Home » Overview » Scientific Methodology and Work Packages


PAINCAGE will pursue the following specific S&T by a cross-disciplinary and modular work-program:


WP1 – Understand the role of the individual components of the NGF target system (NGF, proNGF, TrkA, p75NTR, sortilin) in the signaling and regulation of different forms of NP with the neurotrophic, neuropathic and inflammatory components including OA.

WP2 – Dissect endocannabinoid signaling (ligands and receptor systems) in relation to the NGF pain-related signaling pathways in NP.

WP3 – Validate the NGF involvement in NP by the development and pharmacological/behavioral characterization of insensitivity to pain in new transgenic, pain insensitive, mouse models (HSAN IV and V).

WP4 – Analyze epigenetic mechanisms in NP and OA by focusing on the long-term gene expression changes during NP onset and NGF-targeting analgesic treatments in NP and OA.

WP5 – Control NP and OA onset, progression and perception by pharmacological treatment with antiNGF, antiTrkA and p75-Fc (NGF scavenger) as well as painless NGFR100. Transgenic models will be used to define specific roles of CB1R, TRPV1, CB2R and sortilin in NP.

WP6 – Analyze the safety issues related to the antiNGF therapy and unwanted side effects.

WP7 – Optimize the structure of lead drug candidates for NP.

WP8 – Identify and validate pain related biomarkers and druggable targets in humans, to improve patient stratification.


PAINCAGE focuses on two molecular systems of emerging importance, the NGF and the EC system. Unifying the two systems and studying their functional interactions, at different levels of the pain transmission and perception pathways, is a highly innovative approach.


The input to the project is represented by:


a set of existing candidate targets (e.g. sortilin, TRPV1, CBRs) belonging to the NGF and the EC system,

a set of existing lead biological drugs (alfaD11 anti NGF, antiTrkAMNAC13, p75NTR-Fc),

extensive, and state-of-the-art knowledge, expertise, models and reagents on the NGF and EC systems, both of which are crucially involved in NP.

These inputs will be feed into the first block of Work packages (WP1, WP2 and WP3), that deal with improving the understanding of the NGF (WP1 and WP3) and the EC (WP2) systems in NP, with a particular focus on the interactions between the two.


This first block of WPs, whose activities will be completed by and large by the second year of the project, feeds into WP4, that is devoted to exploiting the understanding gained in the previous block of WPs, to identify and validate new NP- and OA-related targets. This target discovery activity will be particularly focussed on the epigenetic regulation of gene expression during long-lasting analgesic protocols induced by antiNGF and antiTrkA treatments.


WP4 will provide, as an output, new targets for future development, possibly related to the epigenetics regulation in pain, a theme of emerging importance, as well as a validation of sortilin as a target for NP and OA. As a second output, WP4 feeds into WP8, whose activities are also fuelled by the availability of large numbers of DNA, tissue or fluid samples, from NP-affected patients. WP8 is dedicated to the identification of biomarkers, and will provide, as an output, new candidate biomarkers for patient stratification. The bulk of WP8 activities will be therefore carried out in the second part of the project.


The information and results obtained in the first block of WPs (WP1, WP2 and WP3) will also feed a block of WPs (WP5, WP6 and WP7) centered on controlling pain. In particular, the efficacy of antiNGF, antiTrkA and p75NTR-FC in treating, as well as in preventing pain onset in NP and OA models will be compared (WP5). Also, combination treatments with compounds from the NGF and the EC system will be investigated. The same treatments will be assessed in terms of safety endpoints, with a particular focus on those endpoints that have emerged as critical in clinical antiNGF trials, or as potential liabilities of the NGF system as a target (such as liabilities related to possible neurological effects in the central nervous system). WP7 in this block will deal with the structural determination of complexes between NGF and antiNGF and of TrkAECD and antiTrkA, building on the available high resolution structures of the corresponding antibodies. The crystallographic structure of painless NGFR100 will also be determined. Results from WP7 will provide the necessary structural information for the optimization of these lead drug candidates and for the structural design (in future projects) of small-molecule drugs inhibiting NGF and TrkA.


The overall output from this block of WPs will be a set of well-characterized and validated lead therapeutic compounds (p75NTR-Fc and NGFR100) ready to enter clinical trials for NP and OA indications.


Stakeholders and dissemination

The objectives of the PAINCAGE proposal address issues which are relevant to the main initiatives at EU and international levels in the field of brain research. In particular, this project is relevant to the EU Joint Programme – Neurodegenerative Disease Research (JPND) initiative. Indeed, chronic pain has been hypothesized as a form of neurodegenerative disorder (Borsook, 2012). The proposed study may uncover mechanisms common to different neurodegenerative disorders, in particular those related to the NGF system, which underlies both CP and neurodegenerative disorders in the strict sense (such as Alzheimer’s disease). Although pain occurs frequently even in individuals with mild AD, pain is underestimated because of the difficult evaluation in these patients. (Jensen-Dahm et al, 2012).

A better understanding of the role of the NGF system in NP and OA, by the PAINCAGE project, might provide an important contribution to the understanding of altered NGF signaling in both pain, and Alzheimer’s disease .

Moreover, and considering that more than 75% of patients with mild traumatic brain injury (MTBI) reports chronic pain, the PAINCAGE proposal will provide knowledge and new therapeutical opportunities also in this condition, which is highlighted by the International Initiative for Traumatic Brain Injury Research (InTBIR).

Finally, a tight comorbidity is observed between chronic pain states and various neurological and psychiatric disorders, such as depression, stress disorders, anxiety and so on (Bras et al, 2010). For this reason, the PAINCAGE project presents strong elements for cross-interactions with the European Pact for Mental Health 

We envisage that the PAINCAGE project will benefit from interactions with these EU initiatives and that, vice versa, those initiatives will benefit from the feedback and the results of our project.

A key point will be the interaction with the European Medicines Agency (EMA) and US Food and Drug Administration (FDA), as for data dissemination. The results will be presented in scientific meetings and published in the scientific specialised, “peer-reviewed” and non-specialised scientific press.

Numerous endorsement letters from industries and patient’s associations greatly support our studies since the outcomes of this project will significantly improve the patient life quality, the European biotech and pharmaceutical industry, while will reduce social cost and burden. Official signed letters has been received supporting this proposal from the following association of patients, scientific societies, SMEs and large industries:

  • The European Federation of IASP Chapters (EFIC),
  • Belgium Cyprus League Against Rheumatism (CYPLAR), Cyprus
  • Italian Association of Interstitial Cystitis (AICI), Italy
  • International Painful Bladder Foundation (IPBF), Netherlands
  • Italian Society for the study of Headache (SISC), Italy
  • Italian Society for Neuro-Rehabilitation (SIRN), Italy
  • Lay Line Genomics SpA, Roma, Italy (the originator of the PG110 antiNGF antibody under development by Abbott and of the antiTrkA antibody under development by Glemnmark Pharmaceuticals)
  • Lundbeck A/S, Denmark (who holds rights on the sortilin target)
    Glenmark Pharmaceutical S.A., Switzerland (who is developing the antiTrkA mAb licensed from Lay Line Genomics)

Management

The Coordinator will be the Chairman of the PAINCAGE Steering Committee and responsible for the project’s day-to-day operational coordination. The project Coordinator will be the unique interface between the Consortium and the European Commission, concerning the activity of the Consortium as a whole, to promote the harmonization of the project. He will provide and facilitates the access to information or documentations requested by the partners and consolidate the project planning, progress reports, milestone reports, cost statements and budgetary overviews etc, using the inputs from the other partners. He will monitor the status of the project budget and provides information regarding management of the funds of the project to participants, consultants and inspector. He will chair all the relevant meetings that deal with questions concerning the overall project performance, and coordinates the activity of the SC and GA. A project status report will be produced according to the time schedule, with the contribution of all the WP leaders, covering the project advancement in relation to the plan set out in the Part B of

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Glossary


CP: Cronic Pain.

Pain that extends beyond the expected period of healing.

EC

Endocannabinoid

Endocannabinoid System

group of neuromodulatory lipids and their receptors in the brain that are involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory; it mediates the psychoactive effects of cannabis.

Epigenetic mechanisms

mechanisms determining changes in gene expression (active versus inactive genes) that do not involve changes to the underlying DNA sequence. Epigenetic modifications can be physiological (e.g. cells differentiation in different cell-types such as skin cells, brain cells, etc. or they can have damaging effects that can result in diseases like cancer. At least three systems including DNA methylation, histone modification and non-coding RNA (ncRNA)-associated gene silencing are currently considered to initiate and sustain epigenetic change.

NGF: Nerve Growth Factor

Small secreted protein that is important for the growth, maintenance, and survival of certain target neurons (nerve cells). It also functions as a signaling molecule

Nociceptive pain

Nociceptive pain is caused by stimulation of peripheral nerve fibers that respond only to stimuli approaching or exceeding harmful intensity (nociceptors), and may be classified according to the mode of noxious stimulation.

NP: Neuropathic Pain

Neuropathic Pain is caused by damage to, malfunction of the nervous system or disease that affects the somatosensory system. It may be associated with abnormal sensations called dysesthesia, and pain from normally non-painful stimuli (allodynia).

OA: Osteoarthritis

Group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion. A variety of causes—hereditary, developmental, metabolic, and mechanical deficits—may initiate processes leading to loss of cartilage. When bone surfaces become less well protected by cartilage, bone may be exposed and damaged. As a result of decreased movement secondary to pain, regional muscles may atrophy, and ligaments may become more lax.

Transgenic

adj. used for organism or cell of one species into which one or more genes of another species have been incorporated.