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

Chronic pain is the most frequent reason for a patient to see a doctor. Direct nerve injuries such as traumatic injuries as well as indirect nerve injuries occurring secondary to a disease may lead to a severe chronic pain condition clinically known as Neuropathic Pain (NP). Depression, anxiety, and sleep disorders were significantly more prevalent in patients with NP compared to those without such pain. Current drugs are highly unsatisfactory and leave much to be desired. For this reason, expectations are very high, that anti NGF drugs will emerge as the first new class of broadly applicable painkillers in decades, despite safety concerns still lingering, that placed the antiNGF antibodies under development in a sort of clinical limbo. The value proposition for this class of drugs is very clear.

Several tens of millions of patients worldwide suffer from conditions that cause chronic pain, and the number will only increase as population age. More specifically for NP, the exact prevalence of NP is more difficult to evaluate, since not all cases of NP are recognized as such, because NP may occur secondary to a disease which does not necessarily link the experienced pain with neuronal damage. Two studies on the general population in Europe reported the prevalence of pain of predominant neuropathic origin (Torrance et al, 2006) or pain with neuropathic characteristics (Bouhassira et al, 2008) to be 8 % and 7 % respectively. In any event, NP arises following various high prevalence conditions in the peripheral or the central nervous system. Patients who have suffered a stroke, suffer from diabetes or from multiple sclerosis experience NP in 8 %, 16% and 28 % of the cases, respectively (Daousi et al, 2004; Osterberg et al, 2005) and following spinal cord injuries incidence rates are as high as 67 % (Finnerup et al, 2001). Therefore, it is clear that NP affect several tens of millions of patients, all of which are unsatisfactorily treated by currently available drugs.

It is therefore evident that the social impact of the Paincage project is going to be very high. Developing and validating a new generation of analgesic drugs, based on the improved understanding of the NGF and EC involvement in NP, which represents a major outcome of this project to control NP, will therefore improve the quality of life of millions of patients across Europe.

The information gathered in this project and the fulfillment of its objectives will provide major advances in understanding and controlling the mechanisms of Neuropathic Pain, laying the ground for the development of next-generation NGF-targeting drugs as effective NP treatments. Also, the project will provide information to achieve better patient stratification, according to biomarkers related to the mechanisms studied.

To gain knowledge on the mechanisms of different pain syndromes whose treatments are inadequate, such as NP, the new genetic pain models generated in this project, of pain insensitivity (HSAN) and pain hyper-sensitivity (TrkA knock-in mice), will provide unique insights in understanding pain processing and perception, including its cognitive and emotional aspects. The identification of genes that change their expression in response to NP will provide additional information related to the NGF/TrkA signalling pathways involved. Coincidently, it may be possible to link a SNP for NGF and TrkA, or for genes related to the EC system with patients suffering of NP, that will allow us to identify potential high-risk individuals with NP.

Various aspects of the PAINCAGE project are expected to have a strong impact.

Moreover, our studies will provide a mechanistic explanation for the linkage between BDNF signaling, downregulation of KCC2 expression and the aberrant sensory processing that follows a peripheral nerve lesion. By a combined ChIP-seq and whole transcriptomic approach, we aim to map, for the first time, gene targets of histone modifications in peripheral and brain structures, at different stages of NP onset and during antiNGF or antiTrkA treatment.

Moreover, the project will provide a unique and unprecedented opportunity to compare, in side-by-side treatments, the therapeutic effectiveness and safety of antiNGF, antiTrkA and p75NTR-Fc scavenger. This summarizes the best that the industrial pipeline displays currently, world-wide.

Finally, validated targets will provide biomarkers for pain, to enable better patient’s stratification and optimization of their treatments and mechanism-based treatment selection. In conclusion, it is expected that the information provided by the PAINCAGE project will lay very solid grounds for the development of safer and more effective new generation analgesic drugs. This will have a major social benefit, providing solutions to a big social and personal problem, namely chronic pain.

The results obtained will strongly impact quality of life of patients suffering from NP, with great reduction of social costs due to inadequate pain treatment. We also anticipate that the long lasting analgesic effects of this class of drugs will reduce daily dose intake, with welfare benefit and better compliance of patients to treatment.