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Periodic Report Summary 2 - PAIN-OMICS (Multi-dimensional omics approach to stratification of patients with low back pain)

Project Context and Objectives:
PainOmics is a multidisciplinary consortium of leading clinical, academic and SME (small and medium enterprises) researchers in pain and different omics technologies.
The project aims to find a new way to characterize low-back pain (LBP) by detecting biomarkers that can predict and evaluate it.
So far, genome-wide association studies have identified a number of loci associated with pain, but the level of knowledge about underlying mechanisms of different pain syndromes remains inadequate.
The PainOmics consortium will obtain high quality clinical, genetic, biochemical and pharmacological data on well-characterized patients with LBP as well as data on healthy people (controls). It will exploit novel technological approaches made available through the expertise and global leading position of our analytical partners. These involve genomic, epigenomic, glycomic, and activomic approaches.
We believe that the inclusion of these complementary analyses will elucidate pathways through which acute LBP fails to resolve and becomes chronic low-back pain (CLBP).
In addition, these approaches will reveal pathways and biomarkers of chronic pain through which interindividual differences affect symptoms and response to therapy.
The project includes four different study populations from various countries both in Europe and the US.
Participation of leading clinics will enable detection of new biomarkers in two independent large cohorts, included in the retrospective and prospective studies.
In the large retrospective study, the consortium will analyze a cohort of 4,000 patients with CLBP and compare the results with a cohort of 8,000 healthy controls.
In the large prospective observational study, the consortium will perform genetic and “omic” analyses 5,000 patients suffering from acute LBP, evaluating biomarkers that could predict people who will develop chronic pain.
Partner King’s College London (KCL) will also use their large twin cohort study to evaluate differences in CLBP in twins.
Finally, the University of Parma (UNIPR) will analyze the correlation between outcome of procedure and histological-biochemical neuroinflammation and genetic factors, in a population of 130 patients undergoing epiduroscopy.
A complex system biology approach will be used to integrate and understand this multidimensional dataset in order to achieve the aims of identifying novel diagnostic and prognostic biomarkers as well as new targets for therapeutic intervention. The track record of achievement of the partners coupled to participation of research-intensive SMEs is a strong indication that the ambitious work program will be achieved and provides a framework for rapid translation of research discoveries into solutions for the benefit of large numbers of patients.
The project activities are divided into nine work-packages (WP), all interlinked and focusing on the same goal, as shown in the Table 1.

Objectives of the period were:

- To continue the management of the entire project (WP1)

- To complete the sample collection from patients of the retrospective study (WP2)

- To stratify patients enrolled in the retrospective study (WP2)

- To obtain the activomic profiling from retrospective study (WP5)

- To complete the enrolment of the prospective study (WP7)

Project Results:
In the large retrospective study, PainOmics is analyzing a cohort of 4,000 patients with chronic low-back pain (CLBP) who will be compared with 8,000 healthy controls. 2812 patients and 804 controls have been enrolled. By also including patients enrolled for the TwinsUK study, we obtained more than 4,000 cases in total. The remaining controls needed are including from existing cohorts, as stated in the DoW.
The PainOmics Project has also established a collaboration with another global consortium (CHARGE Consortium) to perform an evaluation of the genetic contribution for chronic pain in an even larger sample: more than 40,000 patients with low-back pain. A big publication is planned for the end of this year and another one next year.
IgG glycome analysis in LBP was published in one of the leading journals in the field. Additional analyses on two other cohorts have revealed changes in the glycome that are typical for inflammatory diseases in a subgroup of LBP patients; comparison of LBP patients with or without chronic LBP after acute episode indicate that changes in plasma glycome are a part of the disease phenotype, instead of inter-individual differences that are a predisposition for LBP.
The initial retrospective analysis of patients with LBP has furnished us with several novel Activomic biomarkers that will provide important insights into this and wider Activomic studies. Workflows have been developed for high throughput screening of patient samples that can now be extended to wider populations. Whilst limitations still exist, further discovery efforts are ongoing, in the perspective of the implementing a new generation of Activomic markers.
Otherwise, interesting data for activomics and glycomics emerged from the discovery phase. Results are planned to be published in the first semester of 2017. Using the results of this discovery phase we will determine a suitable sample size for the validation phase.
In the large prospective observational study, the Consortium will perform genetic and omics analyses in patients suffering from acute LBP. A large collection of summary-level data from Genome Wide Association Study (GWAS) related to LBP were pursued, with successful generation of high-quality genome-wide genotyping data, and the first GWAs and miRNA analysis of chronic LBP. We investigated the association between chronic wide-spread pain and epigenomics approach.
1164 patients have been enrolled in the prospective study. The results of this WP can be provided only once enough patients have been enrolled for each “omics” analysis. Based on the first results of preliminary data, omics analysis will be performed on the first 1500 cases enrolled (enrollment will be continued up to March 2017).
Given our new collaboration with the aforementioned global consortium, which will have a sample size of roughly 40,000, performing similar GWAS analyses in other 4,000 patients will not be useful. Hence, in order to increase the cost-effectiveness of the Project we propose to perform more omics analysis in the other cohorts of LBP obtained from the collaboration with the other consortium.
UNIPR will analyze the correlation between outcome of procedure and biomolecular neuroinflammation and genetic factors, in a population of 130 patients undergoing epiduroscopy. Up to the end of August 2016, UNIPR has enrolled 84 patients. In order to reach all patients planned, UNIPR will continue to enroll patients up to September 2017 (with last follow up in October 2017). The analysis of patients already enrolled have indicated that patients who reported an improvement after one month after surgery of epiduroscopy show a slight, but progressive change in the levels of some cytokines.
Twins study of CLBP has been closed and results have been published in two articles in 2015 and 2016 showing the important influence of both psychological factors and epigenetic modification in the pathogenesis of chronic pain.

Potential Impact:
The PainOmics project is expected to significantly expand the level of knowledge of how low-back pain (LBP) is generated and quenched. The final objective is to contribute to improved diagnosis and treatment of LBP guaranteeing an even more personalized approach.
A number of potential biomarkers related to different aspects of chronic low-back pain (CLBP), as well as potential new CLBP targets for therapy are expected to be identified.
The situation with patients having LBP has been more and more serious in past years. It is estimated that the total cost of LBP in Europe is over 100 billion Euros per year, which presents an enormous financial burden to the EU.
This program proposal involves technologies that will serve for development of new diagnostic tools for early and reliable identification of patients at high risk for developing CLBP and guidance of treatment. Furthermore, it will enable deeper insight into molecular events, which may cause development of these conditions. All this can further enable production of targeted therapeutics for CLBP or that will slow down/arrest the progression from acute LBP into a chronic condition.
Such a personalized approach should bring about important improvements both in terms of care and in terms of costs. In fact, the findings could contribute in reducing health costs of treatment. Moreover, with better control of this disease, hospitalizations will decrease, which again means that less surgeries will be needed and therefore less time away from work will occur; and all these will consequently improve productivity in this economically vital demographic group.
There is yet another benefit to this approach related to the fact that the new technologies may will be widely applicable across other chronic pain syndromes and therefore may be used for biomarker discovery as well as the study of molecular aetiology for other acute and chronic pain syndromes.
Personalized medicine with efficient therapeutic strategies tailored to specific molecular pathology is one of the most important goals for improving the quality and costs of healthcare in the developed world.
The scientific results of the PainOmics program will be disseminated through diverse channels of communication, both throughout scientific research community and beyond.
Due to that, there is a strong conviction that the goals of the PainOmics project are of significant importance not only to patients with LBP, but to their family members, medical practitioners, policy-makers, and European citizens in general which means, in other words, to a broader audience.
Furthermore, diagnostic tests which could stratify patients with complex conditions such as LBP have huge market potential. Several factors are important for competitiveness of the SMEs. The PainOmics project will use novel technologies. European research groups will develop these technologies and European organizations that are members of the project consortium will promote them. European clinicians will use them. The SME partners in the project will be in a favourable position to achieve financial gain with production of screening technology components, manufactured for wide distribution both on the markets in their own country, as well as on the global market.

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