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microRNA biomarkers in an innovative biophotonic sensor kit for high-specific diagnosis

Periodic Reporting for period 2 - miRNA-DisEASY (microRNA biomarkers in an innovative biophotonic sensor kit for high-specific diagnosis)

Berichtszeitraum: 2017-12-01 bis 2019-11-30

The miRNA-DisEASY network aims to tackle the emerging needs in clinical diagnostics for the early and selective diagnosis of lung cancer, which is a malignant neoplasm representing the leading worldwide cause of cancer-related death.
This high mortality is due to the poor prognosis of the disease, caused by late disease presentation, tumour heterogeneities within histological subtypes, and the relatively limited understanding of tumour biology. Most lung cancer patients are diagnosed at an advanced stage of disease, and, although a small subset of these patients can be treated with new drugs offering improved survival and reasonable quality of life, the majority of patients can only be treated with palliative chemotherapy. Overall survival remains poor, and many patients die within a few months of diagnosis.
Biomarkers able to stratify for the subtype of lung cancer, prognosticate the course of disease, or predict the response to treatment are in increasing demand. Lung cancer subtyping has traditionally relied on the histopathological observation of resected specimens, bronchoscopic biopsies, fine needle aspirations or sputum, which represent samples with decreasing invasiveness for the patient, but also of increasing challenge for the pathologist, as proportionally fewer tumour cells are captured.
In the last decade, miRNAs measured in resected tumour samples have emerged as biomarkers for tumor diagnosis, prognosis and prediction of response to treatment, thanks to their extreme specificity. Moreover, miRNAs present in sputum, in plasma, in serum or in whole blood have increasingly been explored as less invasive biomarkers for the early detection of cancers.
Given the great relevance of a precocious and a more specific diagnosis of lung cancer, the miRNA-DisEASY programme seeks to address this major world health issue advancing three main project objectives:
1. identification of miRNA biomarkers involved in lung cancer pathogenesis;
2. development of a new and low cost sensor kit to reliably detect the identified miRNA biomarkers;
3. Initial small scale clinical sample testing, that could lead to a significant investment in a healthcare product capable of delivering a high specificity, low invasive test for lung cancer, based on a microRNA biomarker panel.

Inspired by the relevant problems of analyzing clinically valuable miRNAs biomarkers, the partners successfully merged two innovative technologies. The chemical-NAT technology delivers a rapid direct detection of miRNAs from biological fluids with a single mismatch discrimination. The optical-based device brings the advantages of being sensitive, low cost and with an high degree of miniaturization. Accurate miRNAs profiling without extraction, pre-amplification, or pre-labelling of the target is now made achievable.
In the first two years of the miRNA-DisEASY project, UNITN, UFSC, MHH and GNX worked together on the discovery of miRNAs biomarkers in different type of lung cancers.

From the generated work, DestiNA synthesized optimized probes and SMART-nucleobases for the subsequent experimental works.
In the second part of the project, the detection kit was tested by Optoi and successfully validated by Unitn, Optoi and DestiNA with samples from lung cancer patients. The analytical sensitivity of Optoi-DestiNA technology was determined by creating a calibration curve using known concentrations of synthetic RNA-hsa-miR-21 where chemiluminescent signals were detected by the SiPM-based reader. The platform and simplified sample preparation delivered a specific, sensitive and rapid detection of the microRNA, free of errors or variability. Being a direct detection method enabling read-outs of the absolute quantification of mature hsa-miR-21-5p, requiring neither pre-amplification nor pre-labelling of target miRNAs, it demonstrated a significant improvement over many current methods.

The miRNA-DisEASY work plan has recognized the unique chance offered by the Marie Sklodowska-Curie RISE action for mobility and training of R&I staff, and for this reason implemented a strong programme of training of all the seconded staff within the WP4 activities.
The methodology adopted for knowledge sharing was based mainly on: i) Training courses (lectures and laboratory practices); ii) Internal workshops with seminars; iii) Regular meetings.
The intention of the consortium has been to provide efficient training on scientific, technical and management skills to all secondees by foreseeing activities covering all aspects during the periods of mobility.

During the implementation of the project, the consortium has been very active in terms of looking for exploitation opportunities. This activity was in particular driven by the SMEs Optoi and DestiNA for the joint technology, with the support of the academies.
For the whole project lifetime, the intention of the consortium has been to advance, develop and commercialize the promising results, according to Article 28 of the H2020 Grant Agreeement and as regulated also by the Consortium Agreement.
The exploitation plan was constantly updated according to the progress and emerging results of the project and discussed in conjunction with the IPR management during Consortium Meetings.
In the last year, the partners demonstrated the capability to perform accurate microRNAs profiling without extraction, pre-amplification, or pre-labeling of the sample. The data generated during the preliminary validation of Optoi-DestiNA Genomica (in short “ODG”) Device with clinical samples, were published by members of miRNA-DisEASY consortium in a high-ranking chemistry journal.

The project technical achievements are now leading the partners to the discussion on the future exploitation of the miRNA detection kit, which will extend their collaboration beyond the project conclusion and allow them to gradually approach the market.
Progress beyond the state of the art relates the results from the two scientific work packages: the definition of potential miRNAs involved in the differentiation of lung cancer subtypes, and the reach of a technology capable of profiling miRNAs without extraction, pre-amplification and pre-labelling of the target.

Impact of this project is relevant firstly for public health, as micro-RNAs are key gene expression regulators, with great potential as biomarkers for cancer staging, diagnosis, prognosis, and therapeutics. The development of a platform suitable to perform rapid tests at hospitals, emergency centers, GP’s offices and pharmacies is going to help to unlock the full potential of miRNAs as circulating biomarkers for lung cancer, helping to bring to reality the concept of a non- invasive “liquid biopsy”.
During the whole project duration, the impact of the miRNA-DisEASY project has also achieved significant benefits for the seconded personnel, who have experienced the highly international, interdisciplinary and intersectoral character of the project. Interactions among participants from different fields (molecular biology, biotechnology, biochemistry, chemistry, physics, pharmaceuticals, electronic engineering and micro and nanotechnology) have not only enabled secondees to be placed in challenging but very stimulating scientific environments, but also to collaborate in the development of a molecular diagnostic assay platform of global potential.
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