PERIMED

EUROPEAN UNION
European Regional Development Fund

Project № BG05M2OP001-1.002-0005

Personalized Innovative Medicine Competence Center (PERIMED)

PARTNERS

1. The Medical University in the City of Plovdiv
2. The Paisii Hilendarsky University of Plovdiv
3. Institute of Applied Mineralogy – BAS

LABORATORIES

Plovdiv University:

1. Laboratory on Molecular biomarkers and Microbiota;
2. Laboratory on Immunobiomarkers;
3. Laboratory on Biocatalysis and biologically-active substances;
4. Laboratory on Biopolymers and novel materials;
5. Laboratory on Biosensors.

Medical University:

1. Laboratory “Drug delivery systems for targeted effect of drugs and personalized medicine”;
2. Laboratory for molecular genetic analysis.

IMC-BAS:

1. Laboratory for physicochemical control of pharmaceutical formulations.

The main directions:

• Molecular biological methodologies for application in personalized medicine;
• Innovative drug-delivery systems for targeted therapy;
• Bioengineering technologies, biosensors.

Work packages:

• WP 1. Creation and validation of a panel of genes for monitoring of tumor heterogeneity, molecular resistance, tumor load and minimum residual disease in patients with verified breast cancer
• WP 2: Creation and validation of a panel of genes for precise molecular-genetic diagnosis in patients with chronic myeloid leukemia (CML) and monitoring of minimal residual disease
• WP 3. Molecular biomarkers for medical application
• WP 4. Application and development of the method of flow cytometric monitoring of the minimal residual disease in children with acute lymphoblastic leukemia
• WP 5. Creation and introduction of comprehensive personalized approach in critically ill patients
• WP 6. Molecular biomarkers of the microbiota of the gastrointestinal tract
• WP 7. Immuno-biomarkers for tumor and autoimmune diseases
• WP 8. Drug-delivery systems for targeted effect of medications and personalized medicine
• WP 9: physicochemical characterization of innovative medical forms
• WP10. Biocatalysts and natural bioactive substances
• WP 11. Biopolymers and new materials
• WP 12 Biosensors

Equipment required for the implementation of activities planned in the work packages:

• Automated sterile colony picking system.
• Automated system for incubation and phenotypic identification of microorganisms bacteria, yeasts and molds.
• Bioreactors for submerged cultivation of enzyme producing microbial strains.
• Real Time PRC equipped with at least six filters, computer system and software and all of the necessary reagents and consummative for multiplex PCR.
• High Performance Liquid Chromatography System equipped with colonies for analyzes of different bioactive substances, oligosaccharides and other metabolites.
• Encapsulator for sterile production of various micro- beads with enzymes, microbial cells and bioactive substances.
• Laboratory Spray Dryer for pulverization drying of enzymes and other bioactive substances.
• Microplate Reader for various bioactivities testing procedures,
• Laboratory System for Membrane Filtration for purification and concentration of enzymes, proteins and polysaccharides produced by microbial fermentation.
• Pilot system FPLC for purification of enzymes and bioactive compounds.

RESEARCH PLAN

The activities in the PERSONALIZED INNOVATIVE MEDICINE (PERIMED) Competence Center are consistent with the patient-oriented strategies in the field of healthcare and refer to Component 3: “Industry for healthy living and biotechnologies”, in direct relation to priority subsection “Personalized Medicine, diagnostics and individual therapy”.

The establishment of the Personalized Innovative Medicine Center reflects the need for the conduct of significant studies and their direct application in the medical practice and the pharmaceutical industry, with the purpose to provide individual therapy to a large number of patients in Bulgaria. The research program of the Center is based on an interdisciplinary approach, covering the entire cycle of studies in the introduction of innovations in the fields of biotechnology, medicine and pharmacy, diagnostics, development of specialized biomarkers, application of personalized treatment and establishment of innovative pharmaceutical technologies. Within a period of ten years the Center of excellence will provide a competitive advantage in the European Union by reducing the costs for treatment of one patient and by achieving optimum pharmacoeconomic effect.

Substantial progress in the realization of the Personalized Medicine and the implementation of targeted therapy, especially for oncological diseases, was possible thanks to the development of the Molecular Biology, Genetics, Combinatorial Chemistry, Biochemical Pharmacology and the creation of innovative drug carriers for targeted therapy, molecular biotechnology. Finding the “right therapy at the right dose at the right time for the patient”, i.e. the introduction of personalized approach to the clinical practice, requires much more effort. The Personalized Medicine Center brings together researchers from MU – Plovdiv, Paisii Hilendarski Plovdiv University and the Institute of Mineralogy and Crystallography to the Bulgarian Academy of Sciences (IMC – BAS), as the Medical University – Plovdiv has the leading role. The associated partners are: Sveti Georgi University Multiprofile Hospital for Active Treatment, Eurohospital University Multiprofile Hospital for Active Treatment – Plovdiv, Pulmed University Multiprofile Hospital for Active Treatment – Plovdiv, Neopharm – Bulgaria, Lactina Ltd., distinguished researchers from prestigious European universities: University of Szeged – Faculty of Pharmacy, University of Manchester, UK, Instituto De Agroquimica y Tecnologia de Alimentos (IATA), Agencia Estatal Consejo Superior de Investigaciones Cientificas (CSIC) – kSpain, St. Anna Children’s Cancer Research Institute (CCRI) – Austria and others.

The activity of the Competence Center will be developed in three main directions: Molecular and biological methodologies for application in the Personalized Medicine, Innovative drug carriers for targeted therapy and Personalized Medicine, and Bioengineering Technologies and Biosensor. Specialized laboratories will be constructed for the realization of the objectives, in which research will be carried out by specialists in different fields: Medicine, Molecular Biology, Genetics, Oncology, Genomic Medicine, Pharmacy, Biochemistry, Chemistry, Biotechnology, etc. The specialized laboratories will cooperate closely in the future implementation of the final products and their realization.

The Laboratory for molecular genetic analysis will implement activities related to the creation and validation of a panel of genes for monitoring of tumor heterogeneity, molecular resistance, tumor burden and minimal residual disease in patients with established breast carcinoma. By applying advanced methods for genotyping a comprehensive analysis will be performed on the molecular profile of the oncological disease and the selection of genes responsible for the development of malignancy and tumor progression. Through integrated bioinformation approaches the generated information will be analyzed with the aim of identifying the relevant biomarkers for the group of diseases and their inclusion in a panel for simultaneous analysis of multiple targets. Analysis will be made of the minimal residual disease in children with Acute Lymphoblastic Leukemia during the course of chemotherapy, which will be the main criterion for personal adaptation of the treatment and prognosis of relapse-free survival. Gene polymorphisms will be determined for chemotherapeutic-metabolizing enzymes in children with malignant diseases, as the corresponding panel with enzymes will be chosen according to the cytostatics included in the therapeutic protocol. The data obtained will be compared with the level of expression of the organ toxicity upon chemotherapy. Knowing the available polymorphisms is a promising basis for individual dose regimens associated with reduced toxicity and improved prognosis.

The development of this Package will lead to earlier and more accurate diagnosis of oncological diseases by minimally invasive approaches, accurate personalized therapy and prognosis. The frequency and the type of mutations in oncological diseases of the studied population will be established, which will lead to a better understanding of the mechanisms of the pathogenesis of oncological diseases. The planned studies will lead to the creation and the implementation of a new approach in the development of therapeutic strategy for oncological diseases that will provide personalization, availability and optimization of the available resources.

Through integrated bioinformational approaches an appropriate bioinformatics data basis will be established and an analysis will be conducted on the information generated with the aim of identifying the relevant biomarkers for diseases, their inclusion in the panel for simultaneous analysis of multiple targets and referral to appropriate individual therapy.

Accredited and certified laboratories specialized in Molecular Enzymology and Bioprocesses will be constructed for the realization of research studies in the field of molecular biomarkers and microbiota of the gastrointestinal tract. The main practical purpose is the study of the correlation between the balance of the human intestinal microbiota and some socially significant diseases, such as diabetes, liver diseases, colon cancer and some socially important diseases, such as breast cancer and colon cancer, diabetes, liver diseases.

Results from the research studies in the Work Package: Immune biomarkers for tumor and autoimmune diseases are directly integrated with the Laboratory for molecular genetic analysis. The possibility of introduction of antigen-based approach in the treatment of autoimmune and tumor diseases will be evaluated. It is expected to be developed a set of useful molecular markers involved in the autoimmune and anti-tumor response, on the basis of which new therapeutic agents will be developed.

Extremely innovative part of the work of the Center is linked to the implementation of a personalized approach to the treatment of critically ill patients. The development and introduction of a comprehensive customized approach is envisaged for its implementation on the basis of an analysis of the clinical and prognostic value of variables defining the essential organ and system dysfunctions in the intensive care medicine. There is a plan for establishment of multiparameter monitoring system allowing real-time monitoring and analysis of data from respiratory and hemodynamic monitoring, when integrated with laboratory results from the hospital information system. The envisaged studies represent innovative high-tech approach to the specific diagnostic and therapeutic needs of critically ill patients and are based on the principles of the Personalized Medicine. This will lead to more precise planning and performance of the overall diagnostic and therapeutic process, improvement of the quality and safety of the applied therapeutic methods.

The second main direction of the Competence Center – Innovative drug carriers for targeted therapy – will implement its activity through the establishment of two laboratories: “Drug-delivery systems for targeted effect of drugs and personalized medicine” and “Physical and chemical control of innovative formulations”.

The establishment of this unique for Bulgaria and the region laboratory “Drug-delivery systems for targeted effect of drugs and personalized medicine” aims to develop innovative drug-delivery technologies with targeted effect, primarily on the anti-tumor therapy. The results will contribute in various fields of the pharmaceutical science – nanotechnologies, alternative routes of drug administration, targeted therapy. The interdisciplinary approach of the research studies at the Center will contribute to the establishment of specific models of drug delivery systems for achieving targeted therapy. Polymeric nanoparticles and liposomes with optimal control of release and achievement of targeted release will be developed. The mechanism of the intracellular uptake of nanoparticles, their transportation and distribution in different intracellular compartments, as well as the mechanisms for improvement of the therapeutic activity of substances on the cellular level will be studied. Innovative micro- and nanocarriers conjugated to monoclonal antibodies (mAb) will be developed for targeted therapy. Subject of the scientific developments will also be the development of “smart” drug delivery systems – polymeric and lipid nanocarriers with targeted release that are capable of specific response to pathophysiological changes occurring as a result of the disease.

The Laboratory for Drug-delivery systems for targeted effect will work in conjunction with the Laboratory “Physical and chemical control of innovative formulations”. The physicochemical properties of the drug substances and the drug carriers are essential for basic biopharmaceutical properties: solubility, stability, coupling constants, interactions, bioavailability, distribution to specified targets and others, without which it is impossible to assess the potential biological effectiveness of a drug. The data of the specific physicochemical properties of the drug-delivery systems with targeted effect, the immobilized biocatalysts, the natural bioactive substances, the biopolymers, the new materials and the biosensors will contribute to the preparation of effective drugs.

The third direction in the activities of the Center – “Bioengineering Technologies and Biosensors” will develop its research activities in three areas: “Biocatalysts and natural bioactive substances”, “Biopolymers and new materials” and “Laboratory for sensors and biosensors”.

The main objective of the research is the construction of new enzymes through the developed modern scientific infrastructure for advanced integrated research platform, which to synthesize specific new bioactive components or to modify natural biomolecules, whereby changing their biological properties.

All studied new enzymes, biomaterials and bioactive substances will be directed for the establishment of new diagnostic kits for rapid and accurate diagnosis of cancer and other socially significant diseases and application of new more efficient therapeutic products in the personalized medicine.

The Laboratory “Biopolymers and new materials” aims to create innovative polymeric materials, which when applied as drug carriers have the potential to reduce the side effects of medication, to correct the dosage and others.

Laboratory “Sensors and biosensors” will also be created, in which series of biosensor devices will be developed that are applicable in the biomedical analysis and the pharmaceutical production. Methods will be created for rapid and selective monitoring of drugs, metabolic products, toxic products and others in biological environments.

The results of the overall interconnected activities of the Center for “Personalized and innovative medicine” will lead to the creation and implementation of a new approach in the development of therapeutic strategy for oncological diseases and critically ill patients through innovative personalized approach. The personalization of the therapy will increase the efficiency and the safety of the therapeutic methods and the medicines administered to large numbers of patients.

The scientific and the practical results of the Personalized Innovative Medicine Center (PERIMED) will contribute to the introduction of innovative approaches in the global medical practice.

On the basis of the analyzes of the available capacity and the identified opportunities and key scientific areas, in which the researchers from the three partners have a competitive advantage and could develop as leaders in the European and national innovation systems, the research teams determined the following scientific programs/Work