Giuseppe Gaipa is giving a presentation about developing cell-based medicinal products for advanced therapies in an academic cell factory. In the past decade, the technological revolution in biomedical research has led to the development of novel clinical procedures and biological medicinal products for human use collectively known as advanced therapy medicinal products (ATMPs). ATMPs are generated are regarded as a new medicinal product category comprising gene therapy medicinal products (GTMPs), somatic cell therapy products (CTMPs) and tissue-engineered products. ATMPs offer new treatment opportunities for diseases that currently have limited or no effective therapeutic options. This context has led to the creation of Good Manufacturing Practices (GMP)–compliant pharmaceutical facilities (Cell Factories) dedicated to the development, validation and manufacturing of ATMPs. Cell and Gene Therapy Laboratory Stefano Verri (Monza, Italy) is one of the pioneering academic cell factories authorized in Italy by the National Regulatory Agency (AIFA). This facility is currently authorized for manufacturing of cell-based medical products such as Cytokine Induced Killing (CIK) Cells, Chimeric Antigen Receptor (CAR)- engineered CIK cells , and several other cellular products including Mesenchymal Stromal Cells (MSC) and CD133-positive hematopoietic progenitors to be employed in phase I and II clinical trials. An overview of these GMP-compliant platforms will be discussed as well as the clinical impact of some of them. The current Italian scenario of ATMPs-based studies, with particular focus on the academic setting, will be also depicted.
Paula Salmikangas is a biochemist by original training, with a Ph.D. in muscle cell biology. Her main research work career has been in cell and molecular biology of various inherited diseases. She is giving an overview of how in during recent years, several hundreds of cell- and gene-based novel medicinal products called ATMPs have been studied in clinical trials in EU. The legal framework established in 2007 has provided predictability for the approval process of ATMPs and defined the main technical requirements for the products. Also guidance for the various ATMPs has been developed, however,only seven products have passed the marketing authorization assessment with success. What are the key factors and challenges leading to failures? What impact has quality and manufacturing aspects in the approval process, how far has the safety been studied before clinical trials and the MAA? How strong clinical efficacy data has to be to support not only the MAA, but also reimbursement of the product? Are there specific indications, where ATMP development is particularly active? This talk will give an overview on the ATMP sector as it stands today together with examples of main challenges and successes, including future prospects and the “hypes” of today.
Ralf Sanzenbacher is giving an overview of Regenerative Medicine Concepts at Point of Care from the Regulatory Perspective. Worldwide, the concept of Point-of-care (PoC) cell therapy is becoming increasingly attractive. A growing number of companies, medical practitioner and clinical facilities advertise PoC cell therapies for the treatment of various disorders, predominantly in the autologous setting. PoC cell therapy describes a continuous procedure for on-site patient care within one medical procedure, beginning from cell/tissue procurement, cell processing in or closed to the operation area, and ending with administering the resulting cell preparation. Driven by the promise of clinical benefit, simplified manufacturing and reduced overall costs, PoC treatments could sustainable change the cell therapy landscape. Concomitantly, PoC therapies challenge the borderlines of clinical procedure vs medicinal product manufacturing, regulated pharmaceutical research, development and control vs medical practice, with extreme examples of unsound promises to patients. This presentation aims to provide an overview on the current regulatory setting for PoC cell therapy products with a focus on the situation in Germany and to facilitate the discussion on adequate supervision.
Dariusz Sladowski is presenting a topic on develeopment and commercialisation hurdles of ATMPs. There is no doubt that in the near future advanced therapy will provide an effective treatment for skin lesions, some forms of blindness, heart attack and many other health problems. Despite numerous efforts, ATMP use is still far from everyday clinical practice. There are numerous scientific, technological, legal and financial problems which must be solved before a new product can be available for clinical use. The author will present current status of ATMP development in Poland and his own experiences as a scientist, businessmen and legislator.
Alar Irs gives an overview of regulatory challenges. Regulating the advanced therapy medicinal products in a way that ensures the protection of patient safety but does nor obstruct (or even encourages) development is a challenge for every innovation-friendly country. The presentation will generalise the limited domestic experience of the Estonian Medicines Agency in the field and provide the Agency’s view of the near future.
Hele Everaus is giving a lecture about hematopoietic stem cells-from practical applications to future opportunities. Grounded in half a century of research, the study of hematopoietic stem cells (HSCs) is one of the most exciting and rapidly advancing disciplines in biomedicine today. Currently, no other type of stem cells, adult, fetal or embryonic, has attained such a status. HSCs transplants are routinely used to treat patients with cancers and other disorders of the blood and immune system. However, HSCs appear to be able to form other kinds of cells, such as muscle, blood vessels and bone. It is possible to induce bone marrow or HSCs to differentiate into other types of tissues, like brain, muscle and liver cells. New opportunities for the use of HSCs include graft-versus-tumor therapy for currently incurable cancers, autologous transplants for autoimmune diseases and gene therapy and tissue repair for other problems. Concomitant advances in gene therapy techniques and the understanding of cellular plasticity could make HSCs one of the most powerful tools for healing.
Viljar Jaks will present a topic on extracelular matrix - the determinant of tissue regeneration. Extracellular matrix (ECM) has been considered for tens of years an inert scaffold that builds up the mechanical framework of tissues and provides merely a substrate for cell attachment. The advances in ECM biology, however, have showed it as a dynamic structure that actively regulates cell behavior and has a prominent role in regulating tissue regeneration. Furthermore, the role of artificial ECM in regenerative biology in the context of recent advances in 3D bioprinting has enormously increased. Thus, we will outline the main characteristics of normal and artificial ECM and discuss the potential application of the knowledge acquired in the field of ECM biology in regenerative medicine in near future.
Külli Kingo is giving a presentation on the role of interleukin-10 (IL-10) family cytokines in vitiligo. Vitiligo is an idiopathic disease characterized by localized or generalized depigmentation of skin, hair and mucosal surfaces due to loss of melanocytes. There are many evidences that vitiligo is an autoimmune disease: vitiligo is associated with many autoimmunity susceptibility loci, vitiligo may coexist with other autoimmunity diseases, patients with vitiligo have antibodies against melanocytic antigens in the serum, proinflammatory cytokines are overexpressed in the skin and peripheral blood of the patients, and immunomodulative medicines have positive effect in therapy.
The aim of our group was to clarify the role of interleukin-10 (IL-10) family cytokines in the pathogenesis of vitiligo. Analysis of expression levels of IL-10 family cytokines in skin and blood samples demonstrated significantly elevated IL-22 mRNA and protein levels in blood of vitiligo patients compared to controls, while the expression of IL-20RA was decreased both in uninvolved and involved skin samples of patients, supporting the hypothesis that described markers could be involved in the pathogenesis of vitiligo. The results of genotyping of polymorphisms of IL22 and IL20RA genes supported the results of expression analyzes, showing statistically significant effects of haplotypes of IL22 and IL20RA genes in vitiligo susceptibility. To understand the functional basis of the involvement of IL-10 family cytokines in the susceptibility to vitiligo, we studied additionally the role of genes of the melanocortin system in the pathogenesis of vitiligo (genes of melanocortin system have anti-inflammatory properties). The expression levels of genes of the melanocortin system were found to be decreased in lesional skin of vitiligo patients and to be increased in non-lesional skin of vitiligo patients, indicating a possible compensatory regulative role of these genes in the pathogenesis of vitiligo.
Triin Vasar as a plastic surgeon will give a presentation on cell therapy in treatment of soft-tissue defects. Presentation is based on an overview of new developments in dealing with soft tissue defects.
Eero Vasar is presenting a topic on "Who framed Red Bull?". The recent opinion of Hardingham and Do (2016)1 links the development of schizophrenia with alterations in N-methyl-D-aspartate (NMDA) receptor2 function and oxidative stress. These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests that they are mechanistically interdependent and contribute to a common schizophrenia-associated pathology. This report underlines the biomarkers reflecting NMDA receptor hypo-function and oxidative stress in the development of the first episode psychosis.
1 Hardingham GE, Do KQ. Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis. Nat Rev Neurosci. 2016; 17: 125–34.
2NMDA receptors are responsible for neural development, formation of cognitive networks in the brain and hypofunction is related to the first episode psychosis.
Aare Märtson is presenting a topic on bone crafting. Bone grafting is one of the oldest examples of tissue transplantation. In 1820 German surgeon Philips von Walter described, how he replaced a fragment of skull after the trepanation. Marshall Urist (1914-2001) discovered bone morphogenetic protein (BMP) in 1965, a substance that helps bone to regenerate by inducing certain types of connective tissues and other unspecialized cells to become bone cells.
Biological mechanisms of bone grafting contain the following processes: osteoconduction, which is scaffold (collagen, matrix, nano-) function of bone graft. Osteoinduction is mostly carried by BMP and transforming growth factor β (TGF-β), but by other growth factors containing in bone graft as well. Osteogenesis is possible, when vital osteoblasts originating from the bone graft material contribute to new bone growth along with bone growth generated via the other two mechanisms.
Bone graft obtaining has different options: autografts can be obtained from the different part of the skeleton, but grafts obtained from other specimen are called allografts. As bone grafts have limited resources a number of bone substitutes are available on the market. This makes also important existence of bone banks, which is created in 1961 at Tartu University Hospital already.
Guy Wouters is giving a fascinating presentation focusing on veterinary regenerative medicine. Osteoarthritis is reported to be the most common cause of chronic pain in canines in the US and it is estimated that approximately one in five adult dogs in the US is arthritic. In published reports of hospitalized felines 33,9% had arthritis and in those of 12 years of age, approximately 90% had arthritis. Similarities in human and veterinary non-surgical management of arthritis include joint supplements such as glucosamine chondroitin sulphate, weight management, controlled exercise (physic therapy), acupuncture and a heavy reliance on non-steroidal NSAID’s. A safe minimally invasive effective treatment of arthritis could highly improve the quality of life for both human and veterinary patients that suffer this painful debilitating disease and the potential complications associated with current therapy. Autologous adipose-derived mesenchymal stem cell (AD-MSC) therapy involves harvesting fat from the patient, isolating the stem and regenerative cells, and administering the cells back to the patient. Autologous AD-MSC therapy in veterinary regenerative medicine has been established by Fat-Stem.
Adas Darinskas will present his topic on the following: Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease associated with high amputation and mortality rates and poor quality of life. In the last decade, cell-based therapies have been developed as an alternative treatment option for CLI, because a lot of CLI patients are not eligible for conventional treatment. However, therapeutic potential of uncultured adipose-derived stromal vascular fraction (SVF) cells has not been evaluated. In this study, we investigated the efficacy of multiple injections of autologous uncultured adipose-derived SVF cells to treat patients with CLI. Results of this pilot study demonstrate that multiple intramuscular SVF cell injections stimulate the regeneration of injured tissue and are effective alternative to achieve therapeutic angiogenesis in CLI patients who are not eligible for conventional treatment.
Elar Killumets will give an overview from a different perspective. For most of great achievements, the input of more than one stakeholder groups is needed. Although the common interest (win-win potential) is there, quite often the cooperation is not that smooth as one would to assume considering potential gains for each stakeholder. Concept of group identity explains this discrepancy – even the groups have mutual goal or interests, each stakeholder still has its own identity. In my short presentation I talk about:
1. How and why group identity sometimes seriously impedes the collaboration, even when collaborating stakeholders have strong common interests
2. How to overcome those potentially harmful side effects of strong indenty on collaboration of those stakeholders.
Peeter Koppel, SEB Private Banking strategist, is giving an exciting overview of world`s economy, based on a topic of the population of the developed world is aging as debt levels have reached unprecedented heights. This toxic cocktail has put the economies on developed economies on constant life support with no hope of getting back to healthier status. At the same time silver economy is set to thrive. "Silver Economy" means businesses dealing with servicing and generating products for the elderly.
Karin Rosenstein is giving a presentation about adipose derived stem cells and their future perspectives. Adipose tissue is rich of mesenchymal stem cells which can give rise to bone, cartilage and adipose tissue owing to their multipotent capacity. Furthermore, in certain culture conditions it could also differentiate into skeletal muscle, tendon, myocardium, smooth muscle, endothelium and even to neurons. In addition, adipose derived mesenchymal stem cells (ASCs) have positive bystander effect as they secrete growth factors and immunomodulators at the site of injured tissue and thus participate actively in tissue repair and regeneration. Scientists have learned how to isolate, culture and expand ASCs and such cells are already in use in more than 160 clinical trials today related to regenerative medicine and aesthetic procedures. Research data show that in general the quality of stem cells is likely to get worse over time depending both on genetic background and lifestyle. Is it worth to store your ASCs when you are still young and healthy? Can it be done in Estonia?
Jekaterina Kazantseva will give a presentation on topic "Mesenchymal stem cells – drugs or drug-delivery systems? ". The immunomodulatory potential of mesenchymal stem cells (MSCs) is highly exploited nowadays in Cell Therapy and Regenerative Medicine. Critical Limb Ischemia represents a good candidate for cell therapy, where MSCs enhance neovascularization in ischemic limbs and promote the collateral vessels formation due to paracrine and immunosuppressive properties of MSCs. However, MSC transplantation needs to be combined with anti-inflammatory therapy, the effects of which on MSC biology have not been studied yet. Our data disclose the influence of anti-inflammatory drugs on MSC expression profile and reveal unexposed potential of drugs to improve immunomodulating functions and regenerative potential of MSCs.