A bioreactor for growing human mini-organs in vitroobserve them under the microscope in real-time and evaluate the safety of future therapies based on genetic editing of stem cells.
This challenge was taken up by Moab, a young biotech company based in Milan, thanks to the winning of the Crack IT Challenge, funded by the British NC3Rs, a non-profit organization that funds alternative research to the use of animals. The project is developed by a multidisciplinary team of researchers and coordinated for MOAB by Manuela T. Raimondi, professor of bioengineering at the Politecnico di Milano.
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Certain monogenic blood-related diseases, such as sickle cell anemia, thalassemia and primary immunodeficiencies, have the potential to be treated with human hematopoietic stem cells modified by gene editing. Gene editing of hematopoietic stem cells, using innovative technologies including Crispr technologyoffers a high level of accuracy but could still generate cells with oncogenic potential. Currently, studies with animal models to evaluate the tumorigenicity of cell products with modified genome are a regulatory requirement, but they are long, expensive, require the use of a large number of animals and are not always able to guarantee an adequate level. of predictivity and security.
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The Crack IT project gathers the sponsorships of tre known pharmaceutical companies, Bayer, Novartis and Takeda, and aims to develop a model in vitro to replace tumorigenicity studies in vivo, for the safety assessment of genetically modified human hematopoietic stem cells. “The project was already born with the aim of creating a technology and methods that allow us to transfer our experimental activities to the industrial level. This immediately provides for the involvement of the partners towards what is an ambitious and common goal, that is to instill in the patient a cell therapy based on genetically modified and safe stem cells, which will not cause tumors.”, Explains Alessandro Rotilio, managing director of Moab.
The miniaturized bioreactors developed by Moab allow to overcome one of the main problems that characterized tissue engineering, namely the possibility of recreating and monitoring the interstitial perfusion process of cultured tissues in vitro, such as the bone marrow and lymph node. This is because in the past the culture took place inside large bioreactors, which prevented homogeneous oxygenation and real-time monitoring. “We changed our paradigm and developed a plate for microscopy, on which three miniaturized culture chambers were mounted, in order to also guarantee the repeatability of the data obtained.”, Explains Raimondi. This technology has already been tested in foreign laboratories and updated for years by Prof. Raimondi and her collaborators, up to an optimized device ready for preclinical testing in the pharmaceutical industry. Thanks to MOAB it is possible to replicate in vitro a response to drugs comparable to that observed in animalswith solid scientific results already confirmed in the fields of chemotherapy for metastases, stem cells for therapy against neurodegeneration and in cell therapy for muscular dystrophy.
Security is only one of the advantages of the proposed technology; in the best of scenarios, in fact, companies will have a reduction of up to 75% in the costs associated with preclinical tests and a reduction of up to 50% of the time to market for many new drugs, especially biologics.
The development of a new drug takes an average of twelve to thirteen years and costs an average of three billion euros (value increased by 70% in the last ten years). Companies, especially small-medium biotech start-ups, are not always able to bear these costs. Indeed, the development of a radically new therapeutic candidate, be it a traditional drug or an advanced biopharmaceutical such as a therapy based on stamina cellsis subject to regulatory approvals based on three phases: laboratory discovery in vitropreclinical tests in vivo and clinical trials on patients. As far as the drug development process is concerned, there is not only a serious problem of efficiency, but also of efficacy. Currently, of ten thousand new therapeutic agents, only one arrives on the market in the form of a new commercial drug. Therefore, drug development is currently a process with an overall failure rate of 99.9%. 96.4% is due to the failure of the preclinical testing phase, since the efficacy of the drug measured in vitro it is rarely confirmed in the animal. “One of the main problems is that the in vitro tests required by regulatory bodies are out of date”, Explains Raimondi. It is often a culture dish in which there is a single cell population; the drug to be tested is added to the culture medium and the expected activation of specific cell markers is measured. “However, in this simplified in vitro culture condition, the drug induces a cellular response that is not representative of the in vivo response, which is based on cellular interactions that occur in three-dimensional environments, between different cell populations – never limited to that addressed by the drug – and in a very long time, of the order of weeks”, Continues Raimondi.
Today, always more research groups are focusing on realistic culture techniques as organoids, spheroids and culture in humanized bioreactors. These innovative tools also make it possible to better respond to the current European legislation aimed at pushing towards a reduction in animal experimentation which, however, is still irreplaceable to date for verifying some crucial aspects of drug safety. “With this project we are writing a new chapter on the safety of gene editing approaches and biotechnology of the futureconclude Rotilio.