Professor Marycz: – This is the first step towards developing an osteoporosis vaccine

• Osteoporosis – a medical and social challenge
• This revolutionary idea came about thanks to... horses
• How to force bone cells to rebuild cavities
• Professor Marycz: – I invite young and ambitious scientists to join the research team

A silent bone thief

Every third woman after menopause suffers from osteoporosis – the risk of bone fracture is about 40%, while for men it is approx. 13-22%. It is a generalised metabolic bone disease, characterised by low bone mass, impaired microarchitecture of bone tissue and, consequently, increased fragility and susceptibility to fractures. During the initial stage there are virtually no symptoms, which is why osteoporosis is called a silent bone thief. In highly developed countries, such as Poland, complications related to osteoporosis are among the most common causes of death, especially with regards to the elderly. This is because bone fractures lead to muscle wasting, a greater risk of infection, pressure ulcers, pulmonary embolism, and pneumonia.

– Osteoporosis is a social disease, and therefore significant not only because of its scale, but also related economic costs. Moreover, bone defects may occur after tooth resection, which is experienced by many people and it is now an issue with today's ageing society, although it is rarely mentioned due to the lack of awareness in this regard. These are also bone defects after craniofacial injuries as a result of traffic accidents. The scale and range of problems is very wide, because cavities do want to not heal, which directly affects the quality of life of those people who have difficulty speaking, drinking or eating – says Prof. Krzysztof Marycz, who will create a biomaterial using mRNA technology in his project, thanks to which it will not only be possible to inhibit the process of bone erosion, but also rebuild the missing bone material.

From horses to man

mRNA – messenger matrix ribonucleic acid. It was first used for therapeutic purposes in 2001 – a patient's cells were taken, RNA was inserted into them and then introduced into the patient's body. mRNA is a copy of a specific gene, e.g. containing information on how to produce a given protein. The body transfers this information through it from the DNA, or genome, located in the cell nucleus without affecting it. Later on, thanks to the "recipe" contained in the mRNA, a given protein is synthesised in the cytoplasm of the cell, and proteins are responsible for regulating most physiological processes in the body. This attribute was used in the development of a vaccine against SARS-COV-2.

– And I will use it in the osteoporotic process. We started working on this solution a few years ago, before the pandemic. We started off with research on horses. Together with Paweł Golonka we proposed a similar technology, although without mRNA, for filling subchondral cysts in horses. Everything went well, we published a paper showing the spectacular results of the clinical trials, so I started thinking about how to use this experience in finding therapeutic solutions for humans. This is first of all because horses can help with human medicine, but secondly – is it better to help hundreds of horses or millions of people? – explains Prof. Marycz, adding that these questions, or rather the answers to them, became a turning point in the way he thought about science. Horses are his passion – he cannot imagine life without horse riding and it was thanks to horses that he came up with the idea of reversing the bone resorption process by using mRNA molecules and/or small non-coding RNAs (microRNA/miRNA). miRNA molecules regulate mRNA levels, acting at the post-transcriptional level, directly influencing the expected therapeutic effect.

Osteoclasts, osteoblasts and mRNA

In the winning project, the scientist from the Wrocław University of Environmental and Life Sciences proposed using inorganic technology to protect organic molecules: mRNA is to inhibit osteoclasts and promote osteoblasts in the place of a bone defect.

– This is a radical mindset change. Until now, discussions were around supplying bones with calcium. I intend to use the cells that produce calcium, because the problem of osteoporosis are overactive osteoclast cells, i.e. those "eating" the bone. On the other hand, those that build it and enable the deposition of calcium in bones are clearly weaker. So I came up with the idea of blocking osteoporotic cells, i.e. osteoclasts, at the post-transcriptional level, and subsequently activating osteoblastic cells, leading to a situation in which they deposit key proteins in the bone matrix and promote calcium deposition, and thus build bones in cavities – explains Prof. Krzysztof Marycz, adding that the revolutionary nature of this method consists not only of reversing the process that takes place in the bone, but also in the precision of locating the process and regulating it. Biomaterial with mRNA will be introduced into the place of a specific defect, with the doctor controlling the order of activation: firstly, microcapsules of mRNA will open, inhibiting osteoclasts, and then new ones will open - this time with mRNA, stimulating osteoblasts to act. Another novelty is the material in which the mRNA will be placed, which in currently used solutions is suspended in lipids. Hydroxyapatites are used here, i.e. inorganic compounds combined with magnetic nanoparticles.

Implemented by a consortium of: the Wrocław University of Environmental and Life Sciences, the Włodzimierz Trzebiatowski PAN Institute of Low Temperature and Structural Research, where the team of Prof. Rafał J. Wiglusz will produce biomaterial, and the company Vivadental, the project is scheduled to conduct pre-clinical and clinical trials of approx. 15 patients over 60 years of age treated for bone defects of the craniofacial bone, periodontal disease or impaired bone metabolism, incl. patients with osteoporosis.

A chance for the ambitious

– The research team I have appointed is interdisciplinary, because such advanced research in the field of personalised and precise medicine requires it – says Prof. Marycz. He also adds that molecular biologists, specialists in tissue and biomaterial engineering, as well as clinicians, are involved in the research. Professor Marycz further emphasises that this project is an example of the effective use of scientific research in a specific therapeutic strategy, so-called translational medicine.
– My project opens the chance for the development of an entire research group, and what's more, it lets me expand the team – which is why I appeal to young and ambitious scientists – if someone is interested in innovative research in the field of personalised and precise translational medicine, then I invite you to apply and give yourself a chance to participate in a project that opens up the possibility of development and participation in ground-breaking research – says Prof. Krzysztof Marycz.

– I hope we can get to the third stage, which is an osteoporosis vaccine. If in 15 months, using mRNA, it was possible to give humanity a vaccine against SARS-COV-2, then this dream is not unrealistic at all – smiles Prof. Marycz, who admits that inspiration and ideas for research usually appear in the morning after running and covering a distance of 10 kilometres. And it has a very scientific justification: according to the latest scientific reports, the hippocampus – while running – creates new nerve connections, which means that two hours after physical effort the brain is the most active, meaning it is the best time to work.

– And this is how the idea for further research, or dreams, was born – a vaccine against prostate and colon cancer. I have put this dream on the list of tasks that I want to focus on. If there is advanced work on a vaccine against ovarian cancer, because the gene responsible for the development of this cancer is defined here, I am convinced that these two are very real – emphasises Prof. Krzysztof Marycz. He also adds that he wants to make a vaccine against prostate cancer, because, firstly, men suffer from it, and secondly – the death toll of this disease results from shame and fear, which make patients see a doctor when the disease is already advanced, and not then when the first signs that it is worth further looking into appear.

The winning project implemented under the Tango 5 competition of the National Centre for Research and Development is entitled: "Development of a therapeutic platform for accelerated bone tissue augmentation, including in osteoporotic patients, based on nanometric calcium hydroxyapatite doped with supermagnetic iron oxides and functionalised with RNA particles". Its cost is PLN 3,261,249.09. Four projects were selected in the competition, out of a total of twelve. The project implemented by a consortium, which is led by the Wrocław University of Environmental and Life Sciences, received the most funding.

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