03.06.2024: Osteoarthritis is a painful, chronic joint disease. Supported by wings4innovation, the KHAN-I Fund is providing financial resources for a project with the University of Veterinary Medicine, Vienna. The aim of this project is to identify active substances for the regeneration of joint cartilage. In this article, LISAvienna provides insights into the early phase of this drug development project.
Osteoarthritis is by far the most common form of degenerative joint diseases in humans, but also occurs in animals. It affects joint cartilage, the synovial membrane lining the joint and the bone beneath the joint cartilage. Continuous wear and tear and inflammation lead to pain, functional limitations and subsequently to permanent physical impairments. Joint cartilage is unable to regenerate in adult mammals, which is why osteoarthritis is one of the chronic diseases that cannot yet be cured. In some cases, the body manages to build up fibrous cartilage tissue for repair, but this is not as resistant as normal joint cartilage tissue. In humans, symptoms often begin between the ages of 40 to 50 - almost all 80-year-olds are affected to varying degrees. Florien Jenner and Iris Gerner from the University of Veterinary Medicine, Vienna are pursuing an idea to develop drug candidates that could cure or at least significantly improve the status of worn articular cartilage in osteoarthritis. Highly specialized knowledge from developmental biology on the subject of cartilage growth is being used.
Professionel technology transfer
"The aim of our project is to develop drug candidates for a regenerative therapy for osteoarthritis. We are focusing on a cell-free approach because, in contrast to stem cell therapies, this opens the door to standardized and inexpensive products that can be produced and stored easily and are suitable for treating large patient cohorts," says Florien Jenner, Head of the Equine University Clinic at the University of Veterinary Medicine, Vienna. Her research focuses on joint diseases and new approaches to regeneration. She emphasizes: "It's great that wings4innovation and the KHAN-I Fund are supporting and accompanying us in this project. In addition to financial resources, specialist market knowledge of the market and of the processes and requirements in the biopharmaceutical industry is of great value to us. The direct and comprehensive feedback at eye level saves time, avoids mistakes and makes it easier for us to build up the necessary network." A Meet & Greet event organized by the Vetmeduni's Technology Transfer Office was central to the development of the project. In this context, wings4innovation and the KHAN-I fund were introduced and researchers were able to present their ideas for new drugs. Florien Jenner states: “Our technology transfer office was not only trend-setting in terms of networking with wings4innovation and with regard to the application, but also supported us professionally and quickly in drawing up a tailor-made contract that forms the basis for the implementation of the project.”
Experimental model key for success
"The disease model we are using for our analyses is crucial for the progress of the project. In order to achieve sound results, we have invested a lot of energy in establishing the experimental setup, selecting relevant test parameters and control experiments. Only with such a complex, mature, disease-specific test system robust results can be achieved, based on which a drug can then actually be developed," reports Laboratory Manager Iris Gerner, adding: "The challenges are substantial, every detail matters in the laboratory. That's why we had to pause for a few months during the pandemic until certain components that we rely on for our 2D and 3D cell culture were available again. However, in coordination with the wings4innovation team, we were able to extend our project in a cost-neutral manner to compensate for this phase." The success of the therapy and thus the regenerative potential can be measured in the test system in the laboratory and documented and compared by analyzing meaningful biomarkers.
The focus is on topics such as:
- Cartilage formation, including extracellular matrix
- Reduction of inflammation and ageing processes
- Successful cell division and wound healing
What has been achieved so far?
Apart from the short delay caused by the pandemic, the project is developing according to plan and delivering promising results. It builds on detailed knowledge based on many years of intensive research. Important cornerstones were developed as part of an FFG Bridge early phase project and through the Sparkling Science program of the Federal Ministry of Education, Science and Research. It is known from developmental biology that fetal mammals can still fully regenerate their articular cartilage - the project makes use of this knowledge. The application of the active ingredient currently under development is not only of interest to human patients, but also to the veterinary sector. Animals such as dogs, cats, sheep and horses also suffer from osteoarthritis. The project team has already succeeded in isolating cell secretions that are therapeutically effective in the experimental test system and stimulate the formation of joint cartilage. In addition to perinatal, extracellular vesicles that are easy to produce in cell culture, fetal proteins are also crucial. The latter need to be characterized more precisely and are imagined to be produced recombinantly in biopharmaceutical plants for use in drugs in the future. "The cooperation is excellent, based on mutual trust and appreciation, essential factors when basic research and commercialization aspects have to be reconciled," says Peter Nussbaumer, Managing Director of wings4innovation and part of the Khanu management team.
Making targeted use of partner expertise
The project team, consisting of representatives from wings4innovation and Vetmeduni, is working with a number of partners to bring expertise on board - especially from the Viennese life sciences ecosystem. The partners include:
- Evercyte: Viennese company that provides standardized cells for biomedicine - from primary tissues to in-vitro test systems and extracellular vesicles (EVs) for clinical applications. The project uses Evercyte cell lines and EVs produced from perinatal stem cells. In addition, in vitro 2D / 3D test systems were developed to investigate the influence of EVs on inflamed chondrocytes, synoviocytes and fibroblasts.
- TAmiRNA: The Viennese company TAmiRNA specializes in the use of microRNAs as tools in medicine and recently received Europe-wide approval for its non-invasive liver function test, hepatomiR®. In the field of contract research, TAmiRNA is a leader in NGS-based microRNA & mRNA analyses and provides comprehensive support to the w4i project in the areas of RNA-seq and bioinformatics.
- Morphisto: Histology service laboratory in Offenbach am Main and manufacturer of ready-to-use chemicals for laboratory applications. The company stains and analyzes histological samples for the project.
- Joint Metabolome Facility: Joint Core Facility of the University of Vienna and the Medical University of Vienna. In the product, the focus is on mass spectroscopy services.
Further funding and additional partners required
The next important milestone in the project is the use of mass spectrometry to identify the fetal proteins that stimulate the regeneration of articular cartilage in the experimental model. To this end, the difference between effective secretions and less effective ones will be specifically investigated. Drug development can only proceed once this step has been successfully completed. This includes recombinant production of active substances for the necessary preclinical and clinical studies and the combination of these proteins with secretions from perinatal cells. This is not only experimentally challenging, but also costly and time-consuming. The project team emphasizes how important it is to advance the project as far as possible together with KHAN-I. Only with outstanding proof-of-concept data can additional funding be raised later on and partners convinced for further project development. Public funding and financing instruments from Austria Wirtschaftsservice (aws), the Austrian Research Promotion Agency (FFG) and regional funding agencies such as the Vienna Business Agency as well as private venture capital play a central role in further financing. Cooperation with pharmaceutical companies also needs to be established in the future, as they are key partners in bringing drugs to market. In any case, many years of research and development and numerous hurdles still need to be overcome before this approach to regenerative osteoarthritis therapy becomes a medical reality.
How osteoarthritis has been treated so far?
Osteoarthritis leads to pain, inflammation and restrictions in mobility, including permanent physical impairments. Pain-relieving and anti-inflammatory drugs help to alleviate the symptoms associated with damage to the joint cartilage. However, there are no drugs on the market that cure osteoarthritis. Regular exercise is an important pillar of therapy. This stimulates the supply of nutrients and thus the preservation of the cartilage and contributes to muscle development. Supports and orthoses also help to slow down the progression of the disease. Dietary adjustments and weight reduction are also recommended. In acute flare-ups, corticosteriods are injected into particularly affected joints. In very severe cases, where no other treatment can help, an artificial joint replacement (endoprosthesis) is necessary, but this can only be carried out in a small number of joints.
