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Clinical trial of autologous adipose-derived mesenchymal stromal cells (ASC) in the treatment of mild to moderate osteoarthritis

Periodic Reporting for period 4 - ADIPOA2 (Clinical trial of autologous adipose-derived mesenchymal stromal cells (ASC) in the treatment of mild to moderate osteoarthritis)

Reporting period: 2019-07-01 to 2019-12-31

Osteoarthritis (OA) is a chronic and debilitating disease which occurs when the protective cartilage in the joints deteriorates and breaks down. It can affect any joint in your body, but it most commonly occurs in the joints in your hands, knees, hips, and spine. Its symptoms include stiffness, pain, and swelling of the joint. Approximately 70 million Europeans are affected by the condition, and 25% of these individuals cannot perform the major activities of daily living. Treatment options include pain management with non-steroidal anti-inflammatories, corticosteroid injections, and joint replacement but there is currently no cure for OA.

ADIPOA-2 contributed to the development and validation of a revolutionary new stem cell treatment for OA. This therapy uses the patient's own stem cells. These cells are extracted from the patient's adipose (fatty) tissue and cultured under rigorous quality control in cell manufacturing facilities, before being injected into the patient's knee joint, where the stem cells help to reduce inflammation, and promote the repair of damaged cartilage. This treatment has already shown promise in an earlier clinical trial. Now ADIPOA2 is carrying out new research and conducting a larger clinical trial, which will move this treatment closer to the market and offer hope to the millions of Europeans who suffer from pain and debility as a result of OA. ADIPOA2 will also make an important contribution to the development of Europe's stem cell manufacturing infrastructure. This is vital if stem cell therapies are to become part of the therapeutic mainstream. ADIPOA2's research is making significant contributions in the following areas:

Developing cell production infrastructure:
The challenge of upscaling the production of high-quality stem cell products is one of the most significant barriers to the mainstream use of cellular therapies. ADIPOA2 is directly addressing this challenge by producing consistent batches of high-quality autologous (patient derived) stem cells under GMP (good manufacturing practice)- compliant conditions. The cells used in the ADIPOA2 trial were produced in centres in France, Germany and Ireland. This ground-breaking multi-site approach required cooperation between manufacturing centres, helping to develop the production infrastructure that will allow for the wider use of stem cell therapies. ADIPOA2 also contributed to European regulatory experience with stem cell products.

Mechanism of Action:
The ways in which stem cells control inflammation and promote tissue repair are still not fully understood. ADIPOA2 conducting extensive research into the mechanism of action of these cells, helping to explain how they treat osteoarthritis, and how they may function in the treatment of other conditions. This knowledge is crucial to develop new assays and potency tests which will provide a affordable means to evaluate the clinical efficacy of stem cell treatments.

Clinical trial:
Building on the success of the earlier ADIPOA trial, ADIPOA2 initiated a Phase II randomised clinical trial of patient-derived stems cells in the treatment of advanced OA of the knee. This trial will involve the treatment of 150 patients across ten hospitals, located in France, Germany, Ireland, Italy, the Netherlands, and the United Kingdom. The trial assessed the safety and efficacy of the stem cell treatment, and will provide data for the validation and development of this treatment. Although it did not prove possible to complete the trial within the timespan of ADIPOA2, the initial results allowed partners to secure the funding required to continue the trial beyond the lifetime of the project.
In the fourth period of the project we have continued to make progress with our clinical trial and have successfully carried out experimental work on the mechanism of action of stem cells in the treatment of OA.

Our cell production partners had previously harmonised production and shipping procedures to ensure the consistent production of the cell product required for the clinical trial.The complex logistics of scheduling patients and treatments, producing treatment product and moving lipoaspirate and ASC-based treatments around Europe were successfully accomplished.

The project’s work on mechanism of action has involved a range of experiments in order to identify some of the relevant biological functions of ASC efficacy. These have achieved significant results, and experimentation is continuing. WP4 continued work on the development develop an assay that will allow the potency of stem cell products to be reliably and easily determined. The availability of this sort of assay is an important element in the mainstream clinical deployment of ASCs. A potential assay has been identified and validated to determine the immunosuppressive capacity of stem cell preparations. The results of this assay will be correlated with clinical findings as the clinical trial progresses.
The ADIPOA2 project has pushed forward the boundaries in the cell therapy field and in particular in the application of this technology for the treatment of osteoarthritis (OA). It has achieved the following results:
-The ADIPOA2 project has demonstrated, for the first time in the history of treatment for this condition, that a disease-modifying strategy is within our grasp. This is an important milestone considering that several decades of research into pharmacological mediators, enzyme inhibitors, monoclonal antibodies targeting inflammatory mediators and intra-articular injections for viscosupplementation and growth factor delivery have failed to show effectiveness.
-A complex manufacturing strategy for autologous therapy has been developed, validated and performed in independent manufacturing facilities. This shows that the production of a consistent cell product with stringent application of release testing, can be achieved. This is a promising development for the entire cell therapy field.
-A serious clinical and operational obstacle, namely contamination of lipoaspirate tissue, can be overcome by the application of new protocols and the close adoption of these by hospital sites. Since the utilisation of lipoaspirate tissue is now common and contamination has often been reported, these new protocols, resulting in a dramatic reduction, will have a broad impact.
-A new insight into mechanism of action and potency has been generated, involving a meticulous understanding of the interactions between delivered cells and host immune cells.
-A unified regulatory strategy for autologous cell therapy, simultaneously adopted in 6 EU countries, has been put in place. This counters previous approaches, where cell therapy clinics were unregulated and unstandardized.
-A new and valuable standardised imaging modality for MRI has been developed so that every clinical radiology site uses identical protocols for assessment of structural changes in the OA knee.