Chondrocytes from Clinical Grade Embryonic Stem Cells

Osteoarthritis is a debilitating condition of joints affecting 25% of adults over 65 yrs (WHO estimate). It causes pain, disability and loss of independence, which results in a poor quality of life. In the EU it is ranked 12th for disease burden with 35-40 million sufferers and this is set to rise with increased ageing of the population. Current clinical treatment is limited to pain relief with nothing able to delay or reverse the condition. Irreversibly damaged joints are eventually replaced by synthetic prostheses, which are successful in older patients (>65), but less so in younger patients whose life expectancy is much greater than that of the prosthesis and revision surgery is less successful. There is therefore a large unmet clinical need for improved treatment for OA. Current strategies include cartilage repair (ACI) using the patient's own chondrocytes, harvested from intact areas of tissue. However, the outcome of ACI is little better than non-cellular orthopaedic treatments and it requires 2 operations and damage to otherwise intact tissue. Patients' stem cells are also being tested from bone marrow, but this also requires 2 operations and patient specific cell culture. To overcome the problem of the variable quality of the patients' own cells and the need for 2 operations, we have developed a protocol to generate chondrocytes from human embryonic stem cells (hESCs). The protocol is entirely serum free, chemically defined and yields up to 97% chondrogenic cells. We now need to adapt this procedure to deliver cells suitable for clinical applications. This requires the use of entirely validated clinical grade reagents, scale up to generate larger numbers of cells and methods to store and deliver cells to the clinic. We will validate this protocol with a new generation of very high quality (clinical grade) stem cell lines derived in Manchester and by other Centres across the UK. The advantage of using hESCs is that they can be expanded to produce enough chondrogenic cells to treat large numbers of patients, making such a therapy cost-effective on the NHS. Follow-up tests in vivo will grade lines for success in repairing focal defects in rat knee joints (already shown for research grade cells) to allow us to assess the quality of in vivo cartilage repair and assess any incidence of tumour formation, or other adverse effects. The plan will show if hESC derived chondrocytes can be produced, delivered and are able to complete hyaline cartilage repair. This award will allow us to establish the means and methods to move forward towards phase 1 clinical trials for patients with focal cartilage defects.

Current clinical treatment for osteoarthritis, which affects 25% of adults over 65 yrs (WHO estimate), is limited to pain relief and there is no treatment able to delay or reverse the condition. Irreversibly damaged joints are eventually replaced by synthetic prostheses, which are successful in older patients (>65), but less so in younger patients whose life expectancy is much greater than that of the prosthesis and revision surgery is less successful. There is therefore a large unmet clinical need for improved treatment for OA. To address this need we developed a protocol to differentiate pluripotent stem cells to chondrogenic cells at high efficiency and these cells which can repair cartilage defects in a rodent model. The protocol is entirely serum free, chemically defined and yields up to 97% chondrogenic cells. We will now adapt this procedure to deliver cells suitable for clinical applications, meeting current Good Manufacturing Practice (cGMP ) standards. We will employ strategies leading to greater cell expansion; apply our refined protocol to a range of clinical grade hESC lines derived in Manchester and in other Centres, evaluating lines for chondrogenic bias. The differentiated cells will be tested for their ability to repair a surgical cartilage defect, without evidence of adverse effects including the generation of ectopic growths or tumours in i) a rat defect model and ii) in a pilot study for a larger animal, the sheep. We will develop and test methods for the clinical delivery and storage of the cells using fibrin gels, evaluating viability and shelf life.

We intend this preclinical application to lead to the development of phase 1 clinical trials which will provide direct patient benefit and new treatment options for joint trauma and OA sufferers. This will be for focal cartilage defects in the first instance but with potential for repairing larger OA lesions as clinical experience is gained. We will generate hESC-chondrocytes which are suitable for use for patients as part of planning for subsequent clinical trials with our clinical collaborators (Sanjay Anand and David Johnson, Stockport NHS Trust). The development of our protocol will lead the way in providing proof of principle for cell therapies from pluripotent cells for both academics and clinicians.

Academics will benefit from our development and refinement of reproducible protocols, increased understanding of cartilage development and homeostasis. Our work will provide in vitro and in vivo model system for understanding responses to inflammatory mediators and extracellular matrix targeted drugs. We will interact with members of the UK Regenerative Medicine platform hubs to share our findings of translation and learn from their experiences, exploiting their findings where possible e.g. in imaging and safety.

NHS: Our work will start to open up a pathway for this and similar therapies to be incorporated into NHS treatments.
Regulators: Our engagement with the regulators will also help to inform regulatory procedures for cell therapy especially those from pluripotent cells.

Patient Groups and General public: Firstly our projected therapy will provide a cell based treatment and so make a real impact on the quality of life to patients with sports injury and osteoarthritis. Secondly, we will engage with patient groups and member of the public to inform them of our activities and learn further from them regarding patient perception of need, in a continuation of our previous public engagement activities.

Biopharma: We will interact further with companies interested in cell therapy or who may wish to use our findings to generate new in vitro models for testing drugs active in modulating extracellular matrix repair. We will seek advice from biopharma and the Catapult with a view to their active engagement as we move towards the clinic.