- Participants will acquire knowledge on how newly identified experimental and natural factors and agents may be applicable in translational cartilage repair.
25.2.1 - Recent Advances and Opportunities for Cartilage Repair: Focus on Intra-Articular Injection with Cells, Biologicals and Hydrogels
Osteoarthritis (OA) is the most common form of arthritis globally. The degradation and loss of articular cartilage is one of the classical hallmarkrs of OA. Although cartilage destruction is a central feature of OA, synovial inflammation, subchondral bone remodelling and osteophyte development are also important features of the disease. Therefore, in addition to its adverse effects on cartilage, OA can also negatively impact on all the tissues of the joint, including sub-chondral bone, peri-articular ligaments, and skeletal muscle. Symptoms of OA include pain and inflammation in the joints, resulting in reduced mobility, diminished quality of life and long-term disability. OA is increasingly considered a serious, chronic disease and other than joint replacement surgery there is presently no cure. Existing pharmacological medications can provide symptomatic relief, but their effects on the progression of the disease are limited. The lack of effective treatments for OA create exciting opportunities for developing innovative new approaches for cartilage repair and joint preservation. Protection using intra-articular injections of cells, biologicals and biomaterials, including hydrogels is receiving increasing attention. This presentation will focus on recent advances and opportunities for cartilage repair using cell-based gene therapy, viral vector-based gene therapy and biomaterials, including hydrogels. This presentation will also discuss how emerging innovations in biotechnology can impact on the field of OA research and cartilage repair.
The recently published literature will be reviewed with a special focus on intra-articular treatments that incorporate cell-based and viral vector-based gene therapy (Mobasheri 2020; Mobasheri et al., 2020; Uzieliene et al., 2021). Cell-based and viral vector-based gene therapy have the potential to transform the development of new therapeutics for joint disease and are already tested in preclinical animal modesl and human clionical trials. Treatments that incorporate intra-articular injections can potentially combine hydrogels, cells and biologicals creating combination products. The development of a new generation of innovative disease-modifying therapeutics is a high priority for OA and other joint diseases. Biomaterials, hydrogels, viral, non-viral and cell-based gene delivery technologies have the potential to transform orthopaedics and rheumatology. Further research is needed to optimize the transfection efficiency, longevity and duration of gene expression in gene therapy. More research is also needed to understand the mode of action of injectable hydrogels. The development of disease-modifying therapeutics for OA has recently suffered a number of high-profile setbacks. However, there are opportunities for multidisciplinary collaboration to drive new innovation. These approaches can also positively impact on the field of cartilage repair for facilitating the repair of focal cartilage lesions.
1. Mobasheri A. Future Cell and Gene Therapy for Osteoarthritis (OA): Potential for Using Mammalian Protein Production Platforms, Irradiated and Transfected Protein Packaging Cell Lines for Over-Production of Therapeutic Proteins and Growth Factors. Adv Exp Med Biol. 2020;1247:17-31. doi: 10.1007/5584_2019_457.
2. Mobasheri A, Choi H, Martín-Vasallo P. Over-Production of Therapeutic Growth Factors for Articular Cartilage Regeneration by Protein Production Platforms and Protein Packaging Cell Lines. Biology (Basel). 2020 Oct 9;9(10):330. doi: 10.3390/biology9100330.
3. Uzieliene I, Kalvaityte U, Bernotiene E, Mobasheri A. Non-viral Gene Therapy for Osteoarthritis. Front Bioeng Biotechnol. 2021 Jan 13;8:618399. doi: 10.3389/fbioe.2020.618399.
I would like to thank colleagues and collaborators at Kolon TissueGene (Rockville, MD, United States), Flexion Therapeutics (Burlington, MA, United States) and Hy2Care B.V. (Enschede, the Netherlands).
25.2.3 - Biomaterial-Based Local Drug Delivery for Treating Degenerative Joint Disease
Diseases of the musculoskeletal system impose a substantial burden on Western societies, which is ever increasing with ageing of the population. Amongst the diseases with most impact are osteoarthritis (OA) and chronic low back pain caused by intervertebral disc (IVD) degeneration, involving the cartilaginous tissues of these organs. Despite the severity of the problems, medical solutions currently are limited and consist mainly of highly invasive surgery that replaces or immobilises the joint. Treatment with therapeutic small molecules and biologicals is hampered by the limited inaccessibility of the joint and IVD.
Therefore local administration of bioactive molecules is increasingly in focus, although still mainly by repeated administration. Using degradable biomaterials for intra-articular and intradiscal delivery, prolonged presence of therapeutics can be achieved without the need of repetitive injections. Local biomaterial-based drug delivery has several advantages. 1) High and effective local concentrations can be attained for a prolonged time period. 2) Systemic levels are low, offering a new lease of life to drugs that are effective but have unacceptable systemic side effects. 3) Less drug is needed, thereby greatly reducing costs (e.g. growth factors, antibodies). 4) Released drugs have direct access to the diseased tissue. Several polymer material platforms consisting of natural building blocks have been successfully applied to this end, in up to large animal models and even human patients. In particular the delivery of existing anti-inflammatory drugs. A solid body of preclinical evidence was generated on intra-articular release of celecoxib (CXB), an efficient anti-inflammatory drug that however attains insufficient joint fluid levels upon oral intake. This OA drug was delivered by a biomaterial platform that has already been used in human patients for other drug delivery applications. Safety, biocompatibility and long-term pain reduction of CXB-loaded biomaterials was demonstrated in rats and canine patients, with up to a dosage equivalent of 40% of a single oral dose for daily intake. Likewise a delivery formulation based on corticosteroids has been developed and tested in human clinical trials, although release was not sufficiently extended to reach the primary endpoint.
In addition to synthetic drugs, RNA-based interventions have great potency to counter the issues small molecule drug and recombinant protein treatments raise, for several reasons. 1) Small inhibitory RNA inhibits the production and activity of only one target protein, whereas mRNA delivery to the native tissue cell results in the production of one type of active protein, with native tissue posttranslational modifications. This allows precision treatment for patients with specific phenotypes; 2) RNA-based treatments pose no risk for integration into the cell’s DNA, as compared to viral or plasmid gene therapy, an important prerequisite in treatment of non-lethal chronic diseases; 3) RNA paves the way to treatment of diseases and disease processes mediated by so-called undruggable targets. 4) RNA synthesis is fully chemical and thereby cheaper than recombinant protein production and is receiving increased attention since the advent of COVID-19 vaccines. However, a major challenge consists of penetration of particles required for oligonucleotide and mRNA delivery, through the tight avascular extracellular matrix of articular cartilage and the IVD. Involvement of multiple disciplines will allow the development of technologies and tools to overcome these hurdles.