Immunoengineering the next generation of arthritis therapies

Abstract

Immunoengineering continues to revolutionize healthcare, generating new approaches for treating previously intractable diseases, particularly in regard to cancer immunotherapy. In joint diseases, such as osteoarthritis (OA) and rheumatoid arthritis (RA), biomaterials and anti-cytokine treatments have previously been at that forefront of therapeutic innovation. However, while many of the existing anti-cytokine treatments are successful for a subset of patients, these treatments can also pose severe risks, adverse events and off-target effects due to continuous delivery at high dosages or a lack of disease-specific targets. The inadequacy of these current treatments has motivated the development of new immunoengineering strategies that offer safer and more efficacious alternative therapies through the precise and controlled targeting of specific upstream immune responses, including direct and mechanistically-driven immunoengineering approaches. Advances in the understanding of the immunomodulatory pathways involved in musculoskeletal disease, in combination with the growing emphasis on personalized medicine, stress the need for carefully considering the delivery strategies and therapeutic targets when designing therapeutics to better treat RA and OA. Here, we focus on recent advances in biomaterial and cell-based immunomodulation, in combination with genetic engineering, for therapeutic applications in joint diseases. The application of immunoengineering principles to the study of joint disease will not only help to elucidate the mechanisms of disease pathogenesis but will also generate novel disease-specific therapeutics by harnessing cellular and biomaterial responses. STATEMENT OF SIGNIFICANCE: It is now apparent that joint diseases such as osteoarthritis and rheumatoid arthritis involve the immune system at both local (i.e., within the joint) and systemic levels. In this regard, targeting the immune system using both biomaterial-based or cellular approaches may generate new joint-specific treatment strategies that are well-controlled, safe, and efficacious. In this review, we focus on recent advances in immunoengineering that leverage biomaterials and/or genetically engineered cells for therapeutic applications in joint diseases. The application of such approaches, especially synergistic strategies that target multiple immunoregulatory pathways, has the potential to revolutionize our understanding, treatment, and prevention of joint diseases.

Keywords: CRISPR-Cas9; Cartilage; Cytokine; Drug delivery; Gene therapy; Orthobiologics; Scaffolds; Stem cell therapy; Synovium.

Figure 1.

Initiation of OA and RA cellular pathways in early-stage disease. Immunological signals propagate as the disease progresses to all components of the joint organ system. The key cytokine pathways targeted in current OA and RA therapies primarily include TNF, IL-1, and IL-6, although other cytokines (e.g., IL-17) are now being targeted as well. Abbreviations: TCR: Toll-like receptor; MHC: Major Histocompatibility Complex; MMP: Matrix metallopeptidase; ADAMTS: A disintegrin and metalloproteinase with a thrombospondin type; TNF: Tumor necrosis factor; CCL2: C-C Motif Chemokine Ligand 2; VEGF: Vascular endothelial growth factor; BMP: Bone morphogenetic proteins; SASP: senescence-associated secretory phenotype; RANKL: Receptor activator of nuclear factor kappa-B ligand

Figure 2.

Current immunomodulatory strategies rely on three types of approaches: (1) the exogenous delivery of autologous or allogenic cells, (2) genetic engineering or gene therapy to alter resident and exogenous cell populations, or (3) biomaterial-based systems that act by themselves as immunomodulators as well as aid in the delivery of cells or material for genetic engineering of resident cell populations. While each of these strategies may be used on their own, many immunoengineering approaches combine their use for the design of more controlled and precise treatment. Abbreviations: FLS: Fibroblast-like synoviocytes; MSC: Mesenchymal stem cells; iPSC: Induced pluripotent stem cell; NK: Natural killer cell; CRISPR-Cas9: Clustered regularly interspaced short palindromic repeats, (CRISPR)-associated protein 9; siRNA; small interfering RNA; AAV: adeno-associated virus.

Figure 3.

The future of OA and RA immunoengineering will ultimately harness the combined strength of cell and biomaterial immunoengineering strategies to improve upon the use of current anti-inflammatory and anti-cytokine therapies. Furthermore, the inclusion of genetic engineering in both cell and biomaterial systems to alter resident or exogenous cell behavior offers additional potential to these therapies, while the use of iPSCs provides an ever-expanding platform with which to develop personalized and disease-specific treatments. Abbreviations: FLS: Fibroblast-like synoviocytes; MSC: Mesenchymal stem cells; iPSC: Induced pluripotent stem cell; NK: Natural killer cell; NSAIDS: Non-steroidal anti-inflammatory drugs.