Current Models for Development of Disease-Modifying Osteoarthritis Drugs

Abstract

Osteoarthritis (OA) is a painful and disabling disease that affects millions of people worldwide. Symptom-alleviating treatments exist, although none with long-term efficacy. Furthermore, there are currently no disease-modifying OA drugs (DMOADs) with demonstrated efficacy in OA patients, which is, in part, attributed to a lack of full understanding of the pathogenesis of OA. The inability to translate findings from basic research to clinical applications also highlights the deficiencies in the available OA models at simulating the clinically relevant pathologies and responses to treatments in humans. In this review, the current status in the development of DMOADs will be first presented, with special attention to those in Phase II-IV clinical trials. Next, current in vitro, ex vivo, and in vivo OA models are summarized and the respective advantages and disadvantages of each are highlighted. Of note, the development and application of microphysiological or tissue-on-a-chip systems for modeling OA in humans are presented and the issues that need to be addressed in the future are discussed. Microphysiological systems should be given serious consideration for their inclusion in the DMOAD development pipeline, both for their ability to predict drug safety and efficacy in human clinical trials at present, as well as for their potential to serve as a test platform for personalized medicine. Impact statement At present, no disease-modifying osteoarthritis (OA) drugs (DMOADs) have been approved for widespread clinical use by regulatory bodies. The failure of developing effective DMOADs is likely owing to multiple factors, not the least of which are the intrinsic differences between the intact human knee joint and the preclinical models. This work summarizes the current OA models for the development of DMOADs, discusses the advantages/disadvantages of each, and then proposes future model development to aid in the discovery of effective and personalized DMOADs. The review also highlights the microphysiological systems, which are emerging as a new platform for drug development.

Keywords: disease-modifying osteoarthritis drugs; microphysiological system; models; osteoarthritis; personalized medicine; tissue-on-a-chip.

FIG. 1.

OA-associated histopathological changes in joint elements, and representative agents that target different pathological issues. OA, osteoarthritis. Color images are available online.

FIG. 2.

Generation of knee joint MPS through integrating individual tissue modules. Each tissue is perfused with the tissue-specific medium on one side and the “synovial fluid” on the other side, which is shared by all tissues except bone. The flow of the “synovial fluid” is bi-directional so that it can be conditioned and sensed by all tissues, simulating their crosstalk in the native knee joint. The inclusion of patient-specific cells allows the generation of personalized chip and the development of personalized DMOADs. The biomarkers in the “synovial fluid” are used to assess the types and severity of OA, as well as inform the treatment efficacy. DMOAD, disease-modifying osteoarthritis drug; MPS, microphysiological system. Color images are available online.

FIG. 3.

The DMOAD development pipeline that enables precision medicine. In traditional drug development, the potential agents are created (Step 1) and then tested in 2D or 3D disease models (Step 2). The candidates that show efficacy without cytotoxicity are further screened in animal models (Step 3) before one to two drugs finally enter human clinical trial (Step 4). In general, the conventional models for drug testing lack the personalized features of participants in the clinical trials. In the future, as the first step toward “personalized OA medicine,” validated biomarkers will be used to first classify patients into different groups (endotypes or phenotypes). By studying the specific etiologies and pathologies, drug candidates and testing models will be developed for the different patient groups. Next, by using patient-derived cells and simulating the specific disease features of the patient, the personalized models will be applied to develop candidate therapeutics for the specific patient. With the capability of using human cells, including differentiated cells, MSCs, and/or induced pluripotent stem cells, and recapitulating relevant human physiological parameters, MPS represent a potentially high-utility system in the development of personalized DMOADs. In particular, the observations derived from the two physiological models, that is, MPS and animals, can be cross-checked and validated to further enhance the prediction of drug efficacy and toxicity in humans. 2D, two-dimensional; 3D, three-dimensional; MSC, mesenchymal stem cell. Color images are available online.