Current Models for Development of Disease-Modifying Osteoarthritis Drugs
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Published on: May 16, 2016
Meagan J Makarczyk1,2, Qi Gao3, Yuchen He1
1Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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.
Insights
Developing effective disease-modifying osteoarthritis drugs (DMOADs) is challenging due to limitations in current preclinical models. Microphysiological systems offer a promising platform for improving DMOAD development and personalized medicine.
Area of Science:
- Biomedical Engineering
- Pharmacology
- Rheumatology
Background:
- Osteoarthritis (OA) is a widespread degenerative joint disease with no current disease-modifying drugs (DMOADs) demonstrating long-term efficacy.
- Existing OA treatments primarily manage symptoms, highlighting the urgent need for therapies that target disease progression.
- A significant barrier to DMOAD development is the inadequacy of current preclinical models in replicating human OA pathologies and treatment responses.
Purpose of the Study:
- To review the current landscape of DMOAD development, focusing on drugs in Phase II-IV clinical trials.
- To summarize and critically evaluate existing in vitro, ex vivo, and in vivo OA models, detailing their respective strengths and limitations.
- To explore the potential of microphysiological systems (tissue-on-a-chip) as advanced models for OA research and DMOAD development.
Main Methods:
- Comprehensive literature review of DMOAD clinical trials (Phase II-IV).
- Systematic summary and comparative analysis of established in vitro, ex vivo, and in vivo OA models.
- In-depth discussion on the development and application of microphysiological systems for OA modeling.
Main Results:
- No DMOADs have yet gained widespread regulatory approval, indicating significant challenges in the drug development pipeline.
- Current preclinical OA models exhibit limitations in accurately simulating human disease, contributing to high attrition rates in clinical trials.
- Microphysiological systems show considerable promise for predicting drug safety and efficacy and for advancing personalized OA medicine.
Conclusions:
- The development of effective DMOADs is hindered by a lack of predictive preclinical models that recapitulate human OA.
- Microphysiological systems represent a significant advancement, offering a more human-relevant platform for OA research and DMOAD screening.
- Integrating microphysiological systems into the DMOAD development pipeline is crucial for accelerating the discovery of effective and personalized treatments for osteoarthritis.
