Development of novel imaging agents for the prospective quantification of joint damage to reduce animal numbers in osteoarthritis research
Lead Research Organisation:
University of Oxford
Department Name: NDORMS
Abstract
Osteoarthritis (OA) is the most common form of arthritis and a leading cause of pain and disability, where there is progressive loss of joint function due to continual erosion and remodelling of the tissues of the joint. There are currently no modifying treatments for disease and patients rely on simple pain killers and ultimately joint replacement surgery. Investigating the pathways that cause disease has been very challenging as the human condition is very variable in its course, it is difficult to obtain tissues from patients (except at joint replacement surgery) and we currently have no ways of detecting early disease. Animal models of OA have significant utility because disease can be studied at all stages of the condition, tissues are readily available, and the onset of disease is known. In the past 10 years a number of advances have arisen from the use of mouse models of OA induced by surgical joint destabilisation. Combining these models with mice that have genetic modification has revealed several key pathways/molecules important for the OA process. Many academic and pharmaceutical companies use these models for such investigations. Progress in developing novel treatments for OA is very likely to arise from pre-clinical models.
Evaluation of joint damage both in the clinic and in animal models of OA is hampered by the inability to image cartilage accurately and non-invasively. X-ray radiographs measure cartilage loss by a reduction in the joint space, thus are only able to pick up relatively advanced disease. In animal models, joint damage is typically assessed by histology after sacrificing the animals at regular intervals throughout studies (usually 4-12 weeks). The latter increases the number of animals used in each study by the number of time points required. A non-invasive imaging method that would be able to visualise the degradation of the articular cartilage over time would greatly reduce the numbers of animals being used in arthritis research. Such a system, being quantitative, might also increase the reliability of measurements and thus also reduce numbers. We have already demonstrated that it is possible to tag cartilage specific molecules to visualise the cartilage specifically. In this project, we will develop a novel imaging agent that can be combined with microCT scanning to create a sensitive, quantitative cartilage assessment tool in OA. This will initially dramatically reduce the number of animals used per OA study and is potentially translatable into a clinical imaging agent for early OA in humans.
Evaluation of joint damage both in the clinic and in animal models of OA is hampered by the inability to image cartilage accurately and non-invasively. X-ray radiographs measure cartilage loss by a reduction in the joint space, thus are only able to pick up relatively advanced disease. In animal models, joint damage is typically assessed by histology after sacrificing the animals at regular intervals throughout studies (usually 4-12 weeks). The latter increases the number of animals used in each study by the number of time points required. A non-invasive imaging method that would be able to visualise the degradation of the articular cartilage over time would greatly reduce the numbers of animals being used in arthritis research. Such a system, being quantitative, might also increase the reliability of measurements and thus also reduce numbers. We have already demonstrated that it is possible to tag cartilage specific molecules to visualise the cartilage specifically. In this project, we will develop a novel imaging agent that can be combined with microCT scanning to create a sensitive, quantitative cartilage assessment tool in OA. This will initially dramatically reduce the number of animals used per OA study and is potentially translatable into a clinical imaging agent for early OA in humans.
Technical Summary
Preclinical models of osteoarthritis (OA) are widely used for target discovery and drug development. The inability to visualise cartilage sensitively, non-invasively and prospectively is hampering their use and significantly impacting on the numbers of animals used for such studies. Semi-quantitative assessment by histological analysis of the joint post-mortem is the current gold standard, but requires mice to be killed at several time points during the study. The development of A non-invasive imaging method that would be able to visualise the loss of articular cartilage in vivo would greatly reduce the numbers of animals used by being able to follow disease in a single animal. Furthermore, a truly quantitative assessment would improve accuracy and reproducibility, leading to reduction of numbers required to power studies. Whilst ex vivo methodologies have demonstrated that it is possible to develop agents with cartilage specificity, none of these are suitable for in vivo use.
The new imaging agents will develop are based on a small library of chemical compounds we originally developed to increase the retention of potential drugs in joints. Preliminary work shows that these compounds (fluorescently tagged) bind specifically to cartilage following intra articular injection. We will modify this library of compounds to allow visualisation by CT to obtain non-invasive measures of cartilage volume. This will be achieved by incorporation of multiple iodines into the compounds to create CT-contrast agents.
This project grant will fund the development of these new CT-contrast agents. Including their synthesis, in vitro validation, toxicity, and prospective utility in a surgical model of OA. The successful imaging of articular cartilage and quantification of tissue damage during the course of OA will significantly and rapidly reduce the number of animals required in preclinical OA studies
The new imaging agents will develop are based on a small library of chemical compounds we originally developed to increase the retention of potential drugs in joints. Preliminary work shows that these compounds (fluorescently tagged) bind specifically to cartilage following intra articular injection. We will modify this library of compounds to allow visualisation by CT to obtain non-invasive measures of cartilage volume. This will be achieved by incorporation of multiple iodines into the compounds to create CT-contrast agents.
This project grant will fund the development of these new CT-contrast agents. Including their synthesis, in vitro validation, toxicity, and prospective utility in a surgical model of OA. The successful imaging of articular cartilage and quantification of tissue damage during the course of OA will significantly and rapidly reduce the number of animals required in preclinical OA studies
Planned Impact
This research focuses on developing imaging reagents that will allow the assesment of joint damage in a living animals used in osteoarthritis (OA) research. Currently, as such technology is unavailable, assesment of osteoarthritis progression is done by sacrificing the animal and performing histological analysis of the joint. The development of such a technology will reduce the animal numbers used in osteoarthritic research because individual animals may be followed prospectively.
Immediate Impact on reduction of animal use in research:
The reduction that will be achieved by the development of imaging compounds will be 66% in our laboratory. An industrial contact has estimated that this technology would reduce their animal use in OA by 50%. Worldwide, there are at least 15 other academic laboratories with similar animal models and we are aware of at least 5 multinational pharmaceutical companies still actively pursuing OA drug development. Further decreases in animal numbers are likely to arise because of increased sensitivity and better reproducibility of the quantitative measurements.
Further Impact on drug development in human osteoarthritis:
There is currently no disease modifying drug treatment for OA. In patients trials currently depend upon patient reported outcomes (largely pain and disability) or gross morphological changes assessed by Xray. Whilst specialised protocols are being developed to examine the cartilage directly e.g. by MRI, these have not proved to be helpful thus far and are limited by cost and time. An imaging agent that can be used safely in vivo and in combination with CT could be readily translated from pre-clinical to clinical use.
Immediate Impact on reduction of animal use in research:
The reduction that will be achieved by the development of imaging compounds will be 66% in our laboratory. An industrial contact has estimated that this technology would reduce their animal use in OA by 50%. Worldwide, there are at least 15 other academic laboratories with similar animal models and we are aware of at least 5 multinational pharmaceutical companies still actively pursuing OA drug development. Further decreases in animal numbers are likely to arise because of increased sensitivity and better reproducibility of the quantitative measurements.
Further Impact on drug development in human osteoarthritis:
There is currently no disease modifying drug treatment for OA. In patients trials currently depend upon patient reported outcomes (largely pain and disability) or gross morphological changes assessed by Xray. Whilst specialised protocols are being developed to examine the cartilage directly e.g. by MRI, these have not proved to be helpful thus far and are limited by cost and time. An imaging agent that can be used safely in vivo and in combination with CT could be readily translated from pre-clinical to clinical use.