Harnessing the interplay of genetics, cells, and matrix, to deliver insights into musculoskeletal health and new therapies in musculoskeletal disease
Lead Research Organisation:
University of Oxford
Department Name: Botnar Research Centre
Abstract
Since the completion of the Human Genome Project two decades ago, we have entered a golden age of genetic discovery. Our understanding of how genetics determines how we look, how we think, and what diseases we get during our lives is increasingly comprehensive. This golden age promised to revolutionise medicine, with new treatments for common diseases, but this promise has not yet been fully realised. In particular, very common diseases of the musculoskeletal (MSK) system such as osteoarthritis and carpal tunnel syndrome, cause more years of disability and pain than any other disease class. Our research will address this issue, using genetics to improve our understanding and treatment of these debilitating conditions.
The MSK system describes the bones, joints, cartilage, and soft tissues of the body that are responsible for movement. Diseases of the MSK system are responsible for extensive periods of reduced quality of life and physical limitations, but the amount of research into MSK disease does not reflect this importance, partly because of a lack of funding, and partly because historically it has been technically difficult to study MSK diseases.
In our study, we plan to overcome these hurdles by defining the genetic variations that predispose us to four very common, disabling, MSK conditions that have no current treatments beyond painkillers, physiotherapy, and surgery for severe disease (osteoarthritis, carpal tunnel syndrome, frozen shoulder, and Dupuytren's disease). We will use waste tissue collected at surgery to look at the internal biology of the cells, and other molecules that make up the tissue (called the matrix), that are affected by the disease. We will then be able to link the genetic variations to changes in biological function. This will create a major resource that other MSK researchers around the world can use in their work. We will carefully interpret the results of these experiments to decide which genes and pathways are best suited as potential drug targets.
In the second part of our study, we will perform experiments on tissues in the lab to define the effects of interfering with these pathways on how the cells and tissues behave. We will also build special robotic "bioreactors" - robots to mimic the physical forces that these MSK tissues experience in the body. This will allow us to look at the interaction between disease genes and mechanical forces in the body.
We hope that the results of these analyses will provide enough evidence for us to begin human trials of new medicines in these diseases over the next 5-10 years.
Our research team is made up of surgeons, medical doctors, genetics experts, biologists, lab scientists, and data specialists. With our combined expertise and experience, we hope to start human trials of new MSK disease treatments within the next 5-10 years. We are uniquely suited to achieving the aims of this project, as we have previously achieved success in identifying a new treatment in hand osteoarthritis, that is currently undergoing clinical trials. This study will enable us to expand our research to several other conditions and finally begin to deliver on the promise of genetics to improve the health of the population.
We stand at the threshold of a significant leap in medical science. Our work, rooted in the intricate understanding of genetics, aspires to fulfil the long-standing promise of genetics - the promise to reshape the landscape of health and wellness. As we work deeper into this exciting endeavour, we are optimistic about translating our research into effective solutions that enhance public health and reduce the burden of MSK diseases.
The MSK system describes the bones, joints, cartilage, and soft tissues of the body that are responsible for movement. Diseases of the MSK system are responsible for extensive periods of reduced quality of life and physical limitations, but the amount of research into MSK disease does not reflect this importance, partly because of a lack of funding, and partly because historically it has been technically difficult to study MSK diseases.
In our study, we plan to overcome these hurdles by defining the genetic variations that predispose us to four very common, disabling, MSK conditions that have no current treatments beyond painkillers, physiotherapy, and surgery for severe disease (osteoarthritis, carpal tunnel syndrome, frozen shoulder, and Dupuytren's disease). We will use waste tissue collected at surgery to look at the internal biology of the cells, and other molecules that make up the tissue (called the matrix), that are affected by the disease. We will then be able to link the genetic variations to changes in biological function. This will create a major resource that other MSK researchers around the world can use in their work. We will carefully interpret the results of these experiments to decide which genes and pathways are best suited as potential drug targets.
In the second part of our study, we will perform experiments on tissues in the lab to define the effects of interfering with these pathways on how the cells and tissues behave. We will also build special robotic "bioreactors" - robots to mimic the physical forces that these MSK tissues experience in the body. This will allow us to look at the interaction between disease genes and mechanical forces in the body.
We hope that the results of these analyses will provide enough evidence for us to begin human trials of new medicines in these diseases over the next 5-10 years.
Our research team is made up of surgeons, medical doctors, genetics experts, biologists, lab scientists, and data specialists. With our combined expertise and experience, we hope to start human trials of new MSK disease treatments within the next 5-10 years. We are uniquely suited to achieving the aims of this project, as we have previously achieved success in identifying a new treatment in hand osteoarthritis, that is currently undergoing clinical trials. This study will enable us to expand our research to several other conditions and finally begin to deliver on the promise of genetics to improve the health of the population.
We stand at the threshold of a significant leap in medical science. Our work, rooted in the intricate understanding of genetics, aspires to fulfil the long-standing promise of genetics - the promise to reshape the landscape of health and wellness. As we work deeper into this exciting endeavour, we are optimistic about translating our research into effective solutions that enhance public health and reduce the burden of MSK diseases.
Technical Summary
Translating genetic associations into medicines has been disappointing. Musculoskeletal (MSK) disease is responsible for most years lost to disability of any disease class, but is under-researched, partly due to the complexity of cellular / matrix / biophysical interactions. Current treatments often comprise a combination of analgesics, physiotherapy, and surgery. However, treatments based on biological knowledge can be transformative in preventing destructive progression of MSK disease, as exemplified by the development of biologic agents in inflammatory arthritis. Our vision is to develop an MSK Functional Genomics Cluster that will revolutionise our understanding of the functional genetic underpinning of MSK health and disease, generate validated targets for multiple future experimental medicine studies, and provide software, human tissue models, and training for the wider community. Work package 1 (Genetic Target Refinement) will identify critical variants, genes, and pathways implicated in archetypal MSK diseases. We will study the function of genetic variation by harnessing cutting-edge genetic, multiomic (transcriptome, DNA methylation, chromatin accessibility) and matrix analyses, developing new machine learning models to integrate multimodal data. These variants and pathways will be biologically prioritised for detailed functional characterisation in work package 2 (Functional Mechanistic Models). We will study function and perturbation in human ex-vivo, 3D organoid, and bioreactor systems, to validate these targets in human tissues. We will take targets forward to human experimental medicine trials in post-award funding, recreating the pipeline we have already successfully delivered in hand osteoarthritis. We will leverage this experience across the entire functional genomics spectrum to enact a step-change in discovery and validation of targets across a wide variety of MSK disease, transforming the landscape of musculoskeletal medicine in the next decade.
