Clinical trials

Diseases of the skin associated with chronic immune driven conditions, including scleroderma, lupus, dermatomyositis, psoriasis, and atopic dermatitis, significantly impact skin integrity, function, and overall quality of life. These conditions can lead to severe disfigurement, discomfort, and systemic complications, necessitating long-term medical intervention. The prevalence of these skin disorders is rising globally, driven by genetic, environmental, and immunological factors. Unravelling the mechanisms leading to skin manifestations may shed further insights in the overall mechanisms of disease. The DERMATOMICS study will focus on understanding systemic sclerosis (SSc) biology. Systemic Sclerosis (SSc) is a highly heterogeneous rare autoimmune fibrotic condition affecting the skin and internal organs. SSc is classified as a Connective Tissue Disease (CTD), a family of conditions including Systemic Lupus Erythematosus, Sjogren Syndrome and Inflammatory Myositis, all characterised by an autoimmune process affecting the connective tissue of most organs, communed by the presence of anti-nuclear antibodies (ANA). In SSc, patients are affected by a combination of tissue and vascular fibrosis, on the background of a chronic inflammatory process, leading to the highest per patient morbidity and mortality across CTDs. The main driver of mortality to date is interstitial lung disease (ILD), which is the consequence of the fibrotic involvement of the lungs, leading to a progressive loss of functional lung volumes, and ultimately, derangement of lung circulation, hypoxia, increased risk of hospitalisation for lower respiratory infections and death. Current treatments for CTDs include general immunosuppressive treatments, not necessarily targeted to the specific mechanisms underlying their presentation, focusing on reducing inflammation and managing symptoms rather than addressing the underlying causes. Many of these therapies have limited effectiveness or are burdened with significant side effects. Therefore, there is a critical need to develop a comprehensive understanding of the cellular and molecular mechanisms underlying these disorders to identify novel therapeutic targets. Several factors contribute to the risk and severity of SSc, including genetic predisposition, environmental triggers, immune system dysregulation, and lifestyle factors such as diet and smoking. The interactions between these factors are complex and not fully understood. By recruiting participants with SSc, we aim to obtain skin punch biopsies for detailed molecular and genetic analysis. To increase the informative value of our study we plan to implement an extreme phenotype approach and include participants with opposite degrees of severity. Our study aims to elucidate the relationships between the molecular biology of skin cells, skin structure, genetic factors ("DNA"), and environmental influences. The goal is to identify and validate novel therapeutic targets that can lead to more effective and personalised treatment options for SSc, and more broadly for CTDs and CTD-associated skin and lung disease. Modern single-cell technologies will be employed to dissect the cellular diversity within the skin. These advanced techniques have revolutionised our understanding of many tissues, but skin tissues remain underexplored, especially in the context of chronic skin diseases. Protocols for skin punch biopsy and single-cell profiling are well-established, allowing us to systematically analyse how genetic variations influence skin structure and function.

Diseases of bone associated with ageing, including osteoporosis (OP) and osteoarthritis (OA), reduce bone mass, bone strength and joint integrity. Current non-surgical approaches are limited to pharmaceutical agents that are not disease modifying and have poor patient tolerability due to side effect profiles. Developing a fundamental understanding of cellular bone homeostasis, including how key cell types affect tissue health, and offering novel therapeutic targets for prevention of bone disease is therefore essential. This is the focus of OSTEOMICS. A number of factors have been linked to increased risk of bone disease, including genetic predisposition, diet, smoking, ageing, autoimmune disorders and endocrine disorders. In our study, we will recruit patients undergoing elective and non-elective orthopaedic surgery and obtain surgical bone waste for analysis. This will capture a cohort of patients with bone disorders like OP and OA, in addition to patients without overt clinical bone disease. We will study the relationship between the molecular biology of bone cells, bone structure, genetics (DNA) and environmental factors with the aim of identifying and validating novel therapeutic targets. We will leverage modern single cell technologies to understand the diversity of cell types found in bone. These technologies have now led to the characterisation of virtually every tissue in the body, however bone and bone-adjacent tissues are massively underrepresented due to the anatomical location and underlying technical challenges. Early protocols to demineralise bone and perform single cell profiling have now been developed. We will systematically scale up these efforts to observe how genetic variation at the population level leads to alterations in bone structure and quality. Over the next 10 years, we will generate data to comprehensively characterise bone across health and disease, use machine learning to drive analysis, and experimentally validate hypotheses - which will ultimately contribute to developing the next generation of therapeutic agents.