{
  "abstract": "Introduction Despite significant recent international clinical trial activity, the yield of approved compounds for systemic sclerosis (SSc) has been disappointingly low. Our aim was to identify and prioritise potential ‘druggable’ targets with insights from human genetics, by integrating the available evidence with publicly available bioinformatics sources relevant for SSc drug development.Material and Methods Genetic variants for SSc were identified through a search of the GWAS catalog, and the associated-mapped genes were cross-referenced with the OpenTargets platform for drug interactions. Confirmation/validation was demonstrated through structured literature searches and review of the evidence on MEDLINE and & ClinialTrials.gov for each individual drug and its association with SSc.Results Search of the GWAS catalogue produced 245 records concerning associations with SSc which were mapped to 159 unique genes considered of relevance. We identified 82 unique drugs ( figure 1), none of which are included in existing SSc guidelines/recommendations.Key groupings of drug therapies were 1) female sex hormones and function, 2) neurotransmitter-targeting therapies, and & 3) inflammatory-fibrotic pathways. The most common drug therapies identified for drug repurposing in SSc were those broadly encompassing female sex hormones and function. These included selective estrogen receptor modulators (SERMs) (12 drugs) and selective estrogen receptor degraders (SERDs) (5 drugs).Neurotransmitter-targeting drug therapies, including those used for broad-ranging neurological disorders (e.g., movement disorders and psychosis), represented another apparent grouping. These included dopamine-targeting therapies: (12 drugs) and drugs exerting effects through multiple neurotransmitter modulation.Immunosuppressive/modulatory approaches largely targeted the Janus Kinase (JAK)/STAT pathway: JAK inhibitors (7 drugs) and tyrosine kinase inhibitors (TYK) (4 drugs). Concerning known complex matrix biological processes in the SSc, four matrix metalloproteinase inhibitors (MMPs) were identified of potential interest. Amlitelimab (anti-OX40L monoclonal antibody) is currently being explored in CONQUEST, a multicentre randomised controlled platform trial for SSc-ILD. The Janus kinase (JAK)/STAT pathway is an attractive therapeutic target in SSc, targeting known pathobiology.There are few data to provide disease-specific evidence (safety and/or efficacy) for the identified drug therapies for potential repurposing in SSc.Conclusions Our systematic approach, combining evidence from different bioinformatics platforms, has identified drug opportunities for repurposing/druggable targets for SSc. A novel and unexpected finding was the identification of multiple neurotransmitter-targeting drug therapies, particularly relevant to SSc-related Raynaud’s phenomenon and gastrointestinal involvement. Future studies of these candidates for SSc drug repurposing are indicated; many of which are widely available/ and often inexpensive.Abstract P.259 Figure 1",
  "authors": [
    {
      "affiliations": [
        "Division of Musculoskeletal and Dermatological Science, School of Biological Sciences, The University of Manchester, Manchester, UK"
      ],
      "name": "Michael Hughes"
    },
    {
      "affiliations": [
        "UTHealth Houston, Department of Medicine, Division of Rheumatology, Houston, USA"
      ],
      "name": "Zsuzsanna McMahan"
    },
    {
      "affiliations": [
        "UTHealth Houston, Department of Medicine, Division of Rheumatology, Houston, USA"
      ],
      "name": "Shervin Assassai"
    },
    {
      "affiliations": [
        "Division of Medicine, University College London, London, UK"
      ],
      "name": "Christopher Denton"
    },
    {
      "affiliations": [
        "Institute of Health Informatics, University College London, London, UK"
      ],
      "name": "Rui Providencia"
    }
  ],
  "title": "P.259 Advancing drug development for systemic sclerosis by prioritising findings from human genetic association studies",
  "uid": "9a2bf313-9176-563c-839a-1d78c6a1fa64"
}