Accelerating New Treatments for Refractory RA through targeting the FGF Family

In this application we aim to accelerate the development of new treatment for multidrug resistant “refractory” Rheumatoid Arthritis (RA), a major unmet clinical need with vast public health and socioeconomic implications.

In work based on the synovial biopsy-driven Pathobiology of Early Arthritis Cohort (MRC-funded PEAC cohort) we identified specific histopathology [fibroid-paucimmune (FPI) synovial pathotype] and transcriptomic signatures [FGF/FGFR family produced by fibroblast-like-synoviocytes (FLS)] associated with poor response to conventional-synthetic DMARDs.

Notably, these signatures were replicated in an independent observational cohort of TNF-ihibitors (TNFi) inadequate responders and in “resistant” RA patients, refractory to at least two biologic DMARDs(NIHR-funded R4RA randomised clinical trial, The Lancet in press).

Thus, the FGF/FGFR family produced by RA-FLS, emerged as potential driver/biomarker of a multidrug resistant “endotype”, present at all disease stages early,TNFi inadequate responders and refractory RA.

Of relevance, preliminary single-cell RNASeq analysis from our own data and public repositories identified differential expression of FGF/FGFR gene signatures which are retained both in freshly isolated and established RA-FLS cultures supporting the hypothesis that specific pathology and epigenetic inprinting of the FGF/FGFR gene programme in RA-FLS drive multidrug resistance.

Based on this evidence, in this proposal, we will test the above hypothesis with the goal of accelerating new treatments for refractory RA by targeting the FGF/FGFR gene family through the following 3 investigative aims: 1.

Examine systematically the mechanisms underpinning FLS/stromal cell-driven inflammation at the whole tissue (confirmatory studies) and single-cell level across different disease stages and treatment interventions of the RA disease cycle in existing cohorts (PEAC, STRAP, R4RA), in order to prioritize FGF/FGFR family target candidates. 2.

Dissect the regulation of identified FGF/FGFR family target candidates at the single-cell level in matched freshly-isolated FLS and long-term primary RA-FLS cultures obtained from ultrasound-guided synovial biopsies from patients with refractory RA in order to define imprinted vs inducible FGF/FGFR gene family signatures and the underlying epigenetic regulation. 3.

Test potential FGF/FGFR drug candidates in different experimental settings in-vitroand in a SCID mouse model in-vivoin order to determine functional modulation, minimal-inhibitory-drug-concentrations, as well as pharmacokinetic/pharmacodynamic properties of lead Genentech/Roche compounds in SCID animals.

In this proposal we are bringing together the significant clinical and laboratory expertise, as well major infrastructure, patient cohorts and capabilities of two UK MSK TRC Centres (Barts/QMUL and UoM) with existing long-standing collaborations established as part of the MRC/Versus-Arthritis-funded MATURA consortium.

Additionally, this proposal is supported by a large pharma collaborator (Genentech/Roche) with an active interest in targeting FGF/FGFR in its advanced translational pipeline (Phase II/III studies in other disease indications).

Importantly, Genentech has committed a large in-kind contribution, including expensive state-of-the-art technologies (single-cell RNA sequencing and Digital-Spatial-Profiling), senior and postdoctoral investigators’ time, and $100K cash-funds, approximately 25% of the requested budget to Versus Arthritis.