Targeting microRNA-155 as a new treatment strategy for arthritis and pulmonary fibrosis

Medical Research Scotland
PhD Studentship Awards

This project is one of six four-year PhD Studentships funded by Medical Research Scotland (http://www.medicalresearchscotland.org.uk) to be delivered jointly by the named University and Company. The Studentships will provide the first-class academic and commercial training needed to equip the successful student for a science career in an increasingly competitive market.

The role of microRNA-155 as a master-switch determining the balance of inflammation and fibrosis in chronic disorders – delivered by the University of Glasgow and Lamellar Biomedical Ltd (http://www.lamellar.com)

Academic Supervisors: Professor Iain B McInnes & Dr Mariola Kurowska-Stolarska; Industrial Supervisor: Dr Graham Park

RELEVANCE TO HEALTH. Tissue recovery after injury either mechanical or due to infection is orchestrated by sequence of events that comprises inflammation and repair/remodelling. Any malfunctions in these processes lead to disorders. There is an important clinical unmet need for chronic tissue-remodelling disorders including therapy-resistant rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF).
SCIENTIFIC BACKGROUND. Recently, a novel class of post-transcriptional regulators called microRNAs (miRNA, miR) has been discovered and started a new exciting area of research that provides new dimension to drug development for diseases with unmet clinical needs. These small, non-coding RNA species that are around 22 nucleotides long negatively regulate protein production by binding directly to the complementary sequence in 3’ un-translated regions of target mRNA molecules thereby repressing protein production. A single miRNA can regulate many mRNAs; often from related functional biological pathways, and fine-tunes rather than inhibits targets, thereby modulating the homeostatic balance of the biological responses. Therefore, interfering with miRs, given their feature of multiple targeting, offers an appealing therapeutic approach, as it may reduce the requirement of combination therapies if a single drug has multiple and related targets. One of the particular interesting miRs in that context is miR-155.
PILOT DATA. We have identified a potential role for miR-155 in the balance of inflammation and fibrosis in RA and IPF. miR-155 is required for a normal immune function, however excess miR-155 as is seen in RA patients promotes inflammatory arthritis, whereas insufficient miR-155 is associated with experimental fibrosis. Our miR-155 in situ hybridisation studies on RA synovial and IPF lung biopsies mapped miR-155 expression to macrophages and fibroblasts suggesting to us that miR-155 exerts its effect on inflammation/remodelling by regulating pathways in these cells.
Thus, we HYPOTHESISE that miR-155 is a homeostatic master-switch determining the relative dynamics of inflammation and repair/fibrosis.
RESEARCH OPPORTUNITY. Our industrial partner manufactures bio-compatible synthetic phospholipid mimetics of naturally occurring lamellar bodies (LB) that can be exchanged by cells during activation. The Lamellar bodies formulation LMS-611B has the capability to transfect cells both in vitro and in vivo. Naked nucleic acids are usually either degraded quickly or not up taken by cells or induce immune response in vivo. Work carried out by Lamellar Biomedical on gene delivery to the mouse and sheep lung has been successful; and confirmed that LMS-611B have a high transfection efficiency of lung fibroblasts and macrophages. Thus the lamellar body mimetic LMS-611B could be a ideal therapeutic delivery platform for miR-155 mimics and antagonists in pulmonary fibrosis and inflammatory arthritis, respectively.