Pentosan polysulfate sodium prevents functional decline in chikungunya infected mice by modulating growth factor signalling and lymphocyte activation.

Autor: Rudd PA; Institute for Glycomics, Griffith University, Southport, Qld, Australia., Lim EXY; Institute for Glycomics, Griffith University, Southport, Qld, Australia., Stapledon CJM; Paradigm Biopharmaceuticals Ltd, Melbourne, Australia., Krishnan R; Paradigm Biopharmaceuticals Ltd, Melbourne, Australia., Herrero LJ; Institute for Glycomics, Griffith University, Southport, Qld, Australia.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2021 Sep 07; Vol. 16 (9), pp. e0255125. Date of Electronic Publication: 2021 Sep 07 (Print Publication: 2021).
DOI: 10.1371/journal.pone.0255125
Abstrakt: Chikungunya virus (CHIKV) is an arthropod-borne virus that causes large outbreaks world-wide leaving millions of people with severe and debilitating arthritis. Interestingly, clinical presentation of CHIKV arthritides have many overlapping features with rheumatoid arthritis including cellular and cytokine pathways that lead to disease development and progression. Currently, there are no specific treatments or vaccines available to treat CHIKV infections therefore advocating the need for the development of novel therapeutic strategies to treat CHIKV rheumatic disease. Herein, we provide an in-depth analysis of an efficacious new treatment for CHIKV arthritis with a semi-synthetic sulphated polysaccharide, Pentosan Polysulfate Sodium (PPS). Mice treated with PPS showed significant functional improvement as measured by grip strength and a reduction in hind limb foot swelling. Histological analysis of the affected joint showed local inflammation was reduced as seen by a decreased number of infiltrating immune cells. Additionally, joint cartilage was protected as demonstrated by increased proteoglycan staining. Using a multiplex-immunoassay system, we also showed that at peak disease, PPS treatment led to a systemic reduction of the chemokines CXCL1, CCL2 (MCP-1), CCL7 (MCP-3) and CCL12 (MCP-5) which may be associated with the reduction in cellular infiltrates. Further characterisation of the local effect of PPS in its action to reduce joint and muscle inflammation was performed using NanoString™ technology. Results showed that PPS altered the local expression of key functional genes characterised for their involvement in growth factor signalling and lymphocyte activation. Overall, this study shows that PPS is a promising treatment for alphaviral arthritis by reducing inflammation and protecting joint integrity.
Competing Interests: This study was funded by a joint research grant funded from Paradigm Biopharmaceuticals Ltd (https://paradigmbiopharma.com/), Advance Queensland mid-career fellowship awarded to PAR and Griffith University. RK and CJMS are paid employees of Paradigm Biopharmaceuticals Ltd. As staff members of Paradigm Biopharmaceuticals Ltd, RK and CJMS are entitled to long term and short-term incentives. LJH was a paid part-time consultant for Paradigm Biopharmaceuticals Ltd. The specific roles of these authors are articulated in the ‘author contributions’ section. The funders did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript beyond those specified. This research may lead to the use of PPS towards the treatment of CHIKV disease. Paradigm Biopharmaceuticals Ltd. hold the following patents PCT/AU2016/050408 “Treatment of Alphavirus-Induced Inflammation” (published as WO2017/201563) and the Australian patent number is 2016407635 “Treatment of Alphavirus-Induced Inflammation”. Furthermore, iPPS will be available in Australia via Australian infectious disease physicians through the TGA Special Access Scheme (SAS) for patients with chronic RRV-induced arthritis where there are no other treatment options. Access will be available in Q2 CY 2021 as a pay-for-use program, providing a path to first revenues for Paradigm. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
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