Pentosan polysulfate sodium for Ross River virus-induced arthralgia: a phase 2a, randomized, double-blind, placebo-controlled study

Ravindran, Krishnan; Duiker, Melanie; Rudd, Penny A.; Skerrett, Donna; Pollard, James; Siddel, Carolyn; Rifat, Rifat; Ng, Jennifer; Georgius, Peter; Hererro, Lara J.; Griffin, Paul

doi:10.1186/s12891-021-04123-w

Cited by 10 publications

(11 citation statements)

References 32 publications

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“…It is possible that low grade chronic inflammation remains [ 9 ]. In the absence of vaccine, antivirals or targeted therapeutic solutions, RRV disease is generally treated with non-steroidal anti-inflammatory drugs (NSAIDs) or analgesics such as paracetamol, and recent clinical trials have shown some efficacy of pentosan polysulfate sodium (PPS), a sulphated polysaccharide, which is available as a prescription in Australia [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-17 contributes to Ross River virus-induced arthritis and myositis

et al. 2022

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Arthritogenic alphaviruses are mosquito-borne viruses that are a major cause of infectious arthropathies worldwide, and recent outbreaks of chikungunya virus and Ross River virus (RRV) infections highlight the need for robust intervention strategies. Alphaviral arthritis can persist for months after the initial acute disease, and is mediated by cellular immune responses. A common strategy to limit inflammation and pathology is to dampen the overwhelming inflammatory responses by modulating proinflammatory cytokine pathways. Here, we investigate the contribution of interleukin-17 (IL-17), a cytokine involved in arthropathies such as rheumatoid arthritis, in the development RRV-induced arthritis and myositis. IL-17 was quantified in serum from RRV-infected patients, and mice were infected with RRV and joints and muscle tissues collected to analyse cellular infiltrates, tissue mRNA, cytokine expression, and joint and muscle histopathology. IL-17 expression was increased in musculoskeletal tissues and serum of RRV-infected mice and humans, respectively. IL-17–producing T cells and neutrophils contributed to the cellular infiltrate in the joint and muscle tissue during acute RRV disease in mice. Blockade of IL-17A/F using a monoclonal antibody (mAb) reduced disease severity in RRV-infected mice and led to decreased proinflammatory proteins, cellular infiltration in synovial tissues and cartilage damage, without affecting viral titers in inflamed tissues. IL-17A/F blockade triggered a shift in transcriptional profile of both leukocyte infiltrates and musculoskeletal stromal cells by downregulating proinflammatory genes. This study highlights a previously uncharacterized role for an effector cytokine in alphaviral pathology and points towards potential therapeutic benefit in targeting IL-17 to treat patients presenting with RRV-induced arthropathy.

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Section: Introductionmentioning

confidence: 99%

Interleukin-17 contributes to Ross River virus-induced arthritis and myositis

et al. 2022

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“…We have recently reported that PPS is able to improve hand strength in patients suffering from RRV [ 15 ]. By using a well characterised adult mouse model of CHIKV infection [ 16 ], we assessed if PPS treatment could treat the functional signs of CHIKV disease by improving grip strength.…”

Section: Resultsmentioning

confidence: 99%

“…PPS is a repurposed semisynthetic glycosaminoglycan that has been shown to be well-tolerated in both oral and injectable forms. Recently, injectable PPS (iPPS) was administered to a cohort of RRV infected patients with no serious adverse events reported [ 15 ]. We have demonstrated that CHIKV-infected untreated mice develop the classical rheumatic features of local inflammation as observed by foot and joint swelling and histological evidence of arthritis as seen by cellular infiltrates, tenosynovitis and myositis.…”

Section: Discussionmentioning

confidence: 99%

“…Given the extensive burden of CHIKV-induced rheumatic conditions and the complications of non-specific treatments currently available, there is an urgent need for a targeted therapeutic agent. Towards this, we have recently described a novel glycosaminoglycan (GAG)-like molecule, Pentosan Polysulfate Sodium (PPS) for effective treatment of alphavirus-induced arthritides as a result of Ross River virus (RRV) infection [ 14 , 15 ]. Herein, we further characterised the efficacy of PPS towards the treatment of the global CHIKV-induced disease and explored clinically significant pathways altered by PPS treatment.…”

Section: Introductionmentioning

confidence: 99%

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

Rudd

Lim

Stapledon³

et al. 2021

PLoS ONE

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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.

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“…Although pentosan polysulfate treatment did not influence the kinetics of virus infection, it alleviated virus-induced arthritis in C57BL/6 mice [ 139 ]. Furthermore, it was recently successfully evaluated in phase II clinical trials for the treatment of RRV-induced arthritic disease (PARA_004, Paradigm BioPharmaceuticals) [ 210 ]. Pixatimod treatment also reduced the severity of alphavirus-induced arthritis and showed good antiviral effects against different CHIKV strains [ 140 ].…”

Section: Targeting Host Factorsmentioning

confidence: 99%

Antivirals against the Chikungunya Virus

Battisti

Urban

Langer

2021

Viruses

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Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has re-emerged in recent decades, causing large-scale epidemics in many parts of the world. CHIKV infection leads to a febrile disease known as chikungunya fever (CHIKF), which is characterised by severe joint pain and myalgia. As many patients develop a painful chronic stage and neither antiviral drugs nor vaccines are available, the development of a potent CHIKV inhibiting drug is crucial for CHIKF treatment. A comprehensive summary of current antiviral research and development of small-molecule inhibitor against CHIKV is presented in this review. We highlight different approaches used for the identification of such compounds and further discuss the identification and application of promising viral and host targets.

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Pentosan polysulfate sodium for Ross River virus-induced arthralgia: a phase 2a, randomized, double-blind, placebo-controlled study

Cited by 10 publications

References 32 publications

Interleukin-17 contributes to Ross River virus-induced arthritis and myositis

Interleukin-17 contributes to Ross River virus-induced arthritis and myositis

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

Antivirals against the Chikungunya Virus

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