During the SARS-CoV-2 pandemic, the world scrambled to develop effective means to effectively treat and manage COVID. Whereas initial efforts focused on antivirals, it soon became clear that this would not be enough. To be effective, antivirals need to be administered at a stage where inhibiting the virus can change the course of disease.
This strategy is inherently flawed for mosquito-transmitted alphaviruses which are not only difficult to diagnose in the early stages of infection but also have a disease pathology driven by viral-triggered host response. Over the past decade, my team has shown that alphaviral disease, such as that caused by Ross River virus (RRV), is immune-modulated. Therefore, to successfully treat alphaviral-inflammatory disease, the therapy must be ‘disease-modifying’, targeting the underlying pathophysiology of the host rather than the virus itself.
Over the years we have established a number of models systems to study the pathogenesis of alphaviruses. This has provided the unique opportunity to identify new druggable host targets, validate principal candidates and perform extensive preclinical evaluation of leads for future clinical development.
Owing to strong preclinical data, our lead candidate, pentosan polysulfate (PPS), entered clinical trials to treat RRV-induced disease in Australia. Through a phase II randomised, double-blinded placebo-controlled clinical trial we demonstrated that PPS both clinical and statistical improved RRV-induced joint pain/arthralgia, hand grip strength and overall quality of life in patients. Perhaps most significantly, owing to a drug repurposing strategy, PPS has been used under the TGA special access scheme to successfully treat patients with RRV-induced arthritis.
As mosquito-transmitted viruses continue to expand their global distribution there is a critical need for promising therapeutics. By targeting the host in ‘disease-modifying’ therapies, and using a reproposing strategy, we might have a chance at mitigating the potential damages that these viruses cause today and in the future.