A substantial portion of long-COVID (PASC) patients report persistent neurological symptoms. Increasing evidence points towards viral infection-triggered stress and inflammation as early contributors to tauopathy, which can ultimately result in Alzheimer’s disease and dementia. Current treatments focus on symptomatic relief or inflammation reduction, failing to address the underlying molecular mechanisms bridging systemic infection to cognitive decline.
Our inventors have developed a targeted therapeutic strategy which utilizes dendriplex RNA nanoparticles to deliver RNA interference to modulate FKBP5 and IFI204, two newly discovered key regulators involved in the SARS-CoV-2 triggered activation of the Glucocorticoid (GR) signaling pathway driving tau pathology. In vivo treatment with these dendriplexes noticeably reversed infection-associated behavioral and cognitive impairments and prevented accumulation of pathogenic tau in preclinical PS19 mouse models. The dendriplex RNA nanoparticles enables a non-invasive, intranasal delivery system facilitating effective brain targeting, positioning this invention as a strong treatment candidate for COVID-induced neurodegeneration and broader tauopathy intervention.
Figure: Treatment with shFKBP5 and shIFI204 DPX Attenuates Gliosis and Tau Phosphorylation in CoV-2 MA10 Infected PS19 Mice: Downregulation of FKBP51 and IFI204 with pshCombo DPX treatment in CoV-2 MA10-infected mice showed a significant reduction in Tau phosphorylation (pT231) and glial activation (IBA1 and GFAP expression) in the prefrontal cortex of PS19 mice.