Repurposing of Reverse Transcriptase Inhibitors to Alleviate TLR5-mediated Inflammation in Cystic Fibrosis

Background & Unmet Need

• Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CF transmembrane conductance regulator (CTFR) gene
• This hereditary mutation results in inadequate mucus production and compromises bacterial clearance mechanisms, predisposing CF patients to persistent lung infections
• To fight bacterial infections, cells express TLR5 in response to bacterial motor protein Flagellum (FLA), which causes an innate immune response
• Unregulated TLR5 activation in response FLA results in pathogenic inflammation
• Most notably, P. aeruginosa can cause a life-threatening infection in the pulmonary tract of CF patients by triggering excess TLR5-mediated inflammation
• Unmet Need: Anti-inflammatory therapy targeting TLR5 to provide therapeutic relief that does not drive immunotoxicity

Technology Overview

• The Technology: Repurposed reverse transcriptase inhibitors (RTis) to alleviate TLR5-driven inflammation in severe cystic fibrosis
• The Discovery: Expression of endogenous retroelements is significantly altered in the peripheral blood mononuclear cells (PBMCs) of CF patients
• Flagellum (FLA) delivery results in signaling through TLR5, affecting endogenous retroelements (EREs) downstream
• Reverse transcriptase inhibitors (RTis) selectively inhibit TLR5-induced immunity through expression of TEs
• PoC Data: Four RTis inhibited endogenous reverse transcriptase activity and the resulting TLR5-induced inflammatory response in response to FLA, including inflammatory cytokines TNFa and IL-1B
• RTis inhibited TNFa production at all concentrations tested (0.025uM-2.5 uM), and IL-1B at the highest concentration (2.5 uM)

Technology Applications

• Repurposed RTis to alleviate inflammation induced by TLR5 activation in Cystic Fibrosis
• RTis may be used as a cotreatment to alleviate TNF-driven inflammation in sepsis with S. typhi or P. aeruginosa

Technology Advantages

• RTis circumvent increasing antibiotic resistance in P. aeruginosa infection
• RTis bypass inter-individual heterogeneity and immunotoxicity
• Safety and dosages for RTis have been established for individuals on PrEP and people living with HIV
• Production of RTis in commercial quantities has been established by several manufacturers

Figure 1: RTi delivery inhibits cytokine production in response to acute TLR5 activation.