Resolve Therapeutics has announced two e-posters featuring preclinical data on its RNase-Fc fusion protein RSLV-132, and its bispecific RNase/DNase-Fc fusion protein RSLV-145, shared at the 18th World Stroke Congress (WSC; 21–23 October, Seoul, South Korea). One presentation examined the degradation and inhibition of neutrophil extracellular traps (NETs) by RSLV-145 in vitro, while the other evaluated RSLV-132 and RSLV-145 combined with tenecteplase in a murine photothrombotic stroke model.
Resolve states in a press release that it is developing nuclease therapy as a new approach to acute ischaemic stroke based on growing evidence that cell-free nucleic acids are “important mediators” of stroke pathogenesis. For example, thrombi rich in NETs are associated with resistance to thrombolysis, and extracellular ribonucleic acid (RNA) has been implicated in the extension of tissue injury during reperfusion. Therefore—the company adds—digesting NET DNA could restore thrombolytic efficacy, while degrading extracellular RNA could limit reperfusion injury, providing a dual rationale for evaluating nuclease therapy in acute ischaemic stroke.
At WSC 2026, data were presented demonstrating the ability of RSLV-145—a dual RNase/DNase nuclease Fc fusion protein—to effectively digest preformed NETs and inhibit RNA-induced NET formation. In experiments using neutrophils from healthy donors, RSLV-145 degraded preformed NETs within five minutes in a concentration-dependent manner, leaving 59%, 38% and 36% of NET-associated DNA at 17.5, 87.5 and 175nM, respectively (all p<0.0001 versus baseline). RSLV-132, which lacks DNase activity, had no effect on preformed NETs. Additionally, both RSLV-132 and RSLV-145 reduced NET formation induced by RNA-containing immune complexes, with greater inhibition observed for RSLV-145.
A second presentation demonstrated that, when added to tenecteplase and administered 30 minutes after stroke onset, both RSLV-145 and RSLV-132—given as single intravenous doses (10mg/kg)—improved several clinically important outcomes in a murine photothrombotic stroke model. The tenecteplase-plus-RSLV-132 and tenecteplase-plus-RSLV-145 groups each had 35% lower day-three infarct volume than the vehicle group (Bonferroni-corrected p=0.014 for each). The 21% reduction with tenecteplase alone was not statistically significant versus vehicle.
Both combination groups preserved performance on the accelerating rotarod test through day three (Bonferroni-corrected p<0.05 versus vehicle), while tenecteplase alone did not reach statistical significance. Furthermore, both combination groups showed significant within-animal cerebral perfusion recovery between 60 and 120 minutes after treatment, but tenecteplase alone did not. Only the tenecteplase-plus-RSLV-145 group showed a statistically significant improvement on the adhesive tape-removal test versus vehicle (Bonferroni-corrected p=0.014).
These data provide “compelling evidence” for the continued development of nuclease therapy in acute ischaemic stroke, Resolve claims—also noting that, taken together, the NET and stroke-model findings strengthen the rationale for advancing RSLV-132 and RSLV-145 as potential adjuncts to thrombolysis.
“These studies address complementary aspects of the rationale for nuclease therapy in stroke,” said Gábor Illei, clinical strategy leader at Resolve. “RSLV-145 rapidly degraded preformed NETs in vitro, both candidates reduced induced NET formation, and each improved several outcomes when combined with tenecteplase in the mouse model. Ischaemic stroke is an area of large unmet medical need; we look forward to continued development of this promising new approach and ultimately evaluating these molecules in clinical studies.”
