Treatment of COVID-19 patients with a SARS-CoV-2-specific siRNA-peptide dendrimer formulation.

BACKGROUND: Severe acute respiratory syndrome corona virus (SARS-CoV-2) infection frequently causes severe and prolonged disease but only few specific treatments are available. We aimed to investigate safety and efficacy of a SARS-CoV-2-specific siRNA-peptide dendrimer formulation MIR 19® (siR-7-EM/KK-46) targeting a conserved sequence in known SARS-CoV-2 variants for treatment of COVID-19. METHODS: We conducted an open-label, randomized, controlled multicenter phase II trial (NCT05184127) evaluating safety and efficacy of inhaled siR-7-EM/KK-46 (3.7 mg and 11.1 mg/day: low and high dose, respectively) in comparison with standard etiotropic drug treatment (control group) in patients hospitalized with moderate COVID-19 (N = 52 for each group). The primary endpoint was the time to clinical improvement according to predefined criteria within 14 days of randomization. RESULTS: Patients from the low-dose group achieved the primary endpoint defined by simultaneous achievement of relief of fever, normalization of respiratory rate, reduction of coughing, and oxygen saturation of >95% for 48 h significantly earlier (median 6 days; 95% confidence interval [CI]: 5-7, HR 1.75, p = .0005) than patients from the control group (8 days; 95% CI: 7-10). No significant clinical efficacy was observed for the high-dose group. Adverse events were reported in 26 (50.00%), 25 (48.08%), and 28 (53.85%) patients from the low-, high-dose and control group, respectively. None of them were associated with siR-7-EM/KK-46. CONCLUSIONS: siR-7-EM/KK-46, a SARS-CoV-2-specific siRNA-peptide dendrimer formulation is safe, well tolerated and significantly reduces time to clinical improvement in patients hospitalized with moderate COVID-19 compared to standard therapy in a randomized controlled trial.

Shifts in the Genetic Landscape of the Western Eurasian Steppe Associated with the Beginning and End of the Scythian Dominance.

The Early Iron Age nomadic Scythians have been described as a confederation of tribes of different origins, based on ancient DNA evidence [1-3]. It is still unclear how much of the Scythian dominance in the Eurasian Steppe was due to movements of people and how much reflected cultural diffusion and elite dominance. We present new whole-genome sequences of 31 ancient Western and Eastern Steppe individuals, including Scythians as well as samples pre- and postdating them, allowing us to set the Scythians in a temporal context (in the Western, i.e., Ponto-Caspian Steppe). We detect an increase of eastern (Altaian) affinity along with a decrease in eastern hunter-gatherer (EHG) ancestry in the Early Iron Age Ponto-Caspian gene pool at the start of the Scythian dominance. On the other hand, samples of the Chernyakhiv culture postdating the Scythians in Ukraine have a significantly higher proportion of Near Eastern ancestry than other samples of this study. Our results agree with the Gothic source of the Chernyakhiv culture and support the hypothesis that the Scythian dominance did involve a demic component.