Joseph Tabernero and colleagues have carried out a 'first-in-man' Phase I trial of two small interfering RNAs (siRNAs) to treat patients with refractory metastatic disease that involves the liver.

In this trial, Tabernero and colleagues used lipid nanoparticles (LNPs) to encapsulate two siRNAs that target vascular endothelial growth factor (VEGF) and kinesin spindle protein (KSP; also known as KIF11). Inhibition of VEGF targets the tumour vasculature, and inhibition of KSP induces mitotic arrest. One of the limitations of using RNA interference (RNAi) in the clinic is targeting it to the desired organ or tumour. When given parenterally in animal models, the therapeutic, termed ALN-VSP, primarily localized to the liver and spleen owing to their fenestrated endothelium. It also accumulated in tumours owing to their leaky vasculature and enhanced permeability and retention effect. ALN-VSP was given to 41 patients who were enrolled sequentially and assigned one of seven dose levels (0.1–1.5 mg per kg), given as a 15-minute intravenous infusion every 2 weeks. Eleven patients whose disease had not progressed (based on computerized tomography (CT) evaluation) after four cycles (eight doses over 4 months) were allowed to continue in the expansion phase of the trial. Six of these patients received doses at 1 mg per kg and five patients at 1.25 mg per kg until disease progression or the completion of the trial.

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