Abstract: siRNA molecules targeting AGT mRNA that reduce or inhibit AGT production are provided. Pharmaceutical compositions containing such siRNA molecules also are provided, together with methods of their use for treating hypertension. Pharmaceutical compositions containing at least one oligonucleotide covalently linked to, and delivered to a target cell by, a peptide docking vehicle (PDoV) are capable of reducing or inhibiting the production of AGT and treating hypertension. The PDoV may contain a targeting ligand such as a GalNAc moiety conjugated to the PDoV which targets the complex to hepatocytes.

Abstract: Methods of making and using nanoparticle pharmaceutical compositions comprising histidine-lysine copolymers are provided. The solutions spontaneously form nanoparticles when mixed with nucleic acids such as siRNA. Methods are provided where the pH of the nucleic acid solution is controlled prior to mixing leading to a reduction in nanoparticle diameter to a desirable range, typically 100-150 nm, and Polydispersity Index (PDI), both of which improve transport into target cells to improve the efficacy of gene silencing.

Abstract: Improved pharmaceutical nanoparticle compositions and improved methods for preparing the compositions comprising histidine-lysine copolymers and an acetate salt or phosphate anion are provided. The addition of acetate or phosphate anion to the histidine-lysine copolymer prior to mixing with a nucleic acid alters nanoparticle size and polydispersity index of the compositions and provides a more uniform particle size distribution.

Abstract: Methods are provided for improving the manufacture and use of pharmaceutical compositions comprising histidine-lysine copolymers and nucleic acids, which spontaneously form nanoparticles when mixed. The flow rate of mixing and the ratio of copolymer to siRNA strongly affect nanoparticle properties, including size and homogeneity of particles, resulting in greater efficacy in delivery to target cells. Further, an acidic pH of the siRNA solution, as well as the addition of acetate or phosphate salt to the histidine-lysine copolymer prior to mixing with the siRNA also contribute to lower nanoparticle diameters and more uniform particles (lower PDI).