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The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.

Objective To evaluate the effectiveness of phytoestrogens as alternatives for selective dysfunctional changes in the menopausal rabbit model. Design Prospective, vehicle-controlled experimental study. Setting Reproductive pharmacology laboratory in a university department. Animal(s) Twenty-four rabbits with experimentally induced menopause and six intact controls. Intervention(s) Surgical menopause was induced in 24 rabbits by ovariectomy. After 4 weeks of convalescence, three groups (n = 6) were given 100 μg/kg E 2 valerate, 100 μg/kg daidzein, or 6.68 mg/kg red clover extract daily for 12 weeks. The remaining six rabbits served as the operated control group. Main Outcome Measure(s) Vaginal blood flow using Doppler flowmetry, before, during, and after pelvic nerve stimulation; and measured parameters of uterine weight, femoral bone density, clitoral cavernosal histology, and hormone levels. Result(s) After pelvic nerve stimulation, blood flow increased remarkably in the daidzein-treated group. Serum E 2 and uterine weight increased significantly in the estrogen group. Cavernosal structure was well preserved in all three treatment groups, and bone mineral density was lowest in ovariectomized controls (0.3467 g/cm 2 ) and highest in the red clover (0.4012 g/cm 2 ) groups. Conclusion(s) Supplementing isoflavones for menopause leads to significant improvements in bone density, tissue integrity, and vaginal blood flow with minimal effect on uterine weight and may therefore be a viable alternative to conventional regimens using synthetic estrogens.