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Preeclampsia, with the hallmark features of new-onset hypertension and proteinuria after 20 weeks of gestation, is a major cause of fetal and maternal morbidity and mortality. Studies have demonstrated a role for the renin-angiotensin system (RAS) in its pathogenesis; however, small-molecule RAS blockers are contraindicated because of fetal toxicity. We evaluated whether siRNA targeting maternal hepatic angiotensinogen (Agt) could ameliorate symptoms of preeclampsia without adverse placental or fetal effects in 2 rodent models. The first model used a cross of females expressing human Agt with males expressing human renin, resulting in upregulation of the circulating and uteroplacental RAS. The second model induced ischemia/reperfusion injury and subsequent local and systemic inflammation by surgically reducing placental blood flow mid-gestation (reduced uterine perfusion pressure [RUPP]). These models featured hypertension, proteinuria, and fetal growth restriction, with altered biomarkers. siRNA treatment ameliorated the preeclamptic phenotype in both models, reduced blood pressure, and improved intrauterine growth restriction, with no observed deleterious effects on the fetus. Treatment also improved the angiogenic balance and proteinuria in the transgenic model, and it reduced angiotensin receptor activating antibodies in both. Thus, an RNAi therapeutic targeting Agt ameliorated the clinical sequelae and improved fetal outcomes in 2 rodent models of preeclampsia., Introduction As one of the leading causes of maternal mortality worldwide, hypertensive disorders of pregnancy remain inadequately treated (1). Preeclampsia, a subset of such disorders, occurs in 5% to 8% [...]

Background: The hyperphosphorylation, mislocalization, and aggregation of the microtubule associated protein Tau (MAPT) is a driving force in tauopathies, a class of progressive neurodegenerative disorders. These pathogenic intracellular aggregates, known as neurofibrillary tangles (NFTs), are a hallmark in several diseases such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer's Disease (AD). There is a high unmet medical need for new approaches to target Tau in these numerous tauopathies. While anti‐Tau immunotherapies emphasize the clearance of extracellular Tau aggregates, they do not address the intracellular accumulation of NFTs. Method: Here, using our lipophilic C16‐conjugated siRNA for CNS delivery, we identified potent molecules targeting the MAPT gene in both in vitro and in vivo models. Results: Our RNAi molecules targeting the MAPT gene durably reduce MAPT mRNA and Tau protein levels in both in vitro and in vivo model systems. Furthermore, in a 16‐week non‐human primate study, we observed robust target engagement resulting in sustained reduction of MAPT transcript and Tau protein in brain tissue and cerebrospinal fluid. Conclusion: Together, these results suggest that RNAi lowering of Tau could be a novel strategy to address both intra‐ and extra‐cellular accumulation of Tau aggregates, which could have therapeutic advantages for treating tauopathies. [ABSTRACT FROM AUTHOR]

Background: The hyperphosphorylation and subsequent aggregation of the microtubule‐associated protein Tau (encoded by the MAPT gene) is one of the major histopathological hallmarks of numerous tauopathies, including Alzheimer's disease and progressive supranuclear palsy. The intracellular accumulation of aggregated Tau is associated with neuronal loss and disease progression in tauopathies. There is a high‐unmet need to identify strategies to target the intracellular accumulation of Tau aggregates with the aim of slowing tauopathy progression. Method: To model this, we used mice carrying multiple copies of a transgene with a prion promoter driving human MAPT with human tauopathy‐inducing mutation P301S. P301S‐Tau transgenic mice progressively accumulate neuroglial Tau aggregates associated with axonal damage, gliosis, body weight loss, and ambulatory dysfunction. Result: P301S mice treated with a single intracerebroventricular injection of Tau siRNA at eight months of age, had a sustainable decrease in MAPT mRNA and soluble Tau protein for three months following siRNA treatment (reduced ∼83% and ∼59%, respectively). siRNA treatment also prevented the progressive decrease in body weight and abrogated axonal damage, evidenced by decreased neurofilament light (NFL) chain in plasma and cerebrospinal fluid of eleven‐month‐old mice. Importantly, immunohistochemical analysis of misfolded Tau in vivo and HEK293‐4RD‐CFP/YFP Tau aggregate biosensor assay testing in vitro revealed a ∼97% decrease of Tau aggregates in the eleven‐month‐old mice, suggesting there exists a yet‐to‐be identified mechanism of Tau fibril clearance. Conclusion: Together, these results suggest an RNAi therapeutics approach targeting of MAPT mRNA may be sufficient to improve multiple parameters of tauopathy disease progression and a provide a compelling rationale for further development of Tau‐lowering strategies. [ABSTRACT FROM AUTHOR]

Parasitic field oxide transistors are affected by ionizing radiation, becoming active circuit elements leading to loss of device isolation. Test structures are designed, fabricated and characterized allowing analysis of parasitic device layout geometries. Accurate modeling of parasitic devices through determination of effective width/length ratios supports compact model development for use in radiation-hardening-by-design activities. [ABSTRACT FROM PUBLISHER]