Prion Alliance

Intrathecally administered RNase H1-active gapmer antisense oligonucleotides (ASOs) are promising therapeutics for brain diseases where lowering the expression of one target gene is expected to be therapeutically beneficial. Such ASOs are active, to varying degrees, across most or all cell types in the cortex and cerebellum of mouse and non-human primate (NHP) brain regions with substantial drug accumulation. Intrathecally delivered ASOs, however, exhibit a gradient of exposure across the brain, with more limited drug accumulation and weaker target engagement in deep brain regions of NHP. Here, we profiled the activity of a tool, ASO, against Malat1 in three deep brain regions of NHP: thalamus, caudate, and putamen. All neuronal subtypes exhibited knockdown similar to, or deeper than, the bulk tissue. Among non-neuronal cells, knockdown was deepest in microglia and weakest in endothelial stalk. Overall, we observed broad target engagement across all cell types detected, supporting the relevance of intrathecal ASOs to diseases with deep brain involvement.

Antisense oligonucleotides (ASOs) dosed into cerebrospinal fluid (CSF) distribute broadly throughout the brain and hold the promise of treating myriad brain diseases by modulating RNA. CNS tissue is not routinely biopsied in living individuals, leading to reliance on CSF biomarkers to inform on drug target engagement. Animal models can link CSF biomarkers to brain parenchyma, but our understanding of how individual cells contribute to bulk tissue signal is limited. Here we employed single nucleus transcriptomics on tissue from mice treated with RNase H1 ASOs against Prnp and Malat1 and macaques treated with an ASO against PRNP . Activity was observed in every cell type, though sometimes with substantial differences in magnitude. Single cell RNA count distributions implied target suppression in every single sequenced cell, rather than intense knockdown in only some cells. Duration of action up to 12 weeks post-dose differed across cell types, being shorter in microglia than in neurons. Suppression in neurons was generally similar to, or more robust than, the bulk tissue. In macaques, PrP in CSF was lowered 40% in conjunction with PRNP knockdown across all cell types including neurons, arguing that a CSF biomarker readout is likely to reflect disease-relevant cells in a neuronal disorder.

The U.S. Department of Energy, Richland Operations Office (DOE-RL) conducts ecological monitoring on the Hanford Site to collect and track data needed to ensure compliance with an array of environmental laws, regulations, and policies governing DOE-RL activities. Ecological monitoring data provide baseline information about the plants, animals, and habitats under DOE-RL stewardship at Hanford which is required for decisionmaking under the National Environmental Policy Act (NEPA) and Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). The Hanford Site Comprehensive Land Use Plan (CLUP, DOE/EIS- 0222-F), which is the Environmental Impact Statement for Hanford Site activities, helps ensure that DOE-RL, its contractors, and other entities conducting activities on the Hanford Site are in compliance with NEPA.

Prion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), and there are currently no therapeutic options. PrP ligands could theoretically antagonize prion formation by protecting the native protein from misfolding or by targeting it for degradation, but no validated small-molecule binders have been discovered to date. We deployed a variety of screening methods in an effort to discover binders of PrP, including 19F-observed and saturation transfer difference (STD) NMR spectroscopy, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening. A single benzimidazole compound was confirmed in concentration-response, but affinity was very weak (Kd > 1 mm), and it could not be advanced further. The exceptionally low hit rate observed here suggests that PrP is a difficult target for small-molecule binders. Whereas orthogonal binder discovery methods could yield high-affinity compounds, non-small-molecule modalities may offer independent paths forward against prion disease.

In 2016, a rare plant monitoring effort occurred on the portion of the Hanford Site (referred to herein as Central Hanford) managed by the U.S. Department of Energy (DOE). The goal of this effort was to revisit known occurrences of upland rare plant populations on Central Hanford to improve baseline information on locations of rare plant populations on the Hanford Site. Additionally, population stability, viability, and threats were recorded and will be used to inform future management of rare plant species.

<p>NCBI release notes: <a href="https://ftp.ncbi.nlm.nih.gov/pub/clinvar/release_notes/20180201_data_release_notes.pdf">20180201_data_release_notes.pdf</a></p>

NCBI Release Notes: ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/release_notes/20170302_data_release_notes.pdf

The U.S. Department of Energy, Richland Operations Office (DOE-RL) conducts ecological monitoring on the Hanford Site to collect and track data needed to ensure compliance with an array of environmental laws, regulations, and policies governing DOE activities. Ecological monitoring data provide baseline information about the plants, animals, and habitats under DOE-RL stewardship at Hanford required for decision-making under the National Environmental Policy Act (NEPA) and Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). The Hanford Site Comprehensive Land Use Plan (CLUP, USDOE 1999), which is the Environmental Impact Statement that evaluates the potential environmental impacts associated with implementing a comprehensive land-use plan for the Hanford Site for at least the next 50 years, ensures that DOE-RL, its contractors, and other entities conduct activities on the Hanford Site in compliance with NEPA.

The U.S. Department of Energy (DOE) Richland Operations Office (-RL) conducts ecological monitoring on the Hanford Site to collect and track data needed to ensure compliance with an array of environmental laws, regulations, and policies governing DOE activities. Ecological monitoring data provide baseline information about the plants, animals, and habitat under DOE-RL stewardship at Hanford required for decision-making under the National Environmental Policy Act (NEPA) and Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). The Hanford Site Comprehensive Land Use Plan (CLUP,USDOE 1999), which is the Environmental Impact Statement for Hanford Site activities, helps ensure that DOE-RL, its contractors, and other entities conducting activities on the Hanford Site are in compliance with NEPA.

The U.S. Department of Energy, Richland Operations Office (DOE-RL) conducts ecological monitoring on the Hanford Site to collect and track data needed to ensure compliance with an array of environmental laws, regulations, and policies governing DOE activities. Ecological monitoring data provide baseline information about the plants, animals, and habitats under DOE-RL stewardship at Hanford required for decision-making under the National Environmental Policy Act (NEPA) and Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). The Hanford Site Comprehensive Land Use Plan (CLUP, USDOE 1999), which is the Environmental Impact Statement that evaluates the potential environmental impacts associated with implementing a comprehensive land-use plan for the Hanford Site for at least the next 50 years, ensures that DOE-RL, its contractors, and other entities conduct activities on the Hanford Site in compliance with NEPA.