Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials

The Marine Microbial Eukaryote Transcriptome Sequencing Project (MMETSP): illuminating the functional diversity of eukaryotic life in the oceans through transcriptome sequencing

International audienceCurrent sampling of genomic sequence data from eukaryotes is relatively poor, biased, and inadequate to address important questions about their biology, evolution, and ecology; this Community Page describes a resource of 700 transcriptomes from marine microbial eukaryotes to help understand their role in the world's oceans

Co-Principal Investigator

This research was supported by a Joint Statistical Agreement with the Bureau of the Census. The views, opinions, and findings contained in this report are those of the author and should not be construed aa an official Bureau of the Census position, policy, or decision, unless 80 designated by other officia

Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials

The Marine Microbial Eukaryote Transcriptome Sequencing Project (MMETSP): illuminating the functional diversity of eukaryotic life in the oceans through transcriptome sequencing.

Current sampling of genomic sequence data from eukaryotes is relatively poor, biased, and inadequate to address important questions about their biology, evolution, and ecology; this Community Page describes a resource of 700 transcriptomes from marine microbial eukaryotes to help understand their role in the world's oceans

A schematic of the major lineages in the eukaryotic tree of life, showing the relationships between lineages for which genomic resources are currently available and those that have been targeted by the MMETSP.

<p>Lineages with complete genomes according to the GOLD database, as summarized in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001889#pbio.1001889-Burki1" target="_blank">[3]</a>, are indicated by a solid line leading to that group, whereas lineages with no complete genome are represented by a dashed line. Lineages where at least one MMETSP transcriptome is complete or underway are indicated with a red dot by the name. Major lineages discussed in the text have been named and color-coded, but for clarity, some major lineages have not been labeled.</p

Comparing the diversity of microbial eukaryotes at one marine site with that represented in genome data and the MMETSP project.

<p>(A) Taxon assignments for 930 Small Subunit (SSU) rRNA gene sequences from environmental clone libraries built using DNA from three size fractions in sunlit surface waters of the North Pacific Ocean. Four hundred and five sequences corresponding to Syndiniales (nonphotosynthetic members of the dinoflagellate lineage, often referred to as MALV1 and MALV2) were excluded for visualization purposes. Syndiniales are not represented in any complete genome data or the MMETSP, and the vast majority are only known as sequences from uncultivated taxa that often dominate clone libraries <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001889#pbio.1001889-Massana1" target="_blank">[22]</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001889#pbio.1001889-Massana2" target="_blank">[31]</a>. Filter size fractions were 0.1 to <0.8 µm, 0.8 to <3 µm, and 3 to <20 µm. This graph is only intended to give a snapshot of one marine sample; relative distributions vary based on distance from shore and depth, and several studies provide more detailed reviews of available SSU rRNA gene sequence surveys, see e.g., <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001889#pbio.1001889-Amin1" target="_blank">[21]</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001889#pbio.1001889-Not1" target="_blank">[32]</a>. (B) Taxonomic diversity of eukaryotes with complete genome sequences, as summarized in the Genomes Online Database (GOLD: <a href="http://genomesonline.org" target="_blank">http://genomesonline.org</a>). Note that multicellular organisms are included (unlike in A or C); animals, land plants, and multicellular rhodophytes are included in the opisthokont, viridiplantae, and rhodophyte categories, respectively. (C) Taxon breakdown of the MMETSP sequencing project, collapsed at the strain level (for some strains, cells were grown under multiple conditions and these have been counted only once). (D) Comparison of currently available complete genomes and MMETSP transcriptomes by Class for two diverse and well-studied groups of algae, prasinophytes <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001889#pbio.1001889-Marin1" target="_blank">[14]</a> and dinoflagellates <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001889#pbio.1001889-Fensome1" target="_blank">[15]</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001889#pbio.1001889-Saldarriagaa1" target="_blank">[16]</a>. For both lineages, genomes are broken down by Class on the left and MMETSP transcriptomes on the right.</p