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A blood-brain barrier transport vehicle improves brain biodistribution of a TREM2 antibody and enhances microglial metabolism via receptor clustering

ABSTRACT: A blood-brain barrier transport vehicle improves brain biodistribution of a TREM2 antibody and enhances microglial metabolism via receptor clustering

PROVIDER: PRJNA823923 | ENA |

REPOSITORIES: ENA

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A blood-brain barrier transport vehicle improves brain biodistribution of a TREM2 antibody and enhances microglial metabolism via receptor clustering

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-11-23 | GSE200276 | GEO

ATV-TfR and ATV-CD98hc biodistribution in the mouse brain

Project description:ATV-TfR and ATV-CD98hc biodistribution in the mouse brain

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TREM2 regulates microglial cell activation in response to demyelination in vivo

Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. Two STAGE (6weeks 12 weeks),

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ATV-TfR and ATV-CD98hc biodistribution in the mouse brain

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Brain delivery and efficacy of a lysosomal enzyme using a blood-brain barrier transport vehicle

Project description:Brain delivery and efficacy of a lysosomal enzyme using a blood-brain barrier transport vehicle

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Brain delivery and efficacy of a lysosomal enzyme using a blood-brain barrier transport vehicle [RNA-seq]

Project description:The enzyme transport vehicle (ETV:IDS) is a lysosomal enzyme fused to iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II). ETV:IDS treatment significantly improved brain delivery of IDS in a preclinical model of disease, enabling enhanced distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a significant reduction in accumulated substrates in these CNS cell types and peripheral tissues, and in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuronal injury. These results highlight the therapeutic potential of the ETV approach as a new treatment paradigm for MPS II and for other CNS diseases more broadly.

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Cortical bulk RNA sequencing of the microglia specific TREM2 inducible mouse models

Project description:We performed brain bulk RNA-seq aiming to study how microglia TREM2-WT or TREM2-R47H expression affect the overall brain transcriptomic profiles. Using WGCNA gene network analysis, we found the presynaptic transmission pathway was dysregulated after TREM2-R47H expression, not TREM2-WT. This finding was consistent with the impaired presynaptic transmission detected by electrophysiological recording in TREM2-R47H expressing mice. In addition, dysregulated circadian pathways were also identified in TREM2-R47H mice, not in TREM2-WT mice. Altogether, our bulk RNA-seq results provide additional evidence at transcriptomics level that TREM2-R47H expression in microglia affects neuronal functions and brain networks.

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CD98hc is a target for brain delivery of biotherapeutics

Project description:Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TV^CD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATV^CD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATV^CD98hc that impact FcgR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TV^CD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

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Brain delivery and efficacy of a lysosomal enzyme using a blood-brain barrier transport vehicle [RNA-seq]

Project description:Brain delivery and efficacy of a lysosomal enzyme using a blood-brain barrier transport vehicle [RNA-seq]

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Lack of TREM2 differentially affects the phenotype and transcriptome of mice expressing human APOE3 and APOE4

Project description:We aim to investigate the interaction between two of the major genetic risk factors for AD: inheritance of APOEε4 and deficiency of Triggering Receptor Expressed on Myeloid cells 2 (TREM2). Trem2 deletion worsened memory in AD model mice but not in their WT littermates. Interestingly, the lack Trem2 resulted in a significantly less microglia around amyloid plaques in APP mice expressing both APOE isoforms but had no impact on amyloid load. Gene expression analysis identified as Trem2 signature a cluster of highly connected immune response genes, commonly downregulated as a result of Trem2 deletion in all experimental groups, such as Clec7a, Itgax, Cts7, Mpeg1, Csf1r, Cx3cr1, Pik3cg and Spi1/PU.1. In vitro experiments with primary microglia demonstrated a decrease of Aβ phagocytosis in APOE4 versus APOE3 microglia a difference that was augmented by the absence of Trem2. Our data demonstrate that the lack of Trem2 differentially impact the phenotype and brain transcriptome of APP mice expressing human APOE isoforms probably reflecting the difference between APOE isoforms to transport lipids that can affect APOE receptor-binding properties.

2020-07-09 | GSE144125 | GEO

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