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Published on: December 26, 2016
Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in
Lina Vandermeulen1, Ivana Geric2,3, Laura Fumagalli4,5
1Neuroscience Discovery, Janssen Research & Development, Janssen Pharmaceutica NV, 2340, Beerse, Belgium.
Background:
Microglia play important roles in maintaining brain homeostasis and neurodegeneration. The discovery of genetic variants in genes predominately or exclusively expressed in myeloid cells, such as Apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2), as the strongest risk factors for Alzheimer's disease (AD) highlights the importance of microglial biology in the brain. The sequence, structure and function of several microglial proteins are poorly conserved across species, which has hampered the development of strategies aiming to modulate the expression of specific microglial genes. One way to target APOE and TREM2 is to modulate their expression using antisense oligonucleotides (ASOs).
Methods:
In this study, we identified, produced, and tested novel, selective and potent ASOs for human APOE and TREM2. We used a combination of in vitro iPSC-microglia models, as well as microglial xenotransplanted mice to provide proof of activity in human microglial in vivo.
Results:
We proved their efficacy in human iPSC microglia in vitro, as well as their pharmacological activity in vivo in a xenografted microglia model. We demonstrate ASOs targeting human microglia can modify their transcriptional profile and their response to amyloid-β plaques in vivo in a model of AD.
Conclusions:
This study is the first proof-of-concept that human microglial can be modulated using ASOs in a dose-dependent manner to manipulate microglia phenotypes and response to neurodegeneration in vivo.
Insights
Antisense oligonucleotides (ASOs) offer a novel way to target microglial genes like Apolipoprotein E (APOE) and TREM2. This study demonstrates ASOs can effectively modulate human microglia in vitro and in vivo, impacting neurodegeneration models.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Microglia are crucial for brain homeostasis and neurodegeneration.
- Genetic variants in Apolipoprotein E (APOE) and Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are major Alzheimer's disease (AD) risk factors.
- Species-specific differences in microglial protein function hinder therapeutic development.
Purpose of the Study:
- To develop and validate novel antisense oligonucleotides (ASOs) targeting human APOE and TREM2.
- To demonstrate the efficacy of ASOs in modulating human microglial gene expression and function.
- To establish proof-of-concept for ASO-based therapeutic strategies in neurodegenerative diseases.
Main Methods:
- Identification, production, and in vitro testing of selective ASOs for human APOE and TREM2.
- Utilized human induced pluripotent stem cell (iPSC)-derived microglia models.
- Validated ASO activity in vivo using microglial xenotransplantation into mice.
Main Results:
- Confirmed ASO efficacy in human iPSC-microglia.
- Demonstrated pharmacological activity of ASOs in a xenografted microglia model.
- Showed that ASOs targeting human microglia can alter transcriptional profiles and amyloid-β plaque response in an AD model.
Conclusions:
- This study provides the first proof-of-concept for modulating human microglia using ASOs in vivo.
- ASO treatment allows for dose-dependent manipulation of microglial phenotypes.
- ASOs can effectively alter microglial responses to neurodegeneration, offering a potential therapeutic avenue.
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