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Regulation of activated microglia and macrophages by systemically administered DNA/RNA heteroduplex oligonucleotides
Rieko Nishi1, Masaki Ohyagi1, Tetsuya Nagata1
1Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan; Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
Abstract:
Microglial activation followed by recruitment of blood-borne macrophages into the central nervous system (CNS) aggravates neuroinflammation. Specifically, in multiple sclerosis (MS) as well as in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, activated microglia and macrophages (Mg/Mφ) promote proinflammatory responses and expand demyelination in the CNS. However, a potent therapeutic approach through the systemic route for regulating their functions has not yet been developed. Here, we demonstrate that a systemically injected DNA/RNA heteroduplex oligonucleotide (HDO), composed of an antisense oligonucleotide (ASO) and its complementary RNA, conjugated to cholesterol (Chol-HDO) distributed more efficiently to demyelinating lesions of the spinal cord in EAE mice with significant gene silencing than the parent ASO. Importantly, systemic administration of Cd40-targeting Chol-HDO improved clinical signs of EAE with significant downregulation of Cd40 in Mg/Mφ. Furthermore, we successfully identify that macrophage scavenger receptor 1 (MSR1) is responsible for the uptake of Chol-HDO by Mg/Mφ of EAE mice. Overall, our findings demonstrate the therapeutic potency of systemically administered Chol-HDO to regulate activated Mg/Mφ in neuroinflammation.
Insights
Systemic administration of cholesterol-conjugated DNA/RNA heteroduplex oligonucleotides (Chol-HDO) effectively targets neuroinflammation in EAE mice. This novel therapy downregulates Cd40 in microglia and macrophages, improving clinical signs of multiple sclerosis.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglial activation and macrophage infiltration into the central nervous system (CNS) exacerbate neuroinflammation, particularly in conditions like multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE).
- Current therapeutic strategies for regulating these immune cells in the CNS via systemic administration are limited.
Purpose of the Study:
- To investigate the efficacy of systemically administered DNA/RNA heteroduplex oligonucleotides (HDOs) conjugated to cholesterol (Chol-HDO) for treating neuroinflammation.
- To assess the distribution, gene silencing capabilities, and therapeutic effects of Chol-HDO in the EAE mouse model.
Main Methods:
- Systemic injection of cholesterol-conjugated DNA/RNA heteroduplex oligonucleotides (Chol-HDO) targeting Cd40 in EAE mice.
- Evaluation of Chol-HDO distribution to spinal cord lesions and gene silencing efficacy compared to unconjugated antisense oligonucleotides (ASOs).
- Assessment of clinical EAE scores and quantification of Cd40 expression in microglia/macrophages (Mg/Mφ).
- Identification of the cellular uptake mechanism of Chol-HDO by Mg/Mφ.
Main Results:
- Chol-HDO demonstrated more efficient distribution to demyelinating lesions and superior gene silencing in EAE mice compared to parent ASOs.
- Systemic administration of Cd40-targeting Chol-HDO significantly improved clinical signs of EAE.
- Significant downregulation of Cd40 in microglia and macrophages (Mg/Mφ) was observed following Chol-HDO treatment.
- Macrophage scavenger receptor 1 (MSR1) was identified as the key receptor responsible for Chol-HDO uptake by Mg/Mφ.
Conclusions:
- Systemically administered Chol-HDO is a potent therapeutic agent for regulating activated microglia and macrophages in neuroinflammation.
- This approach offers a promising strategy for treating conditions like MS by targeting key inflammatory pathways within the CNS.
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