Modulating a type of microRNA that is involved with macrophage function—promoting tissue repair and regeneration in multiple sclerosis (MS) in the process—is possible with an oligonucleotide packaged in a nanoparticle carrier, researchers said in a session at MS Virtual 2020, the joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the European Committee for Treatment and Research in Multiple Sclerosis.
The approach, they said, could act as a kind of rudder that could steer macrophages' effects once they infiltrate peripheral immune cells. In MS, macrophages are either in the pro-inflammatory or M1 state or a state with a key role in tissue repair and regeneration, the M2 state.
"MiR-15 inhibition can be achieved through delivery of an anti-mRNA oligonucleotide [AMO]," said Frances K. Nally, a second-year PhD candidate at the RCSI University of Medicine and Health Sciences in Ireland.
Researchers previously found that inhibition of miR-155 by interleukin-10 is an important mechanism for macrophages to stay in the repair and regeneration state. A model in which miR-155 was deleted from myeloid cells brought about reduced disease onset and a lower burden of disease in an animal model of experimental autoimmune encephalomyelitis.
They proposed that like the mediating effect of IL-10, inhibition of miR-155 could potentially modulate the macrophage population to an 'M2' or pro-repair phenotype, reducing inflammation and alleviating disease progression.
Researchers investigated four anti-miRNA oligonucleotides for their ability to inhibit miR-155 in raw murine macrophage cells and bone marrow-derived macrophages. They looked at the downstream effect of macrophages' pro-inflammatory function in response to miR-155 inhibition by looking at pro-inflammatory cytokine production and M2 state markers.
Locked nucleic acid-modified anti-mRNA oligonucleotides performed the best for inhibiting miR-155 in the macrophage samples. In these structures, a "bridge" of methylene connects two atoms, resulting in a more rigid formation, Nally explained.
In further studies, the researchers said, they saw changes in the expression of miR-155 target genes that were similar to the phenotype seen with IL-10 mediation.
Nally acknowledged that effects seen in a dish are one thing, but that it is a "very different problem when trying to bring this in vivo."
A star-shaped polypeptide, Nally said, holds promise for being a delivery vehicle for the AMO, she said. Researchers found they are well-tolerated in bone marrow-derived macrophages.
"Future work will test these Star-AMO-155 polyplexes as a delivery system in vivo," she said.
In a question-and-answer discussion, session moderator Thomas Korn, MD, professor of experimental neuroimmunology at the Technical University of Munich, raised questions about the approach that might be worth exploring further. He said that while the data showed an increase in arginase 1, a marker of the anti-inflammatory macrophage state, there was also a strong drop off in inducible nitric oxide synthase (iNOS), which is a key player in the macrophage inflammatory response.
"Is this an indirect effect?" Dr. Korn asked. "How do you explain this? Is this because the macrophages change the phenotype, and then you have less iNOS expression?"
Nally said her team proposes that it is more an indirect effect of miR-155 on transcription factors, but they haven't deeply explored that question yet. She added that much more research will be needed to explore the therapeutic potential of this approach.
Nally and Dr. Korn had no relevant disclosures.
Link Up for Related Information
MS Virtual 2020 Abstract PS02.05: Nally F, Lyons V, De Santi C, et al. Nanomodulation of microRNAs in macrophages.
Nally FK, De Santi C, McCoy CE. Nanomodulation of macrophages in multiple sclerosis.Cells 2019;8(6):543.