Novel Therapeutic Target Identified for Multiple Sclerosis

Blue 3D rendering of microRNA strands

In the fast-growing field of RNA medicine, a topic of keen interest is how microRNAs (miRNAs) affect T cell development and function in a variety of diseases. MiRNAs are a class of noncoding RNAs that regulate gene expression by enhancing the degradation of messenger RNA or inhibiting its translation.

Researchers at Brigham and Women’s Hospital previously identified miR-92a as one of the miRNAs most significantly increased in patients with multiple sclerosis (MS). In fact, in Neurology: Neuroimmunology & Neuroinflammation, they noted that miR-92a levels were positively correlated with scores on the Extended Disability Standard Scale.

Fellow Mai Fujiwara, PhD, of the Ann Romney Center for Neurologic Diseases, Murugaiyan Gopal, PhD, an associate scientist at the center and a principal investigator of the study, Radhika Raheja, PhD, former fellow at the Brigham, and colleagues have now affirmed miR-92a as a powerful, clinically relevant target in MS. In the Journal of Clinical Investigation, they give preliminary information about the effects of pharmacologically inhibiting miR-92a in central nervous system (CNS) autoimmune disease.

Background

In healthy people, naïve CD4+ T cells differentiate into regulatory T cells (Tregs) and inflammatory T helper (Th) cells such as Th1 and Th17. The balance is kept in check by complex networks of cytokines and transcription factors.

In people with MS and other autoimmune diseases, Tregs become dysfunctional when exposed to an inflammatory cytokine microenvironment. They convert into pathogenic Th1-like or Th17-like cells, leading to unchecked tissue inflammation.

As detailed below, the new study is exciting because inhibition of miR-92a restored Treg/Th17 equilibrium. In mice and in human cells, the therapy simultaneously promoted Treg responses while limiting pathogenic T cell responses.

Disease-promoting Role of miR-92a

The researchers began with several key observations about miR-92 in experimental autoimmune encephalomyelitis (EAE), a well-defined animal model of MS:

  • Key role in CNS autoimmunity—miR-92a was elevated in wild-type mice when EAE was induced. Mice bred to lack miR-92a had less severe EAE associated with reduced Th1 and Th17 cells and increased Tregs
  • Targeting of Foxo1—miR-92a directly targeted Foxo1, a transcription factor that’s indispensable to Treg and Th17 cell development and function. miR-92a thereby enhanced Th17 differentiation while impairing the differentiation and suppressive function of Tregs, promoting CNS autoimmunity
  • Effect on Th1 cells—miR-92a loss itself did not directly alter Th1 differentiation, but it appeared to indirectly promote Th1 cells by inhibiting Treg responses, another way of sustaining autoimmunity

Results of miR-92a Silencing

The research team investigated the therapeutic potential of miR-92a inhibition:

  • Administering a synthetic miR-92a inhibitor to mice with EAE reversed their Treg/Th17 imbalance without apparent toxicity
  • Treatment with an miR-92a inhibitor promoted Treg induction and impaired Th17 differentiation in CD4+ T cells from mice and those from healthy control subjects and patients with MS

Translational Outlook

Secukinumab, a monoclonal antibody that targets interleukin-17 produced by Th17 cells, has not shown promise against MS in clinical trials. miR-92a inhibition may have an advantage because it’s a two-pronged approach: it addresses not just the inflammatory arm of the immune system but also the Treg dysfunction.

miR-92a has been shown to be a key regulator of the growth of new blood vessels. According to a meeting report from the Oligonucleotide Therapeutics Society, a single dose of a miR-92a inhibitor known as MRG-110 was safe and well-tolerated by healthy volunteers in a phase I clinical trial on its wound-healing capabilities.

Another study, reported in Nucleic Acid Therapeutics, showed infusion of MRG-110 silenced miR-92a expression in the peripheral blood compartment of healthy individuals. Both of these reports suggest miR-92a inhibition could be feasibly tested in patients with MS.

Leave a Reply