Therapeutic Effects of Mir-145-5p Antagonism in a Mouse Model of Multiple Sclerosis
Year Awarded: 2020
Term: 3 years
Funding Amount: $366,600
Affiliation(s): Ottawa Hospital Research Institute
Researcher(s): Dr. Rashmi Kothary
Impact Goal(s): Understand and Halt Disease Progression
Background: Multiple Sclerosis (MS) is a disease in which the insulation around the nerve fibres, known as myelin, becomes damaged by the immune system. This damage can result in loss of muscle control and partial paralysis. Oligodendrocytes are a specialized cell type that produce myelin sheaths around nerve fibres. Oligodendrocytes need to undergo elaborate shape changes prior to being able to wrap membranes around nerve fibres. The ability of oligodendrocytes to repair damaged myelin diminishes over time, partly due to the presence of inhibitory factors at MS lesion sites, and thus severity of the condition increases. It is therefore critical that approaches that enhance remyelination (or repair) are identified.
Overview: This research hypothesizes that an orchestration of gene networks, rather than single genes, are critical to the progression of oligodendrocytes to becoming myelin-producing factories. Dr. Rashmi Kothary and team will investigate the impact of manipulating specific molecules called microRNAs that can regulate a specific set of genes implicated in the development of oligodendrocytes. Research has shown that the microRNA molecule, miR-145-5p, is increased in MS lesions. Prior work in mice with decreased miR-145-5p (a gene knockout) resulted in delayed disease onset, reduced clinical severity, and reduced duration of paralysis after induction of MS-like disease (EAE induction). This research will test whether acute antagonism of miR-145-5p has therapeutic benefit in a mouse model of MS. The researchers hypothesize that transient inhibition of miR-145-5p molecules during onset of disease in the mouse model with MS-like disease (EAE) will result in reduced severity of disease. The researchers will induce EAE in mice, treat them with miR-145-5p antisense oligonucleotide at disease onset, which decreases miR145-5p. They will then determine whether this decreases expression of miR145-5p, and then evaluate disease progression, and examine the pathways altered in the central nervous system and lymphoid tissues.
Impact: This proposal will assess the therapeutic value of inhibiting one microRNA (miR-145-5p) and will determine if this has an impact on both central nervous system repair and immunomodulation. If transient inhibition of this microRNA improves disease outcomes, then it would open up the potential for testing such an approach for the treatment of MS in humans.