Overview MicroRNA Therapies

MicroRNAs (miRNAs) are as the name suggests are very small double-stranded RNA (22-24 nucleotides) molecules that regulate the cellular pathways by preventing the messenger RNAs they target being translated into proteins.  There approximately 2300 different miRNA species expressed in humans, each of which is capable of regulating hundreds of other genes, fine-tuning the expression of biological pathways in health and disease. Dysregulation of miRNA expression, either too much or too little, can have a profound impact on health. Such alterations in miRNA expression play causative roles in the development of many human diseases including cancers, cardiovascular, dementia, diabetes, fibrosis and ageing.

MicroRNA therapies have almost limitless therapeutic potential

Restoring miRNA levels in diseased, damaged or old cells, kick-starts cellular repair processes leading to tissue regeneration. Synthetic MicroRNAs can be readily synthesised at scales from micrograms to kilograms using solid-state chemistry. While the active molecules themselves share the same sequence as the endogenous molecules, they are chemically modified to enhance activity, stability and cellular uptake. Where increased miRNA expression causes disease, inhibitors can be created to block their activity.

Delivery is Key

Delivery is the main barrier to the therapeutic use of miRNA targeting technology. Currently, the liver is the only organ that oligonucleotide therapies can be reliably delivered. However, a notable exception to this is local delivery where injecting miRNA therapies directly to target tissues overcomes this issue. Local delivery has many benefits compared to systemically delivered treatments:

  • Reduced dose 
  • Limited systemic uptake (only the cells that need the drug receive it)
  • Improved safety
  • Reduced cost of goods

 Many MSK diseases, e.g. tendinopathy, OA and lower back pain, are local diseases that are easily accessed using injection, making them ideally suited for treatment with miRNA therapies. 

Example miR-29a replacement therapy for tendinopathy

Tendinopathy is the medical name for diseases associated with overuse and injury of the tendon.  The main physiological features of tendinopathy are the over-production of collagen 3, increased vascularisation, hyperproliferation of tendon cells (tenocytes) and adhesion formation. Clinically this manifests as weakened tendons that are prone to re-injury, inflammation and pain.  In 2014, Causeway’s co-founders, Neal Millar and Derek Gilchrist discovered that the injury loss of a single type of miRNA: miR-29a was key to the activation of the disease pathways responsible for tendinopathy. Re-introduction of a chemically modified miR-29a mimic (TenoMiR) in mouse, equine in vivo and human tendon explant models, switched off these key disease pathways allowing tendons to regenerate to their normal state (1).  

At the molecular level tendinopathy is indistinguishable between humans, mice and horses including the sequence of miR-29a itself, suggesting the effectiveness of TenoMiR observed in animal models is likely to be reproduced in humans. A human clinical trial designed to test TenoMiR’s safety and efficacy in patients with Lateral epicondylitis (Tennis Elbow) is currently underway. 
(1) Millar et al., 2014,  Nature Comms (6) 1-12,