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A new antisense oligonucleotide therapy?

Current treatments for osteoarthritis (OA) can alleviate the symptoms of joint pain, but do not modify the course of disease. One strategy to overcome this therapeutic limitation is to target the underlying pathogenic mechanisms that degrade the cartilage. New research demonstrates that injection of miR-181a-5p antisense oligonucleotides might be a suitable therapeutic method to achieve this goal.

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“Three years ago, we conducted a screen for microRNAs in patients with varying degrees of spinal facet joint cartilage degeneration,” explains Mohit Kapoor, corresponding author of the new study. “Our results showed that miR-181a-5p has an active role in degenerating facet cartilage.”

In this follow-up work, Kapoor and his team tested locked nucleic acid antisense oligonucleotides that can target miR-181a-5p from mice, rats and humans. They show that these oligonucleotides limit expression of catabolic and apoptotic markers by murine and human cartilage cells in response to IL-1β and in cultured knee cartilage explants from patients with OA.

In support of these findings, the researchers show that intra-articular injection of the oligonucleotides can protect rats from cartilage degradation (measured by OARSI scores) in an OA model driven by needle puncture of the facet joint.

Similar results were obtained in mice using a different OA model, by surgical destabilization of the medial meniscus. In this model, reduction in cartilage destruction resulted from the oligonucleotides being injected into the joints 2 or 4 weeks after surgery to induce OA. This time frame might indicate that the effect of this method has therapeutic (not just prophylactic) potential.

“intra-articular injection of the oligonucleotides can protect rats from cartilage degradation”

“We are now conducting a series of studies to investigate the safety and best therapeutic dose, as well as optimal method for the local delivery of miR-181a-5p antisense oligonucleotides to the joints,” says Kapoor. “If the oligonucleotides prove to be safe and effective, this could be a potential OA disease modifying therapy and not just a symptom modifier,” he concludes.


Original article

  1. Nakamura, A. et al. microRNA-181a-5p antisense oligonucleotides attenuate osteoarthritis in facet and knee joints. Ann. Rheum. Dis. (2018)

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Correspondence to Nicholas J. Bernard.

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Bernard, N.J. A new antisense oligonucleotide therapy?. Nat Rev Rheumatol 14, 685 (2018).

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