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#apaperaday: Oligonucleotide Enhancing Compound Increases Tricyclo-DNA Mediated Exon-Skipping Efficacy in the Mdx Mouse Model

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Oligonucleotide Enhancing Compound Increases Tricyclo-DNA Mediated Exon-Skipping Efficacy in the Mdx Mouse Model

Today’s paper is on oligonucleotides by Bizot et al on endosomal escape enhancers for exon skipping antisense oligonucleotides by Bizot et al from Goyenvalle published in Cells. Doi 10.3390/cells12050702.

Exon skipping oligonucleotides have been approved for Duchenne. However there is room for improvement. Authors improve efficiency using a different chemistry: the tryciclo DNA (tcDNA) linked to a palmitic acid group for increased delivery. However these and all other oligonucleotides suffer from endosomal entrapment. Authors here test a combination of tcDNA targeting mouse exon 23 of dystrophin in the mdx model with UNC7938, an enhancer of escape from late lysosomes.

First they treated the animal with 15 mg/kg IV in a single injection and analyzed it a day later. With UNC they saw slightly more skip and slightly more dystrophin in skeletal muscles and significantly more in heart. Then authors injected weekly for 4 weeks and analyzed at different time points (3 days, 1, 3 and 6 weeks). Now with UNC they saw more skip and dystrophin at week 1 and 3, but no more at week 6.

Authors discuss that perhaps after 6 weeks also mice without UNC will have increased release from oligonucleotides in the endosomes (depot). Authors saw increased oligonucleotide levels in nuclear fractions with UNC.

My speculation is that once oligonucleotides are free they will go to the nucleus and stay there for longer. Finally authors do a long term (12 week) study where they also assess heart function because increases are primarily seen in the heart.

Deficits between mdx and wild types are small but significant and treatment with oligonucleotide and UNC improved function while oligonucleotide alone (at higher dose with more frequent treatment) did not.

Treatment was well tolerated and did not affect liver and kidney function or histology. Authors discuss that while there is an immediate effect of increasing oligonucleotide and skipping and dystrophin, the effect dissipates with time probably due to the mentioned depot effect. Authors indicate the counterbalance of the depot effect may affect longevity of effects. More studies are needed to assess if this is the case. Nice work that shows why it is important to not only look at a single time point.