CureDuchenne’s chief scientific advisor, Dr. Mike Kelly reviewed the recent paper by Annemieke Aartsma-Rus and other researchers. This is complicated but very important science, we attempt here to explain the findings.
The most advanced drugs in clinical development for the treatment of Duchenne (the exon-skipping drug candidates’ drisapersen and eteplirsen as well as the stop-codon read through drug candidate ataluren) target and repair the faulty mRNA of the protein dystrophin.
Understanding the factors that influence the amount of protein transcript is therefore important, and this paper examines the correlation between transcript levels and protein levels in mice and patients.
The authors report that the amount of dystrophin protein and the dystrophin transcript (mRNA) in the heart of wild-type mice was greater relative to other muscles (although in certain cases the difference was small and non-significant). Interestingly, the transcript level was also greater in the heart of mdx mice relative to other muscles, but overall, the levels of transcript were surprisingly comparable between both the mdx and wild-type control mice.
These results suggest that the levels of transcript are not constant across the gene and that certain factors involved in the transcriptional process of the DMD gene might be differentially represented or differentially activated or repressed among different muscle groups.
A 5’-3’ imbalance in the transcript was demonstrated in both wild-type and mdx mice; transcript levels at the 5’-end of the gene were significantly higher than those observed at the 3’-end in mdx mice (a much smaller difference was observed in wild-type mice). A similar result was seen in patients with Becker muscular dystrophy, were the transcript was shown to be significantly less stable than that observed in muscle transcripts from a healthy control.
The effect of transcript imbalance on the quantification of exon-skipping was examined in mice, where a significant correlation was observed between the dystrophin protein levels produced and the transcript imbalance rather than the absolute level of transcript; i.e. the efficiency of exon-skipping is more closely related to the amount of transcript that is complete, rather than the total amount of transcript present.
More work is needed to better understand transcript imbalance as it relates to dystrophin protein production using exon-skipping. This work sets the stage for further studies that may provide more insight into transcript imbalance and the factors that influence the production of a full transcript in different muscles.