BMN 351 is a clinical stage ASO therapeutic candidate for exon51 skipping amenable DMD patients. We have developed an exploratory biomarker to test the hypothesis that treatment with BMN 351 improves the quality and composition of patient muscle. This data may provide a more comprehensive biological view of the pharmacodynamic response in target tissue. Transcriptional changes are tractable with limited biopsy material using RNAseq and targeted ddPCR assays for cell-types and functional pathways of interest.
In the hDMDdel52/mdx mouse model of DMD, bulk RNAseq from skeletal muscle was generated and identified a comprehensive transcriptome-wide signature of disease that reverted towards normal with BMN 351 treatment. Genes from three biologically relevant pathways stood out as differentially expressed in the disease model compared with WT controls: muscle development, extracellular matrix, and adaptive immune response. Quantitative ddPCR assays were developed for select targets, and a composite score was developed for the ratio of predominantly myoblast-expressed to myofiber-expressed genes. The myoblast : myofiber index was elevated in un-treated DMD mice and was reduced toward WT controls with BMN 351 treatment, correlating with improved muscle function measured as gait score.
In a set of DMD and healthy control samples, a similar set of disease-associated transcripts were confirmed as differentially expressed in humans. The composite myoblast-expressed : myofiber-expressed transcript ratio was elevated in patients compared to controls, and reduced for most patients after 13 to 25 weeks of treatment with BMN 351 in an ongoing Phase 2 study. The results suggest near full-length dystrophin induced by BMN 351 treatment is having a positive effect on DMD muscle, altering gene expression in the direction of healthy controls. Ongoing transcriptional analysis will evaluate relationship with functional improvement in patients. Data from this exploratory biomarker provides complementary evidence of BMN 351 mechanism of action and benefit in target tissue.