Macrolides: a potential treatment for myotonic dystrophy type 1
Publication Date
July 27, 2026
Creator
Jammeh, Binta
Abstract
Myotonic dystrophy (DM) is the most prevalent adult muscular dystrophy. DM is categorised in two types: DM1 and DM2. DM1 is caused by expansion of the cysteine-thymidine-guanine (CTG)n repeat in the 3-prime-untranslated region of the dystrophy myotonia protein kinase (DMPK) gene. DMPK transcripts with extended CUG repeats accumulates in the nucleus, forming aggregates called foci, sequestering key RNA binding proteins. The repeat expansions can have numerous detrimental downstream effects on cells, including mis-splicing. Due to the complicated nature of DM, there is no current cure for the disorder.
Many experiments and therapeutic approaches have been explored to mitigate mutant CUGexp RNAs. Some experimental studies have utilised different approaches using existing drugs to develop further treatments for DM1, employing “drug repositioning” strategies, including using erythromycin (ERM) which are extensively used clinically to treat many chronic diseases, such as acute inflammatory and genitourinary tract infections.
For this project ERM was compared to azithromycin (AZM) to establish if AZM may be a better treatment option for DM. In human fibroblast cell-line derived from DM1 patient, the in-cell concentration of AZM and ERM was established at doses known to remove RNA foci aggregates. Following the cell culture experiment, we performed an in vivo study to assess drug concentrations in human skeletal actin long repeats (HSALR) DM1 mice model, looking at the brain, heart, muscle and plasma drug levels. Subsequently, reverse transcription polymerase chain reaction (RT-PCR) assay was conducted, to explore to the possibility of reversing aberrant splicing seen in DM1, targeting genes such as Atp2a1, Mbnl1, Clcn1 and Nfix, which function as robust biomarkers in DM1 pathology. We discovered that ERM concentrations in muscle and in heart were significantly lower than AZM. However, in tissue neither drug achieved the high levels of accumulation seen in cell culture. ERM at oral doses of 500mg/kg or AZM at 1g/kg, were not able to correct splicing deficits in the HSALR mouse model. However, a milder phenotype was detected in the HSALR mice than expected from the literature. Therefore, the lack of efficacy warrants further investigation, and may be a result of phenotypic drift in the mice used.
Item Type
ethesis
Thesis Type
MRes
Supervisors
School of Life Sciences
Subjects (LC)
Associated Schools / Departments
UoN Repository URI
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