Myotonic Dystrophy is a highly disabling multisystemic disease with no cure available. DM1 symptoms affect mainly the nervous system, the heart, and the musculoskeltal system, although other alterations in other systems or organs have also been reported. In its most common form, onset of symptoms occurs during adolescence and affected individuals have a significantly shortened lifespan of 48-55 years.
ARTHEx proposes a new and novel therapeutic approach for the treatment of DM1. In DM1, we propose to inhibit miRNAs repressing MBNL1/2, to compensate for MBNL loss of function. This approach has been validated in different animal models.
AntagomiR is used to silence endogenous microRNA
We discovered that microRNAs that repress MBNL1/2 expression are overexpressed in muscle biopsies of patients and in different animal models of the disease including human cells and muscles of the HSALR mouse model. Subcutaneous injections of anti-miRs (also know as antagomir) inhibiting these microRNAs in the mouse model, increased MBNL proteins expression and rescued muscle myotonia, strength, histopathology and other molecular manifestations of the disease (Cerro et al. 2018). The technology has been patented (PCT/EP2017/073685) and national phases will be applied in March 2019.
Figure 1 summarizes the mechanism of action for the product in development.
What is the DM
DM is an autosomal dominant rare genetic disease with variable presentation. It is the most common muscle dystrophy in adults and it is a highly disabling as it typically causes severe neuromuscular symptoms including cardiac conduction defects, myotonia, and progressive muscle weakness and wasting (atrophy). Neuropsychological dysfunction is also a common symptom of DM1. The cause of DM1 is well known, namely the accumulation of mutant transcripts containing expanded CUG repeats in the 3´UTR of the dystrophia myotonica protein kinase (DMPK) gene. CUG repeats form the disease’s hallmark ribonuclear foci. Toxic RNA retains RNA-binding proteins that are thus depleted from their normal cellular targets.
Chief among these are the Muscleblind-like proteins (MBNL1-3), whose sequestration contributes to DM1 in several ways. Thus, mutant DMPK RNA triggers toxic gene misregulation events at the level of transcription, translation, gene silencing, alternative splicing and polyadenylation of subsets of transcripts. MBNL1 controls fetal-to-adult splicing and polyadenylation transitions in muscle and MBNL2 likely has a similar role in the brain, whereas Mbnl3 deficit results in age-associated pathologies that are also observed in myotonic dystrophy. No treatment has yet been specifically developed for DM1 despite intensive efforts. These strategies include preventing MBNL protein sequestration using small molecules or using oligonucleotides to degrade or block the toxic RNA (Konieczny P. et al. 2017 and Overby S.J. et al. 2018).
There is ample evidence that MBNL1 and MBNL2 functions are the limiting factors in DM1. Therefore, boosting their expression is a potential therapeutic avenue. Indeed, overexpression of Mbnl1 could rescue disease-associated RNA missplicing and muscle myotonia in a DM1 mouse model that expresses 250 CTG repeat units from a human skeletal actin promoter (HSALR) (Kanadia et al. 2006). Consistently, compound loss of muscleblind-like function reproduces cardinal features of DM1 such as reduced lifespan, heart conduction block, severe myotonia, and progressive muscle weakness (Lee et al 2013).