Pipeline

A new therapeutic approach
for treatment of Myotonic Distrophy
Antagomir for unmet genetic diseases

Myotonic Dystrophy

Myotonic Dystrophy Type 1 (DM1) is a highly disabling multisystemic disease with no cure available. DM1 symptoms affect mainly the nervous, the cardiac, and the      musculoskeletal systems, although other alterations in other systems or organs have also been reported. The onset of symptoms occurs during adolescence in its most common form, and affected individuals have a significantly shortened lifespan.
ARTHEx proposes a new and novel therapeutic approach for the treatment of DM1. We propose to inhibit miRNAs repressing MBNL proteins to compensate for MBNL loss of function. This approach has been validated in different in vitro and in vivo models of the disease

What is DM1

DM1 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. It is 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 DM. The genetic 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 aggregate forming ribonuclear foci, the disease hallmark. Toxic RNA retains RNA-binding proteins MBNL, that are thus depleted from their regular cellular targets. Loss of function of MBNL proteins triggers gene misregulation events at the level of transcription, translation, gene silencing, alternative splicing, and polyadenylation of subsets of transcripts. There is ample evidence that MBNL functions are the limiting factors in DM1. Therefore, boosting their expression is a potential therapeutic avenue. Indeed, overexpression of MBNLbnl could rescue disease-associated RNA missplicing and muscle myotonia in a DM 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 DM such as reduced lifespan, heart conduction block, severe myotonia, and progressive muscle weakness

Unfortunately, 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)..