Modeling muscle regeneration in RNA toxicity mice

Abstract

RNA toxicity underlies the pathogenesis of disorders such as myotonic dystrophy (DM1). Muscular dystrophy is a key element of the pathology of DM1. The means by which RNA toxicity causes muscular dystrophy in DM1 is unclear. Here we have used the DM200 mouse model of RNA toxicity due to the expression of a mutant DMPK 3’UTR mRNA to model the effects of RNA toxicity on muscle regeneration. Using a BaCl2 induced damage model, we find that RNA toxicity leads to decreased expression of PAX7, and decreased numbers of satellite cells, the stem cells of adult skeletal muscle (also known as MuSCs). This is associated with a delay in regenerative response, a lack of muscle fiber maturation, and an inability to maintain a normal number of satellite cells. Repeated muscle damage also elicited key aspects of muscular dystrophy including fat droplet deposition and increased fibrosis and the results represent one of the first times to model these classic markers of dystrophic changes in the skeletal muscles of a mouse model of RNA toxicity. Using a ligand conjugated antisense oligonucleotide (LICA) ASO targeting DMPK sequences for the first time in a mouse model of RNA toxicity in DM1, we find that treatment with IONIS 877864, which targets the DMPK 3’UTR mRNA, is efficacious in correcting the defects in regenerative response and the reductions in satellite cell numbers caused by RNA toxicity. These results demonstrate the possibilities for therapeutic interventions to mitigate the muscular dystrophy associated with RNA toxicity in DM1.

RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing

“…These proteins are involved in the processing and localization of RNA, particularly for contractile protein synthesis. Furthermore, this accumulation of RNA alters the splicing process, as it also sequesters cleavage and splicing factors, such as hnRNPs and snRNPs, strengthening the hypothesis that the dystrophic phenotype of patients with DM1 may result from a more general alteration of the pre-mRNA post-transcriptional processing [ 28 ].…”

Molecular Mechanisms in Pentanucleotide Repeat Diseases

“…ASOs have shown encouraging results for several neurodegenerative and neuromuscular disorders [ 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 ]. In preclinical studies, non-allele specific ASOs acting by RNase-H degradation have been successful for SCA1 [ 171 ], SCA3 [ 173 , 174 ], SCA7 [ 177 ] and DM1 [ 178 ].…”

“…ASOs have shown encouraging results for several neurodegenerative and neuromuscular disorders [ 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 ]. In preclinical studies, non-allele specific ASOs acting by RNase-H degradation have been successful for SCA1 [ 171 ], SCA3 [ 173 , 174 ], SCA7 [ 177 ] and DM1 [ 178 ]. In addition, ASOs leading to polyQ exon skipping [ 175 , 176 ], namely combining two ASOs for ATXN3 exon 9 and 10 skipping, have shown therapeutic value in SCA3 [ 176 ].…”

Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1

“…We noted that subcutaneous injection of 25 mg/kg of IONIS 486178 conjugated to a C16 palmitic acid via an HA linker (IONIS-877864) in DMSXL mice results in a 90% reduction in human DMPK mRNAs in muscles compared to about 60% for the same dose of the unconjugated ASO [ 64 ]. Yadava et al investigated the effect of IONIS-877864 on muscle regeneration by inducing muscle damage with BaCl 2 in DM200 mice [ 103 ]. DM200 mice induced to express the CUG-expanded transgene featured impaired muscle regeneration and decreased muscle fiber maturation following muscle injury.…”