So far, clinical and basic research studies have contributed to clarify the most important aspects concerning the pathogenesis of myotonic dystrophy type 1 (DM1) and type 2 (DM2). These studies have highlighted the “toxic” effect of ubiquitously expressed, mutant pre-mRNAs harboring abnormally expanded CUG (DM1) or CCUG (DM2) sequences, which would cause their nuclear accumulation and eventually lead to the aberrant alternative splicing of other genes.
Such discoveries have offered a rationale for a “gene therapy” in myotonic dystrophies through antisense oligonucleotides targeting the removal of the toxic CUG- (or CCUG-) RNAs. Such an approach, successfully tested on animal models of DM1, has shown problems concerning adequate intratissue delivery of the oligos in the first human clinical trial. This issue, however, is particularly relevant in myotonic dystrophies, whose multisystem involvement requires delivery of antisense oligonucleotides to the various affected tissues.
On the other hand, besides RNA toxicity, other molecular mechanisms could contribute to the pathogenesis of myotonic dystrophies, possibly explaining some phenotypic differences occurring between DM1 and DM2.
The assessment of clinical therapeutic trials in myotonic dystrophies is further complicated by the poor definition of their natural history and the slow muscle disease progression. Indeed, various diagnostic tools validated as outcome measures of muscle disease severity did not result reliable in detecting significant muscle disease progression in DM1 patients, within the time span of a therapeutic trial.
Aiming to elucidate these important topics, an article collection will be launched for research papers focusing in particular on:
- Assessment of the pathophysiology, of comprehensive diagnostic protocols and/or of biomarkers related to specific clinical manifestations in DM1 and DM2;
- Validation of reliable outcome measures of disease severity for future clinical trials in DM1 or DM2; and
- Evaluation of novel treatments, including either gene-based or pharmacological therapies, tested either on cellular or animal models, and in human clinical trials.
So far, clinical and basic research studies have contributed to clarify the most important aspects concerning the pathogenesis of myotonic dystrophy type 1 (DM1) and type 2 (DM2). These studies have highlighted the “toxic” effect of ubiquitously expressed, mutant pre-mRNAs harboring abnormally expanded CUG (DM1) or CCUG (DM2) sequences, which would cause their nuclear accumulation and eventually lead to the aberrant alternative splicing of other genes.
Such discoveries have offered a rationale for a “gene therapy” in myotonic dystrophies through antisense oligonucleotides targeting the removal of the toxic CUG- (or CCUG-) RNAs. Such an approach, successfully tested on animal models of DM1, has shown problems concerning adequate intratissue delivery of the oligos in the first human clinical trial. This issue, however, is particularly relevant in myotonic dystrophies, whose multisystem involvement requires delivery of antisense oligonucleotides to the various affected tissues.
On the other hand, besides RNA toxicity, other molecular mechanisms could contribute to the pathogenesis of myotonic dystrophies, possibly explaining some phenotypic differences occurring between DM1 and DM2.
The assessment of clinical therapeutic trials in myotonic dystrophies is further complicated by the poor definition of their natural history and the slow muscle disease progression. Indeed, various diagnostic tools validated as outcome measures of muscle disease severity did not result reliable in detecting significant muscle disease progression in DM1 patients, within the time span of a therapeutic trial.
Aiming to elucidate these important topics, an article collection will be launched for research papers focusing in particular on:
- Assessment of the pathophysiology, of comprehensive diagnostic protocols and/or of biomarkers related to specific clinical manifestations in DM1 and DM2;
- Validation of reliable outcome measures of disease severity for future clinical trials in DM1 or DM2; and
- Evaluation of novel treatments, including either gene-based or pharmacological therapies, tested either on cellular or animal models, and in human clinical trials.
