Towards therapies for muscular dystrophies : targeting TGF-beta and myostatin signalling to improve muscle quality and development of reliable outcome measures for preclinical mouse models

Abstract

The muscular dystrophies are a heterogeneous collection of

inherited and progressive myogenic disorders sharing similar clinical

“dystrophic” characteristics. Many therapies are currently being tested in

clinical trials and several of them achieved marketing authorisation. Additionally, many promising treatments are currently being tested in preclinical animal models. At a pathological level, patients show chronic inflammation and degeneration of muscle fibers, which eventually are replaced by adipose and fibrotic tissue leading to loss of muscle tissue and function. Targeting pathways involved in regulation of muscle regeneration and fibrosis can improve muscle quality and function. This would be beneficial for many patients with neuromuscular disorders, which share similar pathology. There is a great demand to accelerate the translation of potential new treatments from the bench to the clinic. Therefore, natural history studies and reliable outcome measures are required for preclinical mouse models improving study design and comparison between studies. To address the lack of a therapy targeting muscle pathology, the thesis focuses on evaluating therapeutic potential of antisense oligonucleotides inhibition of TGF-β and myostatin type I receptors and elucidating their function in muscles. Additionally, this thesis contains a natural history dataset that can be useful to design preclinical studies in dystrophic mouse models.