Towards therapies for muscular dystrophies associated with the dystrophin-glycoprotein complex

Abstract

The focus of this thesis is on therapeutic efforts that are being made for muscular dystrophies associated with the dystrophin-glycoprotein complex to restore the primary defect, or therapies which focus on delaying, limiting, or ameliorating the pathology associated with the disease progression. Chapter 1 provides an introduction. In Chapter 2, the efficacy of chemically modified antisense oligonucleotides targeting exon 53 of the human DMD gene in the hDMDdel52/mdx mouse model was studied. Chapters 3 and 4 focus on different approaches for the inhibition of myostatin signaling. Chapter 3 describes a proof-of-concept study to assess the delivery of chemically modified, conjugated siRNAs to dystrophic muscle and their ability to downregulate Alk4 transcript, which encodes for a key component in the myostatin signaling pathway. In Chapter 4, the effects of myostatin inhibition with soluble ActRIIB treatment on muscle pathology was assessed in Sgca-null mice, whereby treatment was either initiated prior to the development of the disease, or when the muscle pathology was already advanced. In Chapter 5, the potential benefit of branched chain amino acid supplementation, and its safety in combination with corticosteroid treatment, was assessed in mdx and D2-mdx mice. Chapter 6 discusses and summarizes the results of the different chapters.