Insulin-like growth factor-1 and Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle-wasting disorder caused by the absence of dystrophin, leading to muscle degeneration, weakness, and loss of mobility. While genetic therapies aim to restore dystrophin, alternative strategies targeting secondary defects are crucial for improving muscle function and slowing disease progression. This thesis explores novel therapeutic approaches centered on the IGF-1 signaling pathway, which plays a key role in muscle growth and regeneration. Key strategies include downregulating IGF-binding proteins to enhance IGF-1 bioavailability, modifying alternative polyadenylation to increase IGF-1 levels, and modulating splicing to promote the MGF isoform, which supports muscle repair. These RNA-based approaches were tested in cellular and animal models, highlighting both their potential and the need for improved delivery methods. Additionally, a humanized DMD mouse model was characterized to enable preclinical testing of exon-skipping therapies aimed at restoring dystrophin expression. Despite challenges, these findings provide valuable insights into IGF-1-based therapeutic interventions that could benefit not only DMD patients but also individuals with other neuromuscular disorders.