About the PhD thesis

MicroRNAs are a heterogeneous class of non-coding RNAs that exert posttranscriptional control of gene expression under both physiological and
pathological conditions. Through their ability to coordinately regulate extensive gene networks, microRNAs can modulate entire signaling pathways, making them attractive therapeutic targets for complex disorders such as metabolic and neuromuscular diseases. MicroRNA-22 (miR-22) is an evolutionarily conserved microRNA highly expressed in metabolically active tissues and implicated in the homeostatic control of energy metabolism, cell proliferation, and differentiation.

Building on prior genetic loss-of-function evidence from obesity models, the
PhD project allowed to develop and characterize a potent antisense oligonucleotide achieving robust and sustained silencing of miR-22-3p in vivo and evaluate its efficacy in preclinical murine models of obesity through clinically relevant weight-loss paradigms. Anti–miR-22 therapy induced durable weight loss, significantly reducing weight regain following diet-induced weight reduction by limiting fat mass expansion while preserving lean mass. Hepatic transcriptional profiling revealed suppression of lipid biosynthetic programs alongside activation of pathways governing mitochondrial biogenesis and metabolic homeostasis. Notably, miR-22 inhibition also enhanced myogenic differentiation and development programs in skeletal muscle, suggesting counteracting obesity-associated muscle wasting.

Therapeutic investigation of the anti–miR-22 therapy in a murine model of
progressive degenerative neuromuscular disorder, Duchenne muscular dystrophy, highlighted improvements in motor performance and muscle strength by promoting a fatigue-resistant oxidative phenotype and enhancing the autophagy in myocytes.

Collectively, this PhD project demonstrated that miR-22 inhibition exerts
broad therapeutic benefits across distinct multi-pathway diseases, supporting its potential as a versatile complementary intervention alongside existing therapies to improve clinical outcomes in obesity and neuromuscular disorders.