Utrophinbased

Utrophin-based refers to therapeutic approaches that use utrophin, a cytoskeletal protein closely related to dystrophin, to compensate for the loss of dystrophin in muscular dystrophies such as Duchenne muscular dystrophy (DMD). Utrophin is encoded by the UTRN gene and shares structural domains with dystrophin. In healthy adult muscle, utrophin expression is relatively low at the sarcolemma, but it is abundant during development and at neuromuscular and myotendinous junctions. In dystrophin-deficient muscle, upregulation or relocation of utrophin to the sarcolemma can help stabilize the dystrophin-glycoprotein complex and reduce membrane fragility.

Therapeutic strategies aim to enhance utrophin function or expression as a means to restore sarcolemmal integrity and improve muscle resilience. This can involve utrophin upregulation with small molecules or regulatory interventions, gene therapy to deliver utrophin or utrophin-like constructs, and gene-editing approaches to modulate regulatory networks that control utrophin expression. Preclinical studies, particularly in animal models of DMD, have shown that increased utrophin at the sarcolemma can ameliorate muscle pathology and improve function, supporting the potential of utrophin-based therapies as a dystrophin-sparing strategy.

Despite promise, several challenges remain. Utrophin cannot perfectly mimic all functions of dystrophin, and achieving appropriate, sustained expression at the sarcolemma without off-target effects is complex. Delivery methods, long-term safety, and the translational relevance of animal model results are ongoing areas of research. As of now, utrophin-based therapies remain investigational, with no approved treatments, but they continue to be explored as a complementary or alternative approach to dystrophin restoration in dystrophinopathies. See also Duchenne muscular dystrophy, dystrophin, and dystrophin-glycoprotein complex.