From molecular correction to functional rescue: delivery, tissue state, and immunobiology as the principal constraints on dystrophin-restoring therapy in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) arises from thousands of distinct mutations at a single X-linked locus that converge on loss of functional dystrophin, and this convergence on one molecular endpoint-rather than any genetic uniformity-has long made the disease appear a candidate for straightforward molecular correction. Three decades of work indicate that the difficulty lies less in restoring dystrophin than in restoring it adequately along four axes: amount, retained domains, breadth of coverage across skeletal muscle, diaphragm, heart and brain-the constraint being extent of coverage rather than correctness of sarcolemmal localization, which these platforms achieve reliably-and persistence in regenerating tissue. We argue that DMD is best understood as a systemic delivery problem superimposed on a progressive regenerative disorder, in which cargo design, biodistribution, cardiac coverage, immune response, disease stage and endpoint design jointly determine clinical benefit. AAV-microdystrophin has shown that body-wide expression is achievable, but delivers a truncated protein from an episomal genome at a dose whose upper bound was set by toxicity in other indications and whose minimum effective value was established in mdx mice rather than titrated in patients, leaving the therapeutic window better defined at its toxic than at its lower boundary. Exon skipping establishes that low-magnitude restoration is not trivial; genome editing addresses durability but adds integration risk; non-viral carriers permit redosing yet lack the potency required for a compartment comprising a third of body mass. Immunobiology constrains the field at several sequential levels, each now partially modifiable. Because the immunological burden of body-wide delivery can itself limit benefit, safety and efficacy are not fully separable, and progress is better judged by corrected muscle mass relative to immunological burden than by peak biopsy expression.