Combined Treatment with Peptide-Conjugated Phosphorodiamidate Morpholino Oligomer-PPMO and AAV-U7 Rescues the Severe DMD Phenotype in Mice
Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by an absence of the dystrophin protein, which is essential for muscle fiber integrity. Among the
developed therapeutic strategies for DMD, the exon-skipping
approach corrects the frameshift and partially restores dystrophin expression. It could be achieved through the use of antisense sequences, such as peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) or the small nuclear
RNA-U7 carried by an adeno-associated virus (AAV) vector.
AAV-based gene therapy approaches have potential for use in
DMD treatment but are subject to a major limitation: loss of
the AAV genome, necessitating readministration of the vector,
which is not currently possible, due to the immunogenicity of
the capsid. The PPMO approach requires repeated administrations and results in only weak cardiac dystrophin expression.
Here, we evaluated a combination of PPMO- and AAV-based
therapy in a mouse model of severe DMD. Striking benefits
of this combined therapy were observed in striated muscles,
with marked improvements in heart and diaphragm structure
and function, with unrivalled extent of survival, opening novel
therapeutic perspectives for patients.