Abstract
This review recollects my initial research focus on revertant fibers (expressing dystrophin in the background of frame-shifting mutation) in Duchenne muscular dystrophy (DMD) muscles in Professor Terrence Partridge's Muscle Cell Biology Laboratory in MRC Clinical Research Science Center, Harmmersmith Hospital, London, UK. Our data indicated that revertant fibers are most likely resulted from epigenetic random events which skip exon(s) flanking the mutated exon, leading to the restoration of the reading frame. Some of these events establish themselves as relatively permanent skipping patterns, a mechanism similar to multiple transcript species established in various cell types. With this hypothesis, antisense oligonucleotide-mediated exon skipping is likely to have a great chance to achieve restoration of therapeutic levels of dystrophin in DMD muscles. This leads to our first reports of local and systemic efficacy of antisense oligonucleotide-mediated exon skipping for DMD treatment. The experience under Terry's mentorship shaped my thinking and led me to explore another revertant feature in the dystroglycanopathy caused by mutations in the Fukutin Related Protein (FKRP) gene which functions as a glycosyltransferase. Mutant FKRPs retain partial function and produce a fraction of normal to no detectable levels of laminin-binding α-dystroglycan (matriglycan) in most of the muscle fibers. Reversion to near normal levels of matriglycan expression in muscles with FKRP mutations depends on muscle regeneration and in muscles of neonate mice, suggesting that changes in metabolism and gene expression could be sufficient to compensate for the reduced function of mutant FKRP genes even those associated with severe congenital muscular dystrophy (CMD). This is now supported by our successful demonstration that supply of FKRP mutant mice with ribitol, a precursor for substrate of FKRP, is sufficient to restore the levels of matriglycan with therapeutic significance. Our data overall suggest that rare events of reversion in muscular dystrophy, and likely other diseases could provide unique insight for mechanisms and therapeutic exploitation.