Duchenne muscular dystrophy (DMD) is a lethal genetic disorder that shortens patients’ lifespans and results in progressive skeletal and cardiac muscle degeneration. The symptoms emerge at the onset of muscle growth in boys 2-5 years old. They grow up bound to wheelchairs and ventilators, and eventually succumb to an early death after cardiac failure (2). Two decades in the making, a new therapy called antisense oligonucleotide (AON) mediated exon skipping was recently approved by the FDA (1, 3). The workings of this therapy, at first glance, seem slightly discordant. The therapy removes additional exons beyond ones already deleted or mutated in the patients’ genes. But this counterintuitive procedure is part of what makes exon skipping so potent against DMD: it deletes a fragment of the gene to preserve the whole.
DMD arises from a mutation in dystrophin, the largest gene of the human genome. This gene codes for the protein dystrophin, a part of a protein complex responsible for protecting active skeletal and cardiac muscles from strain (2). It has two domains on each end of its rod-like form which connect key components of the cytoskeleton and extracellular matrix of muscle cells together (1, 2). In DMD patients, the dystrophin protein is altered due to the effects of a frameshift mutation in their genetic code. A frameshift mutation is a result of a nucleotide deletion or insertion in a gene sequence leading to a disrupted reading frame where anything beyond the site of mutation is made nonfunctional. The truncated form of dystrophin is unable to perform its linking function and the muscle plasma membrane becomes susceptible to mechanical stress. Because of this, muscles undergo increased fibrogenesis, or “replacement of muscle tissue with fibrous and fatty acids,” which leads to progressive muscular degeneration in DMD patients.
The recently approved exon skipping therapy, Eteplirsen, targets exon 51 of the dystrophin gene using antisense oligoribonucleotides, or AONs. AONs are strands of RNA complementary to a known exon that is hindering formation of a functional dystrophin. AONs can anneal to this exon and obscure it from splicing machinery so that it can be excised along with surrounding introns (3). Once the target exon is removed, the reading frame shifts back in-frame to form a “more stable and partially functional dystrophin,” which produces symptoms of the far milder Becker muscular dystrophy (BMD) (2). Specifically, Eteplirsen uses Phosphorodiamidate morpholino oligomers (PMOs), a type of AON targeting exon 51. In clinical trials using intravenous doses of Eteplirsen, patients “appeared to have a slower disease progression than matched untreated natural history controls.” These studies show that Eteplirsen has the potential to alleviate symptoms of 13-14% of DMD patients (1).
By harnessing the splicing machinery of the cell and restoring the dystrophin reading frame, more functional dystrophin can be regenerated and the debilitating effects of DMD can be mitigated (1, 3). The challenge moving forward is to find ways to tailor these exon skipping therapies for patient subgroups with differing sizes and locations of the dystrophin mutation. AONs for the variety of mutations in patients will still need to be developed individually, presenting challenges in widespread use of AONs for all DMD patients (1). Unfortunately, this therapy does not work for approximately 20% of DMD patients that have lesions in essential sections of the dystrophin gene, namely the functional domains on the ends (2, 3). For these 20% of patients, no matter if the reading frame is restored, there would still be deletions present in the gene that would confer the DMD phenotype (1). The focus of researchers in the future would most likely be to explore regions known to have high incidences of mutation in DMD patients that are not located in functional domains. For now, this counterintuitive approach of deleting a fragment to preserve the whole seems to work: Eteplirsen and other experimental exon skipping therapies may be the new hope for DMD patients.