Gene therapy stops, and may reverse, muscular dystophy in mice

A gene therapy for Duchenne muscular dystrophy (DMD) has halted the muscle decline associated with the condition in mice, and has also shown promise at repairing the muscles.

DMD is a genetic condition caused by a mutation in the gene that encodes dystrophin, meaning the protein it encodes is not produced. The dystrophin protein has a critical role in the structure and function of muscles, with mutations in the dystrophin gene leading to progressive muscle fibre degeneration and weakness. Gene therapy aims to replace a faulty gene with a healthy gene, however, the full-length dystrophin gene – the longest in the human genome – cannot be delivered into cells due to its size.

'It's like ordering a king-sized bed that won't fit through your front door, so we broke it up into smaller pieces and it assembles all by itself,' said Professor Jeffery Chamberlain from the University of Washington School of Medicine in Seattle, senior author of the study published in Nature.

The researchers designed a novel delivery system, using a series of adeno-associated virus (AAV) vectors to shuttle parts of the dystrophin gene into muscle cells along with instructions for the fragments to reassemble once inside the cells. The reconstructed gene is then able to produce a functional, full-length protein. The virus used as a vector is altered so that it does not cause diseases in the recipient.

DMD predominantly affects males as dystrophin is located on the X chromosome, with patients exhibiting symptoms around the age of three. Eventually, the condition impacts muscles involved in the functioning of the heart and lungs. DMD currently has no cure, with current drugs only slowing the progression of the disease and patients having a life expectancy of around 20 or 30 years.

Other gene therapies for DMD have focused on the delivery of a shortened version of dystrophin into cells. Elevidys received accelerated FDA approval in 2023 (see BioNews 1196) but the therapy has not met its primary endpoint of significantly improving motor function. Similarly, CIFFREO was reported to have not met primary or secondary endpoints in a Phase 3 clinical trial (see BioNews 1244).

'Gene replacement methods using AAVs have been challenging for DMD and some other disorders due in part to a modest carrying capacity and the need for very high doses,' the study's authors explained in their paper. 'In this study, we demonstrated the feasibility of expressing large genes by splitting the coding sequence into two or three parts transportable by AAVs, which are then efficiently reconstituted into a large functional protein.'

While this novel therapy has proven successful in mouse models, human trials are not yet underway and are set to begin in two years' time. The hope from authors of this study is that their method may lead to the reversal of muscle wasting seen in patients with DMD, and restore healthy muscle tissue.

CRISPR-based genome editing techniques are also currently in development by other research teams, having shown the restoration of functional dystrophin production in mice (see BioNews 1093).