A new gene therapy treatment for Duchenne muscular dystrophy show promise of arresting the decline of the muscles of those affected by this inherited genetic disease, and perhaps, in the future, repairing those muscles. The laboratory results not only show promise to treat patients with this severely debilitating and incurable disease, but the technological advancement researchers used to create it may facilitate the development of other therapies in the future.
The new method, which has had success on mouse models, was published in the 17 July 2024 issue of Nature. It uses a series of adeno-associated viral vectors or AAVs, which are tiny shuttles derived from a virus that is commonly used to deliver gene therapies into human cells. Instead of one AAV, this gene therapy uses a series of AAVs which take parts of the therapeutic protein inside the muscles, along with embedded instructions to begin assembling the necessary genetic fix once within the body. The added genetic code successfully produced dystrophin in mice, the protein lacking in patients with muscular dystrophy.
“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 wrote. “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.”
The gene that is defective in people with Duchenne muscular dystrophy is the largest gene in nature, said Jeffery Chamberlain, the study’s senior author and director of the Wellstone Muscular Dystrophy Research Center and is the McCaw endowed chair in muscular dystrophy at the University of Washington School of Medicine. Up until now, there was no way to deliver adequate protein fixes into the muscles.
Currently, there is no cure for the Duchenne muscular dystrophy and available treatments and drugs only slow down the disease. The disorder is X-linked and males with the gene on the X chromosome begin exhibiting symptoms around age four and usually die in their 20s or 30s.
In the lab, this method not only halted further progression of the disease, but it reversed much of the pathology associated with dystrophy. Eventually, researchers hope that this method might lead to a reversal of the muscle wasting and restore normal health of the muscle tissue.
The latest approach also uses a new type of AAV vector that allows the use of lower doses and therefore may reduce or eliminate some of the side effects of previous approaches, Chamberlain said. This then kicks off an immune response which can damage the heart or liver, he explained.
The researchers concluded: “This method could be implemented for many other diseases involving large genes exceeding the packaging capacity of AAV vectors.”
