A new gene therapy treatment for Duchenne muscular dystrophy (DMD) shows promise of not only arresting the development of the muscles of those affected by this inherited genetic disease but perhaps repairing those muscles in the future.
Muscular dystrophy gene therapy researchers Jeffrey Chamberlain (left) and Hichem Tasfaout in their lab. Image credit: Chamberlain lab
The UW Medicine-led research focuses on delivering a series of protein packets inside a shuttle vector to replace the defective DMD gene within the muscles. The added genetic code will then start producing dystrophin, the protein lacking in patients with muscular dystrophy.
Currently, no cure exists for the disease and available treatments and drugs only slow down the disease. In the case of Duchenne muscular dystrophy — the study's focus — patients, all males since the affected gene is on the X chromosome, begin exhibiting symptoms around 4 years old and usually die their 20s or 30s.
Findings on the new gene therapy were published in Nature.
UW Medicine neurologist and geneticist, Dr. Jeffery Chamberlain, the study’s senior author, has worked his entire career on finding therapeutics and a cure for muscular dystrophy. He is 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.
The research project was led by molecular biologist Dr. Hichem Tasfaout working in the Chamberlain lab.
What has stymied researchers to date is that the gene that needs to be fixed “is the largest gene in nature,” he said. Up until now, there was no way to deliver the needed protein fixes into the muscles and their genes.
“Think of having a king-sized bed delivered that you can’t get through your door,” Chamberlain said.
The new method, which has had success on mouse models, uses a series of adeno-associated viral vectors or AAVs, which are tiny shuttles derived from a virus that are being 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, with embedded instructions to begin assembling the necessary genetic fix within the body.
Revisiting the king bed analogy: Not only are the parts taken in piece by piece, but the delivery workers begin assembling the bed inside the house.
The next step for the therapy is human trials, which should begin in approximately two years, Chamberlain said.
In the lab, this method has not only halted further progression of the disease, but also has reversed much of the pathology associated with dystrophy. Eventually, Chamberlain and Tasfaout hope that this method might lead to a reversal of the muscle-wasting and restore muscle tissue's normal health.
The latest approach also uses a new type of AAV vector that allows the use of lower doses, which causes many side effects of previous approaches to be reduced or eliminated, Chamberlain said.
“When we infuse a large dose of these delivery shuttles, the body goes “woah, what’s going on here,”” he said.
This then kicks off an immune response which can damage the heart or liver, he said.
Chamberlain related his childhood memory of watching the Jerry Lewis Telethon, which he said might have sparked the passion that guided his career. He ended up appearing on the telethon seven times as an expert discussing the science of therapies.
“When you meet families and patients, it just inspired me to work that much harder,” he said.
Source: University of Washington