Jeffrey Chamberlain believes that providing new dystrophin genes is the best way to treat Duchenne muscular dystrophy, although combining gene transfer with other strategies interests him.
Jeffrey Chamberlain’s interest in Duchenne muscular dystrophy (DMD) began in 1986, when mutations in the dystrophin gene were first identified as the underlying cause of the disease.
At that time, Chamberlain was working in a lab at Baylor College of Medicine in Houston, trying to find out what was causing weakness in mice that seemed to have some type of muscular dystrophy. He began to think the problem might be a deficiency of dystrophin.
Fortunately, it turned out that Chamberlain and his colleagues were correct: The naturally weak mouse was dystrophin-deficient due to a mutation in the dystrophin gene. Dubbed the mdx mouse, it (along with mdx variations, several of which were characterized by Chamberlain) became a key tool for studying human DMD and potential DMD treatments. Those treatments include what would come to be known as gene-transfer therapy, or simply gene therapy — adding therapeutic genes to treat a disease.
In 1990, Chamberlain moved to the University of Michigan, Ann Arbor, and then to the University of Washington, Seattle, in 2000, taking his interest in developing a molecularly based therapy for DMD with him.
He believed then, as now, that providing new dystrophin genes is the best way to treat the disease, although other strategies interest him as potential add-ons.
In the early days of gene-transfer therapy, a large viral delivery vehicle — the AV — was being used in animal experiments to carry the enormous dystrophin gene to muscle fibers. However, it soon became clear from a clinical trial in an unrelated disorder that this large viral shell was a red flag to the immune system, telling it to attack cells it entered. Most experts in the muscular dystrophy field, including Chamberlain, stopped using it by 2000.
The focus shifted to a much smaller viral delivery vehicle — the AAV — but there was an immediate and obvious problem for the DMD field. Dystrophin is among the largest genes in the body, and it simply wouldn’t fit inside an AAV shell.
For Chamberlain, the solution seemed clear: The dystrophin gene would need to be shrunk so that it could fit inside an AAV delivery vehicle — known as a vector.
Smaller dystrophin genes
Chamberlain had already been developing dystrophin genes that were missing different sections and then testing them in mice to see whether the proteins made from them were still functional. (Some were, and others were not.)
Calling their small genes minidystrophins and their even smaller ones microdystrophins, Chamberlain and his colleagues sought to determine which parts of the dystrophin gene were essential and which could be jettisoned so that a smaller gene could be used as a treatment. As a gene gets smaller, "how well it works takes a hit," says Chamberlain. "We're still trying to tweak the microdystrophins."
Nevertheless, he says, he's "still excited about this for DMD. It’s still the most promising therapy out there. It can be applied to all patients, regardless of their mutation." (Some other treatments in development for DMD are for specific dystrophin mutations.)
Outwitting the immune system with drugs
The immune system is a formidable foe to gene transfer that has to be recognized but is not insurmountable, Chamberlain believes. "Every problem has a solution, as long as you keep your eyes open and are aware of what the problems are."
Chamberlain was recently part of a team that treated dystrophin-deficient dogs with microdystrophin genes that were encased in AAV vectors and injected into multiple muscles. By adding temporary treatment with three drugs that suppress the immune system, they found the dogs produced dystrophin protein for at least two years, including a year-and-a-half after the drugs were stopped.
Pinch-hitting with utrophin
Another possibility that could get around the immune system, Chamberlain says, could involve using genes for a protein called utrophin, instead of dystrophin. Utrophin is very much like dystrophin, but it has the advantage of already being present in the muscles of dystrophin-deficient patients and therefore being much less likely than dystrophin to draw the unwanted attention of the immune system.
"If dystrophin is going to cause problems, I'm in favor of going forward with utrophin," Chamberlain says.
As bullish as Chamberlain is about gene transfer, he’s not opposed to using other strategies, perhaps in combination with gene transfer. “Since exon skipping [a gene-modifying strategy in development for DMD] does not presently target the heart, maybe we could target the heart with AAV vectors and use exon skipping for the rest of the body. Inflammation may need to be addressed with anti-inflammatory drugs, and we may need to do stem cell transplants to bring in new muscle in older patients. There’s no perfect, one-shot therapy. We need to bring in many of these things and take advantage of the strengths and weaknesses in all of them.”
His mantra: "You have to remain positive, identify problems and solve them as they arise." Two decades ago, Chamberlain says, many people thought gene therapy for DMD was not possible, "but that didn’t keep us from trying it. And we’re so much closer now."
Want To Know More?
This article is part of a special series titled Gene Therapy: The Next Generation, which includes these additional articles profiling researchers who are pursuing next-generation gene therapy for DMD:
For more information about Chamberlain's gene transfer research, be sure to read: