Nationwide Children’s Podcast Explores Therapy Development for DMD

In a podcast from Nationwide Children’s Hospital, longtime MDA grantee Jeffrey Chamberlain describes advances in gene transfer therapy and stem cell therapy for Duchenne muscular dystrophy

Different strategies to treat Duchenne muscular dystrophy and other types of muscular dystrophy are emerging “from work coming out of the Duchenne field,” says Jeffrey Chamberlain, an MDA grantee at the University of Washington in Seattle and member of MDA’s Scientific Advisory Committee.
Article Highlights:
  • Current treatment options for Duchenne muscular dystrophy are limited, with a focus on treating symptoms and slowing the course of the disorder; newer strategies are aimed at significantly modifying or eliminating the disease.
  • Advances are being made in the development of gene transfer therapy and stem cell therapy for DMD, the results of which may apply to other types of muscular dystrophies, as well.
  • A key element of gene transfer therapy is finding a vehicle able to deliver the gene to where it needs to go in the body; scientists are refining methods for gene delivery using vehicles derived from viruses.
  • Stem-cell-based approaches include transplanting healthy donor cells or correcting a patient's own stem cells using gene transfer prior to transplantation.
by Amy Madsen on July 31, 2013 - 3:31pm

In a July 2013 podcast from Nationwide Children’s Hospital in Columbus, Ohio, longtime MDA grantee Jeffrey Chamberlain discusses recent advances in the development of gene therapy (gene transfer) and stem cell therapy (transplantation) for Duchenne muscular dystrophy (DMD), the results of which may apply to other types of muscular dystrophies, such as Becker muscular dystrophy (BMD), as well.

The 30-minute podcast is based on a paper by Chamberlain and colleagues, published online March 29, 2013, in Muscle & Nerve. (See Gene and Cell-Mediated Therapies for Muscular Dystrophy for a summary.) A transcript is provided along with the podcast on the Nationwide site as part of the feature called This Month in Muscular Dystrophy.

Chamberlain is a professor of neurology, medicine and biochemistry at the University of Washington School of Medicine in Seattle and a member of MDA’s Scientific Advisory Committee. At the May 2013 MDA/AFM Symposium on “next-generation” gene therapy, he reviewed recent developments in gene therapy delivery methods.

Chamberlain is interviewed in the podcast by Kevin Flanigan, a specialist in neuromuscular disorders and a principal investigator in the Center for Gene Therapy at Nationwide Children's Hospital.

Progressing from ‘what causes this disease’ to ‘what can we do about it’

Current treatment options for DMD are limited, with a focus on treating symptoms and slowing the course of the disorder. Newer strategies are aimed at significantly modifying or eliminating the disease.

“Recent developments in the field are extremely exciting,” Chamberlain says in the podcast, noting that when he first started working on muscular dystrophy research, “it was a question of what causes this disease.”

Now, the focus is on what can be done about the disease, he says, and it’s a completely different mindset. “We’re no longer talking about eventually what can happen, but what can we do here, now.”

Chamberlain notes that one strategy may not be best, but several strategies — possibly including gene therapy and stem-cell-based therapies — may work together to have a major impact on muscle disorders.

Gene therapy delivery methods are being refined

Chamberlain discusses the use of viruses to construct delivery vehicles able to transport genes into cells, such as muscle fibers, throughout the body.

First, he says, it’s important to note the distinction between a virus and a virus-based (viral) delivery vehicle. Viruses enter the body and make their way into cells, where they deliver DNA elements that can make people sick. In order to make a viral delivery vehicle, scientists take out the virus DNA and replace it with DNA containing the gene they want to deliver.

Three major virus types have been studied extensively for their potential to work as gene delivery vehicles: retroviruses, adenoviruses and adeno-associated (AAV) viruses.

Initially AAV-based delivery was largely ignored, Chamberlain says, “because it’s a very small virus, and the dystrophin gene responsible for Duchenne muscular dystrophy is a huge gene.” Scientists gravitated toward using larger viruses instead, such as the adenovirus, that could carry big genes.

Although the adenovirus showed promise as the basis of a delivery method for gene transfer therapy, scientists found that its ability to spread throughout the body — to deliver genes systemically — was limited.

Retrovirus-based delivery vehicles also were considered, with the most commonly studied variety being a lentivirus (derived from the human immunodeficiency virus, or HIV). The challenge with using lentivirus-based delivery vehicles for gene therapy, Chamberlain notes, is that, as with adenovirus-based vehicles, they’re unable to effectively spread to muscles throughout the body.

Scientists have found that AAV-based vehicles can be injected into the bloodstream, where they home in on muscles all over the body. Although they're unable to accommodate the large dystrophin gene, scientists are working on producing smaller versions of the gene — called mini- or micro-dystrophin — that comprise the most important parts of the dystrophin gene and can fit in the AAV delivery vehicle.

Putting in cells that are able to repair muscles

For muscle diseases and muscular dystrophies in general, stem-cell-based therapies are “a very promising approach,” Chamberlain says.

A number of different types of stem cells exist, and Chamberlain points out that in the muscle disease field, embryonic stem cells have “not emerged as a very interesting alternative.”

One approach is focused on isolating stem cells that reside in muscles (muscle-specific stem cells), and that are naturally programmed to develop into muscle cells. These cells can be taken from a healthy donor, coaxed to multiply in the laboratory, and then transplanted into the patient. A variation on this method is to take the muscle stem cells from the patient, correct them in the laboratory using gene transfer, and then put them back into the person from whom they were taken. (Also see DMD, BMD: Combining Gene Therapy and Stem Cell Transplantation.)

Scientists have found that AAV delivery vehicles don’t work well with muscle stem cells. By contrast, lentiviral delivery vehicles do. Lentiviral vehicles can carry new genes into muscle stem cells in laboratory containers. These corrected cells will then multiply and can be transplanted into the patient's body, where they can, it is hoped, repair damaged muscle fibers.

“I think, in terms of stem cell treatments for patients, muscle has emerged as one of the most promising targets for stem cell therapy,” Chamberlain notes.

Collaboration and shared information moves the field forward

Chamberlain points out that “sometimes people worry about competition versus sharing." But, he says, “It's nice to have multiple groups trying things because everybody is trying to do something a little bit differently. Most of these groups are talking to each other, sharing data, sharing information, and the field as a whole is moving forward quite rapidly.

“I'm excited about the progress.”

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