Muscles are vital for everyday human life. Skeletal muscle contractions enable us to move, stop, and stay upright. Without these complex fiber-like cells, voluntary functions, including swallowing and speaking, would be impossible. At the same, our ability to pump blood, a life-sustaining involuntary function, is only possible because of the cardiac muscle that enables our hearts to contract.
Muscular dystrophies are the most common genetic muscle diseases. There are more than 100 such diseases. Of these, Duchenne muscular dystrophy (DMD) and Facioscapulohumeral Muscular Dystrophy (FSHD) are the most prevalent. While new therapies offer hope, there are no cures for these diseases.
Right now muscle researchers at UW Medicine are coming closer to changing that. Investigators affiliated with the Institute for Stem Cell and Regenerative Medicine (ISCRM), the Senator Paul D. Wellstone Muscular Dystrophy Research Center, and the Center for Translational Muscle Research (CTMR) are pursuing several potentially life-saving treatments that could soon significantly improve the wellbeing of patients.
Momentum for muscular dystrophy research accelerated about twenty years ago. In 2003, lobbying from parent groups moved the NIH to establish several centers of excellence to advance muscular dystrophy research toward urgently needed therapies for patients. The Senator Paul D. Wellstone Muscular Dystrophy Research Center, the first of six centers nationwide, was established at the University of Washington in 2004.
Jeff Chamberlain, PhD is a Professor of Neurology, Biochemistry, Medicine/Medical Genetics and the McCaw Chair in Muscular Dystrophy, an ISCRM faculty member, a Director of the Wellstone Center (with Dr. Stephen Tapscott as co-director), and Vice President of the American Society of Gene and Cell Therapy. The Wellstone Center is currently funded by a five-year $7.5 million dollar award from the National Institute for Arthritis, Musculoskeletal, and Skin Diseases (NIAMS), and supports translational research into developing treatments for DMD and FSHD.
Duchenne muscular dystrophy is caused by a mutation in the dystrophin gene. Chamberlain and his collaborators are attempting to fix the underlying problems by using a harmless virus to carry a synthetic, miniaturized version of the gene to cells. That approach is known as AAV Vector gene therapy. Making this form of gene therapy ready for human trials has required many years of problem solving.
“One of the first accomplishments of the Wellstone Center was showing that we could actually treat mice with DMD in a body-wide manner and completely suppress the disease,” says Chamberlain. “Work from our Center was the first to identify a method for gene delivery to all the muscles in the body. The focus since then has been trying to refine that technology.”
Packaging has been one hurdle. Dystrophin is the largest known human gene. A 2019 paper published in the journal Molecular Therapy detailed aspects of the effort to compress the dystrophin gene and deliver it to the right cells. In another feat of engineering, Chamberlain and ISCRM faculty member Stephen Hauschka devised a system to regulate the amount of protein the gene produced in cells.
Eventually, the vector technology, known as AAV micro-dystrophin, was licensed to the biotech company Solid Biosciences and entered human clinical trials, where it is showing promising results. Additional companies, including Sarepta Therapeutics and Genethon are also conducting clinical trials using vectors developed by the Wellstone Center, and Roche has plans to do so as well.
Another challenge stems from the biology of the disease. Because DMD progresses slowly, measuring how well a therapy works can take years of careful tracking. Nonetheless, Chamberlain says the data released two years into the trial appears to be encouraging. “It certainly looks like the kids are improving. They have been stabilized and seem to be showing increases in strength, although we have to watch for a while longer to be sure and continue calibrating the dosing to maximize the safety.”
Facioscapulohumeral Muscular Dystrophy (FSHD) is the second most common muscular dystrophy and the most common adult onset form. Stephen Tapscott, MD, PhD, an investigator based at Fred Hutchinson Cancer Center, leads the FSHD research effort at the Wellstone Center. His lab identified the molecular basis of the mutation and is now conducting clinical studies to understand how the defective gene causes this complicated dystrophy. Joel Chamberlain, PhD, another Wellstone Investigator and ISCRM faculty member is developing an AAV-mediated gene therapy for FSHD.
More recently, Jeff Chamberlain has begun to adapt the AAV vector technology to other muscle disorders, including Limb Girdle Muscular Dystrophy – a condition arising from a mutation in the gene FKRP, leading to a progressive loss of muscle functioning, typically leading to difficulty breathing, heart problems, and loss of mobility. Other members of the Wellstone Center, including Niclas Bengtsson, PhD, and Julie Crudele, PhD, are spearheading similar attempts to treat Desmin body myofibrillar myopathy and inclusion body myositis.
“We’re really at a point now where we’re able to build on the work that’s come out of the Wellstone Center and apply it to four or five different types of muscular dystrophy,” says Chamberlain. “And we’re hoping progress on these fronts will move other therapies into clinical trials the way we have done with DMD.”
At the same time, the researchers have begun to study another aspect of DMD. Much of the work so far has focused on skeletal muscle – the limbs and lungs. Many DMD patients, however, also experience heart problems as they get older. Currently, less is known about how well the gene therapy works in cardiac muscle. “That’s one big area where our interests in the Wellstone Center overlap with the CTMR,” says Chamberlain.
Chamberlain emphasizes the importance of having a robust, supportive community of muscle researchers at UW Medicine. “Our center is focused on developing new treatments for muscular dystrophy. The services and expertise the CTMR provides allows us to expand our repertoire of techniques and methods. That, in turn, helps us make discoveries with tremendous translational value.”
Funded by a five-year $4.3 million Center Award from the National Institute for Arthritis, Musculoskeletal, and Skin Diseases (NIAMS), the CTMR enables researchers to accelerate and expand skeletal muscle research, facilitate novel insights into muscle pathologies, and move therapeutics toward the clinic and the marketplace. The center provides access to a mechanical device core, a metabolism core, a quantitative analysis core, and pilot grants for young investigators looking to fund their own research projects.
Mike Regnier, PhD, an ISCRM faculty member and Professor of Bioengineering directs the CTMR, which is based on the UW Medicine South Lake Union campus. “The idea for the center came from years of collaboration within the muscle research community,” says Regnier. “We saw a need for a way to bring people together, to pull in new professors and postdocs, and to offer them tools, facilities, and expertise.”
Together, Chamberlain, Regnier, Hauschka and their ISCRM colleague David Mack, PhD are assessing the efficacy of the AAV vector gene therapy in heart muscle and designing newer versions of the gene therapy that will specifically improve heart function. Preliminary tests performed in partnership with researchers at Ohio State University indicate that the approach can help prevent heart failure in mice, a finding Chamberlain believes will translate to human patients.
Gene therapy is just one strategy the UW researchers are testing. Using CRISPR-CAS-9 technology, the team is also exploring the possibility of repairing the mutations that cause muscular dystrophy, or even using the two methods together. This study, one of the first examples of combining gene editing with traditional gene therapy, was detailed in a 2021 paper in Molecular Therapy.
“We see this as a potential alternative,” says Chamberlain. “You can replace the defective gene or try to fix the gene that patients already have. Ultimately, some patients may benefit from one more than the other, and in some cases, the best intervention might be a combination of the two.”