X-linked myotubular myopathy (XLMTM) is a rare, but devastating muscle disorder caused by a mutation in a gene that carries instructions for muscle development. When the gene malfunctions, those encoded instructions don’t get translated properly, and muscle development is severely impaired, leaving boys born with the disease unable to move, eat, or even breathe without assistance.
Now, a gene therapy developed in part by researchers at the Institute for Stem Cell and Regenerative Medicine (ISCRM) is helping patients with XLMTM live longer and more active lives. In a multipart breakthrough that unfolded in 2017 and 2018, an ISCRM team showed that a gene therapy could completely restore muscle function in dogs with naturally-occurring XLMTM.
For the first time, researchers had proof that a neuromuscular disease could be treated in a large animal model. ISCRM faculty member David Mack is an Associate Professor of Rehabilitation Medicine and a key contributor to what is commonly known as the dog study. “First we demonstrated that the gene therapy worked for this disease,” explains Mack. “Then we found the optimal dose that allowed us to bring the therapy to a clinical trial. The questions we are asking now take us closer than ever to the clinic.”
Specifically, the XLMTM team wants to know what exactly the gene therapy corrects at the molecular level, what it doesn’t correct, and what biomarkers will signal when to re-dose boys who have received treatment. Answers to these questions are now at the heart of a new paper published in the journal Molecular Therapy. “This is about the downstream consequences of the gene therapy,” says Mack. “Everything we are learning will teach us how to develop the best possible clinical management plan for patients.”
Mack also notes that the recent findings may also help inform current and future clinical trials, such as the trial being led by Audentes Therapeutics, a private company focused on commercializing treatments for rare neuromuscular diseases. In October 2019, Audentes released promising data from an XLMTM patient trial testing the gene therapy developed in part by ISCRM researchers, including Mack and former colleagues Casey Childers and Alan Beggs.
Jean-Baptiste Dupont, a former postdoc in the Mack Lab, and the paper’s lead author, explains the significance of the findings. “Over the last few years, the improvements in muscle strength and respiratory function have been so impressive compared to what we’re used to seeing in other muscle disorders. What we’re discovering now about the molecular and genetic underpinnings of the disease will help us treat boys with XLMTM even more effectively and inform how we approach other muscle diseases as well.”
In the investigation, Mack and Dupont explored how the gene therapy led to improvements in muscle function in dogs with XLMTM. By comparing dogs that received treatments with those that did not, the research team identified several genes that played particularly important roles in the progression of the disease and pinpointed RNA biomarkers that are useful in diagnosing and tracking the disease in individual patients. In a near future, these tests, which now require a muscle sample from XLMTM boys, could be done with a routine blood draw.
“We think about this as three levels of understanding,” says Mack. “At the molecular level, we are looking at the core biology of MTM. At the tissue level, we are learning how to use gene therapy to unblock muscle growth. And at a more systemic level, we are identifying new biomarkers to track and correct the disease over time.”
One challenge central to the study was how to manage the vast amount of data available to the researchers. “When you’re looking at 25 muscle samples and each muscle contains more than 15,000 active genes, that’s a lot of information,” explains Mack. “Jean-Baptiste was able to develop a brilliant visualization system that helped us get our minds around the data in ways that weren’t possible before. And, this is a platform we can we use on all the other diseases we study.”
Indeed, XLMTM is just one of the muscle diseases being studied at ISCRM and the University of Washington. One galvanizing force is the Center for Translational Muscle at UW Medicine, where cutting edge capabilities integrating mechanical devices, quantitative analysis, and metabolomics are accelerating research into muscular dystrophy, heart disease, ALS, and other muscle disorders. “The new muscle center if perfectly placed to help move our XLMTM research from the lab to clinic,” says Mack. “As we dig deeper and attempt to study this gene therapy at the protein level, access to the world-class facilities becomes even more important. And we’ve got that right here.”
Funding sources:NIH/NIAMS R01-HL115001,Will Cure Foundation, Joshua Frase Foundation,Association Française contre les Myopathies (AFM-Telethon), Myotubular Trust UK.