Strong Hope

The symptoms of this fatal illness begin at birth. Parents notice muscle weakness and tightness in their child’s hips, knees, and elbows. As the illness progresses, the child suffers from poor muscle tone, limited mobility, inflammation, and fibrosis, which further reduce mobility. In the most severe cases, children require assistance for every movement, from eating to sitting upright. While many children succumb to the illness before the age of 10, medical advances like feeding tubes have allowed others to live into their 20s and 30s, albeit with constant care.

To date, there is no effective intervention for merosin-deficient congenital muscular dystrophy type 1A, or MDC1A—but Mahasweta Girgenrath’s work has provided evidence for a combination treatment that could improve the quality of life for children with the disease, and possibly extend their lives.

Girgenrath, an assistant professor of health sciences at Boston University’s Sargent College of Health & Rehabilitation Sciences, had been using mouse models to elucidate the mechanisms of MDC1A for more than a decade when she attended a scientific meeting that changed the trajectory of her research. Organized by the new parent-led advocacy group Cure CMD, the 2009 conference brought together clinicians, scientists, and pharmaceutical-industry representatives to share research about treating congenital muscular dystrophies. For Girgenrath, it was neither the scientists nor the physicians whose counsel was most influential.

“What was huge for my research direction was meeting parents of children with muscular dystrophy,” Girgenrath says. She recalls one mother of a 16-month-old who was desperate for an intervention to slow the progression of the disease. While agonizing, the mother’s story was not unique; after hearing similar stories from countless parents, Girgenrath “recognized that these children need more immediate treatment. It helped me to prioritize what needed to happen first.” She began looking for ways to use her preclinical research to help patients now, turning to drugs already on pharmacy shelves.

Girgenrath had been involved in identifying two major pathways that cause the symptoms of MDC1A: a dearth of healthy muscle cells and an inability to regenerate muscle. In her lab, she had successfully tested treatments to address these pathways in an MDC1A mouse model. When this mouse was genetically engineered to overexpress the protein insulin-like growth factor 1 (IGF-1), it led to improved muscle regeneration. Another study, which inactivated a mouse gene that promotes apoptosis—the normal developmental process of programmed cell death—showed even more robust results. But in both of these single mode therapies, the problems of inflammation and fibrosis remained.

Girgenrath believed that she would have even more success from two treatments that, given together, simultaneously blocked apoptosis and boosted cellular regeneration. Combination approaches are common in treating such conditions as HIV and many cancers, but relatively untested in muscular dystrophy. “It seemed clear to me very early that this disease has so many components and so many disease drivers, if you target just one component, you only get so much benefit,” she says.

“What was huge for my research direction was meeting parents of children with muscular dystrophy. I recognized that these children need more immediate treatment.” —Mahasweta Girgenrath

When Girgenrath combined the treatments in mice—blocking apoptosis and stimulating growth—the results exceeded her expectations. Not only did the approach provide more powerful relief of symptoms than the individual treatments, it also reduced the muscle fibrosis and inflammation that are debilitating hallmarks of the disease. “There was a measurable improvement in growth and muscle mass, and in fact the interventions seemed almost synergistic,” Girgenrath says. “Patients with this disease, like these mice, don’t grow very well and have significant inflammation and ongoing fibrosis. If we can improve these children’s overall growth, it will give them not only an improved quality of life but likely an advantage to their overall longevity.”

Even as her hypotheses were being confirmed in the laboratory, Girgenrath was thinking about how her research findings might be brought to patients in the near future. She began to consider the therapeutic potential of the off-label use of drugs whose safety had already been assessed. The antihypertensive drug losartan has been shown to reduce fibrosis and inflammation in animal models. “Losartan also works on some pathways that may lead to programmed cell death,” Girgenrath says. “We now have preclinical data that show if we give losartan to the sick mice that overexpress IGF-1, they get bigger and show no fibrosis at all. We are looking at whether losartan can be combined with a growth-promoting factor like IGF-1 or growth hormone, both approved for use in children. This therapeutic combination would have tremendous translational potential.”

Girgenrath is working with physicians at the Mayo Clinic and National Institutes of Health to lay the groundwork for future clinical trials to test the use of losartan in children. In time, she hopes it will be possible to bring the combination approach to patients as well, through the dual treatment of losartan and growth hormone. Immediate treatment is a priority.