In our latest video, “Spotlight on Muscular Dystrophy and Stem Cell Research” CIRM grantee and Stanford scientist Helen Blau illustrates new methods of modeling to more accurately map how a therapy might work in humans.

Dr. Blau studies Duchenne muscular dystrophy (DMD), the most severe form of muscular dystrophy that affects 1 in 3500 boys and leads to progressive muscle degeneration and death by the second decade of life.

Mouse models for research

It’s been nearly thirty years ago that dystrophin, the mutated gene that causes DMD, was identified. Without the large structural protein encoded by dystrophin, the muscle cell walls become stressed, leaky and eventually degenerate. A mouse model of DMD with a naturally occurring mutation in the dystrophin gene has been available nearly since 1989. But many potential therapies that tested well in mouse models don’t work in humans.

Part of the reason is the mouse doesn’t have quite the same disease, while using laboratory mice has been vital to understanding human biology and treating human diseases, in some cases these “models” of humans don’t actually model well to how a therapy might work in humans.

Indeed, although the DMD mouse model leads to a futile cycle of muscle degeneration and regeneration seen in humans, these mice show none the hallmarks of DMD in humans: paralysis, curvature of the spine, cardiac dysfunction and shortened lifespan.

An alternative solution

Blau’s lab set out to solve the mystery of the DMD mouse model. They focused on the muscle stem cells that constantly regenerate dying muscle cells lacking normal dystrophin. In humans, this stem cell pool eventually runs out because it must keep replacing stressed muscle cells. But in DMD mice, the stem cells never deplete. Blau proposed that telomeres were responsible.

Telomeres are stretches of DNA at the ends of chromosomes. They work like the clear plastic caps on shoelaces. When those caps wear down, the laces fray and must be replaced. Telomeres behave the same way. With each cell division, they shrink. When they disappear, the chromosome becomes unstable, and the cell dies. Mouse telomeres are five times longer than human telomeres. Blau hypothesized that mouse muscle stem cells avoided depletion because their telomeres stayed intact longer, even under constant stress.

Blau’s lab then created DMD mice with slightly shortened telomeres. These mice finally mimicked human DMD. They showed paralysis, curved spines, and most importantly, cardiac dysfunction—the main cause of shortened lifespans in boys with DMD. With this improved mouse model, Blau and her team can now study the disease more accurately and develop new therapies.