Designed proteins to treat muscular dystrophy

Jun 28, 2017

The cell scaffolding holds muscle fibers together and protects them from damage. Individuals who suffer from muscular dystrophy often lack essential components in this cell scaffold. As a result, their muscles lack strength and become progressively weaker. The research team of Prof Markus Rüegg at the Biozentrum, University of Basel, has now designed 2 proteins that stabilize the cell scaffolding link it to the muscle fiber and thereby restore muscle structure and function. Their findings are published in the current issue of Science Translational Medicine.

In their study the scientists led by Prof Markus Rüegg investigated congenital muscular dystrophy. In an animal model, they demonstrated for the first time that 2 proteins designed by the researchers not only recover muscle force and increase body weight in the sick animals but also significantly prolong survival.

This form of muscular dystrophy results from a genetic defect in laminin-α2. This protein is a key component of the cell scaffolding and connects it with the inner part of the muscle fiber, ensuring the stability of the tissue. Consequently, as a result of gene defects in laminin-α2 the muscles are extremely unstable and even normal use of the muscles leads to muscle injuries, inflammation, and finally to the degeneration of muscle fibers. In these diseased muscles, which are unable to produce laminin-α2, another laminin takes over. This protein, called laminin-α4, however, is only a poor replacement because it is not well integrated into the cell scaffolding.

The researchers designed 2 proteins that allow the integration of laminin-α4 and anchor it to the muscle cell. "Using these linkers, we were able to stabilize the muscle fibers," explains Rüegg. "When animals with a laminin-α2 defect express the 2 linkers, there was a significant improvement in muscle structure and force and an increase in body weight. We were particularly pleased to observe that these animals also had an almost normal lifespan. Some of them even survived their healthy siblings." Furthermore, the scientists examined muscle biopsies of patients with congenital muscular dystrophy. They found very similar structural defects and laminin-α4 was also found in place of laminin-α2 in the diseased muscle fibers.

"Both of the designed linker proteins may possibly be used in the future as a gene therapy treatment for congenital muscular dystrophy," says Rüegg. "Our study is a nice example of how the understanding of a disease on the molecular and cellular level results in new therapeutic options. We are now interested in whether these linker proteins also improve muscle function as well as affect survival in advanced stages of congenital muscular dystrophy."

Source: News Release
University of Basel
June 28, 2017