Med School study develops models to further muscular dystrophy research

May 13, 2013, 10:40 p.m.

Researchers in the School of Medicine recently published a study detailing the development of mouse models that use luciferase, the gene that makes fireflies glow, to follow the progression of limb-girdle muscular dystrophy through noninvasive imaging of the luminescent decaying muscle cells.

The researchers, who worked in the lab of Professor of Neurology and Neurological Science Thomas Rando, began developing the mouse model in 2008. The study was co-authored by Rando, clinical assistant professor Leland Lim, research associate Katie Maguire and Sedona Speedy, an undergraduate student at Northwestern University.

To create the mouse models, Rando’s lab inserted the luciferase gene into the genome of the mice at the embryonic level. When the mice developed, all of their cells carried the gene, according to Rando, allowing the researchers to “decide through another genetic trick which cell it gets turned on in.”

“Our genetic trick is to turn it on only in the muscle stem cells,” Rando said. “You could use this same mouse model and turn on luciferase in another stem cell population just as easily now that we’ve created this.”

According to Maguire, the researchers injected the mice when they were two months old with a substance that turned on the luciferase in their stem cells. After giving them injections for five days, the researchers began the process of conducting monthly imaging on the mice to monitor disease progression.

“You just inject them with a substance called luciferand, and you wait 23 minutes, and then you put them into the imaging chamber and then you image them,” Maguire said. “It really doesn’t take that long to actually do the imaging.”

Maguire and Speedy carried out parallel histological analyses of mice in order to compare the histological method of monitoring the disease to the researchers’ new method. The multi-day histological process in which tissues are collected, cut and antibody-stained was previously the primary method of studying the progression of muscular dystrophy in mice.

“When you have to actually evaluate the effectiveness of a drug, it requires a lot of different time points, a lot of different treatments, so a lot of different mice,” Maguire said. “The paper just shows that instead of doing all these histological analyses, we can just rely on the noninvasive imaging using the luciferase as our reporter.”

According to Rando, current treatments for muscular dystrophy are minimally effective and only work in the short term. Rando said that the mouse models will allow researchers to study treatments in living animals over time.

“This should greatly facilitate the translation of that from an idea from a test in the mouse to getting that to humans,” he said. “What it means for human therapy is that we can take many more ideas through animal testing at a much higher rate in a much shorter amount of time.”

Maguire agreed that the mouse model could eventually contribute to discoveries that benefit human patients.

“We can’t make glowing humans, but we can test drugs, and we can test therapies,” Maguire said. “I also have other models that I’m establishing using similar technology—there will be more glowing mice coming.”

According to Rando, the researchers will continue to conduct studies of therapeutic treatments using the existing mouse models, expanding the scope of their research to include other types of muscular dystrophy and testing out other models.

The lab also plans to distribute the mouse models to outside researchers studying muscular dystrophy and other topics such as exercise science and studies on sarcopenia, an age-related loss of muscle mass.

“We can’t possibly do all those studies here, so our goal really is to share this resource with the community,” Rando said.

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