A discovery about muscular dystrophy disorders has been made that suggests new possibilities for treatment. Researchers found that stem cells in the muscles of muscular dystrophy patients may, at an early age, lose their ability to regenerate new muscle, due to shortened telomeres.
Duchenne muscular dystrophy is a rapidly progressive disease that causes whole-body muscle weakness and atrophy due to deficiency in a protein called dystrophin. Researchers have developed a new gene transfer approach that uses an adeno-associated virus vector to deliver a modified dystrophin gene to muscle, restoring muscle strength in a mouse model that closely mimics the severe defects seen in patients.
Researchers have demonstrated the efficacy of an innovative gene therapy in the treatment of Duchenne muscular dystrophy. After injecting microdystrophin (a ‘shortened’ version of the dystrophin gene) via a drug vector, the researchers managed to restore muscle strength and stabilise the clinical symptoms in dogs naturally affected by Duchenne muscular dystrophy.
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 two 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.
Muscular dystrophy is a term used to describe many different muscular diseases caused by genetic defects. To date, there are no treatments available to stop disease progression. In their study, the scientists led by Prof. Markus Rüegg have investigated a specific type of muscular dystrophy, called congenital muscular dystrophy. In an animal model, they demonstrated for the first time that two proteins designed by the researchers not only recover muscle force and increase body weight in the sick animals but also significantly prolong survival.
Severe impairments due to congenital muscular dystrophy
Congenital muscular dystrophy is a rare and severe form of a muscular dystrophy that presents at birth or during infancy. “The children born with this disease are also called ′floppy infants′ because of the poor muscle tone and weakness,” says Judith Reinhard, first author of the study. “The disease becomes more severe with increasing age, as the muscle wasting progresses.” Affected children are often unable to walk independently or they lose this ability with age. The respiratory muscles are also affected. The lifespan is often short and many patients die before reaching adulthood.
Defective gene — defective cell scaffolding
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.
Proteins anchor cell scaffolding and stabilize muscle fibers
The researchers designed two 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 two 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.”
Materials provided by Universität Basel. Note: Content may be edited for style and length.
I flew home to Pennsylvania in December to tell my dad I was pregnant with my first child. By then it had been more than a year since my father had been able to get out of the hospital bed that had taken up permanent residence in my parents’ living room. He could no longer stand, lift his arms to feed himself, or use the bathroom on his own.
“We’re having a baby.” I stood next to his bed and puffed my barely-three-months-pregnant belly toward him. He couldn’t speak, but his entire face smiled. His hand trembled as he moved it toward my stomach to touch it.
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“He kicked,” I lied and made myself smile when he made contact. It was too soon for the baby to move. But I wanted to make him happy.
Two days later my dad went to sleep. He didn’t wake up. He was 62.
The genetic mutation that caused Dad’s muscular dystrophy, the disease that caused other diseases that ultimately killed him, lives on an obscure region of his fourth chromosome called q35. Growing up, our family doctors told me I couldn’t inherit it. They were wrong.
I was married for six months when my husband Nick and I started talking to my doctor about having our own baby. The conversation covered all the standard genetics questions and the not-standard ones. Yes, my dad has this disease. No, I’m not a carrier. Are you sure? Actually, I wasn’t. I couldn’t remember the exact conversation with my family doctor. I couldn’t remember if I’d long ago created the narrative in my mind that I wanted to believe.
They took a lot of blood. Six weeks later, I heard back from a chirpy genetics counselor named Violet.
“Hi, Jo! I was surprised by your results,” she informed me in the same tone someone will tell you the winner of The Bachelor. “You do have the genetic mutation.”
I’d read once that some people swoon, actually pass out, when they hear bad news. My joints turned to butter, and I sat down on the floor to listen numbly to her directions about what to do next.
Two voices fought for supremacy in my head.
The first: You should just give up. Stop working. Fuck it! Let your roots grow out, dye your hair green, and sit with the gutter punks down on Haight-Ashbury smoking crack … because why not?
And the second: It doesn’t matter what the tests say. You’ll fight. You’re strong. You’re stronger than you know.
The first voice was so clearly mine. The second was Nick’s.
I couldn’t imagine wanting a baby, living with it in my body for three months, and then ending its brief life because of something that might happen to it in 40 or 50 years.
“You should divorce me,” I said to my husband that night, my brand-new husband who loved skiing and hiking and climbing and riding things. “Maybe the good of being married to me doesn’t outweigh the bad anymore,” I said to him the night after I talked to Violet. “You should find a hot and healthy new wife.” I paused. “Maybe not hot, but someone sturdy!”
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He looked at me like I was nuts and scratched his head. “You know, I measured it. I had these tools to measure the good and the bad of being married to you, and I set up the machine and I did all of these calculations, and you know what happened? The damn machine broke, the good outweighed the bad so freakin’ much.”
I married a good man.
We met with a neurologist to determine whether the muscular dystrophy had already started degrading my muscles. He couldn’t find anything tangible. Yet.
“Because this kind of muscular dystrophy affects the facial muscles, people often have a hard time smiling, and so people often think they’re unhappy,” the doctor said. “Do people often think you are unhappy?”
“So you’re saying a symptom of this kind of muscular dystrophy is resting bitch face?” I made a joke because it was true. Weren’t old men on the street always telling me to smile more? I’d spent most of my adult life being told to “wipe that puss off my face.” I cut to the chase. “What about our kids?”
“They have a fifty-fifty chance. You can’t screen for it in an embryo, so IVF won’t help. You can test a fetus, but not until about twelve weeks, and then you have the option of terminating the pregnancy.” The words terminating the pregnancy hung in the air like a storm cloud ready to burst any second. I opened my mouth but couldn’t say anything. I pinched my thigh above the knee, hard. My nails curled into my skin. I needed to feel something. “We should go,” I finally whispered to Nick. “I just want to go home. Please.”