Posts tagged muscular dystrophy

Controlling the amount of oxygen that stem cells are exposed to can significantly increase the effectiveness of a procedure meant to combat an often fatal form of muscular dystrophy, according to Purdue University research.

A genetic mutation in patients with Duchenne muscular dystrophy causes the constant breakdown of muscles and gradual depletion of stem cells that are responsible for repairing the damage and progressive muscle wasting. A healthy stem cell tends to duplicate in a regular pattern that creates one copy of itself that continues to function as a stem cell, and a differentiated cell, which performs a specific function. In a healthy person, a torn or damaged muscle would be repaired through this process.

Stem cell therapy - implanting healthy stem cells to combat tissue wasting - has shown promise against muscular dystrophy and other neurodegenerative diseases, but few of the implanted stem cells survive the procedure. Shihuan Kuang, a Purdue assistant professor of animal sciences, and Weiyi Liu, a postdoctoral research associate, showed that survival of implanted muscle stem cells could be increased by as much as fivefold in a mouse model if the cells are cultured under oxygen levels similar to those found in human muscles.

"Stem cells survive in a microenvironment in the body that has a low oxygen level," Kuang said. "But when we culture cells, there is a lot of oxygen around the petri dish. We wanted to see if less oxygen could mimic that microenvironment. When we did that, we saw that more stem cells survived the transplant."

Liu thinks that’s because the stem cells grown in higher oxygen levels acclimate to their surroundings. When they’re injected into muscles with lower oxygen levels, they essentially suffocate.

"By contrast, in our study the cells become used to the host environment when they are conditioned under low oxygen levels prior to transplantation," Liu said.

In the mouse model, Kuang and Liu saw more stem cells survive the transplants, and those stem cells retained their ability to duplicate themselves.

"When we lower the oxygen level, we can also maintain the self-renewal process," Kuang said. "If these stem cells self-renew, they should never be used up and should continue to repair damaged muscle."

The findings, reported in the journal Development, shows promise for increasing the effectiveness of stem cell therapy for patients with Duchenne muscular dystrophy, which affects about one in 3,500 boys starting at about 3-5 years old. The disease, which confines almost all patients to wheelchairs by their 20s, is often fatal as muscles that control the abilities to breathe and eat deteriorate.

Source: Purdue University

8-Aug-2012

The molecular missteps that disrupt brain function in the most common form of adult-onset muscular dystrophy have been revealed in a new study published by Cell Press. Myotonic dystrophy is marked by progressive muscle wasting and weakness, as well as excessive daytime sleepiness, memory problems, and mental retardation. A new mouse model reported in the August 9 issue of the journal Neuron reproduces key cognitive and behavioral symptoms of this disease and could be used to develop drug treatments, which are currently lacking.

The red dots are the toxic RNAs accumulating in the nucleus (blue) of a myotonic dystrophy cell (these are induced pluripotent stem, or iPS, cells) and the green is a neuronal marker. Credit: Charizanis et al., Neuron.

"The new animal model reproduces important aspects of myotonic dystrophy brain disease, so this model may be useful to develop biomarkers and test future drug therapies," says senior study author Maurice Swanson of the University of Florida.

Previous studies had shown that mutated genes underlying the disease produce toxic ribonucleic acids (RNAs) during transcription, and these RNAs cause the production of incorrect forms of proteins in muscle tissue by blocking the actions of a protein called MBNL1. As a result, proteins typically found in fetal muscles increase in abundance, while the normal suite of proteins found in adult muscles decrease in number. However, until now, it was not clear whether molecular abnormalities similar to those in muscle tissue of individuals with mytonic dystrophy also occur in the brain, resulting in the cognitive neurological problems.

In the new study, Swanson and his team focused on a related protein called MBNL2, which is found in the brain. They developed a new mouse model that lacked a functional Mbnl2 gene. These animals experienced an increase in the amount of rapid eye movement sleep as well as learning and memory deficits, similar to human patients.

The researchers also found extensive evidence of toxic RNAs in the hippocampus, as well as signs that fetal proteins were being produced in the brains of adult mutants. This pattern was also evident in the autopsied brain tissue of humans who had myotonic dystrophy. “This study should accelerate our understanding of how myotonic dystrophy mutations impact brain development and function,” Swanson says.

Source: EurekAlert!

ScienceDaily (July 16, 2012) — While Spider-Man is capturing the imagination of theatergoers, real-life spider men in Upstate New York are working intently to save a young boy’s life.

UB researchers are developing a treatment for muscular dystrophy using a peptide found in the venom of a Chilean rose tarantula. (Credit: Image courtesy of University at Buffalo)

It all began in 2009, when Jeff Harvey, a stockbroker from the Buffalo suburbs, discovered that his grandson, JB, had Duchenne muscular dystrophy. The disease is fatal. It strikes only boys, causing their muscles to waste away.

Hoping to help his grandson, Harvey searched Google for promising muscular dystrophy treatments and, in a moment of serendipity, stumbled upon University at Buffalo scientist Frederick Sachs, PhD.

Sachs was a professor of physiology and biophysics who had been studying the medical benefits of venom. In the venom of the Chilean rose tarantula, he and his colleagues discovered a protein that held promise for keeping muscular dystrophy at bay. Specifically, the protein helped stop muscle cells from deteriorating.

Within months of getting in touch, Harvey and Sachs co-founded Tonus Therapeutics, a pharmaceutical company devoted to developing the protein as a drug. Though the treatment has yet to be tested in humans, it has helped dystrophic mice gain strength in preliminary experiments.

The therapy is not a cure. But if it works in humans, it could extend the lives of children like JB for years — maybe even decades.

Success can’t come quickly enough.

JB, now four, can’t walk down the stairs alone. When he runs, he waddles. He receives physical therapy and takes steroids as a treatment. While playing tee ball one recent day, he confided to his grandfather, “When I grow up, I want to be a baseball player.” It was a heartbreaking moment.

"Oh, I would be thrilled if you could be a baseball player," Harvey remembers replying. He’s doing everything he can to make sure that JB — and other boys like him — can live out their dreams.

Source: Science Daily

ScienceDaily (Feb. 22, 2012) — While RNA is an appealing drug target, small molecules that can actually affect its function have rarely been found. But now scientists from the Florida campus of The Scripps Research Institute have for the first time designed a series of small molecules that act against an RNA defect directly responsible for the most common form of adult-onset muscular dystrophy.

In two related studies published recently in online-before-print editions of Journal of the American Chemical Society and ACS Chemical Biology, the scientists show that these novel compounds significantly improve a number of biological defects associated with myotonic dystrophy type 1 in both cell culture and animal models.

"Our compounds attack the root cause of the disease and they improve defects in animal models," said Scripps Research Associate Professor Matthew Disney, PhD. "This represents a significant advance in rational design of compounds targeting RNA. The work not only opens up potential therapies for this type of muscular dystrophy, but also paves the way for RNA-targeted therapeutics in general."

Myotonic dystrophy type 1 involves a type of RNA defect known as a “triplet repeat,” a series of three nucleotides repeated more times than normal in an individual’s genetic code. In this case, the repetition of the cytosine-uracil-guanine (CUG) in RNA sequence leads to disease by binding to a particular protein, MBNL1, rendering it inactive. This results in a number of protein splicing abnormalities. Symptoms of this variable disease can include wasting of the muscles and other muscle problems, cataracts, heart defects, and hormone changes.

To find compounds that acted against the problematic RNA in the disease, Disney and his colleagues used information contained in an RNA motif-small molecule database that the group has been developing. By querying the database against the secondary structure of the triplet repeat that causes myotonic dystrophy type 1, a lead compound targeting this RNA was quickly identified. The lead compounds were then custom-assembled to target the expanded repeat or further optimized using computational chemistry. In animal models, one of these compounds improved protein-splicing defects by more than 40 percent.

"There are limitless RNA targets involved in disease; the question is how to find small molecules that bind to them," Disney said. "We’ve answered that question by rationally designing these compounds that target this RNA. There’s no reason that other bioactive small molecules targeting other RNAs couldn’t be developed using a similar approach."

Source: Science Daily