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Early signs of gait deviation in Duchenne muscular dystrophy

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  #1  
Old 15th September 2011, 01:34 PM
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Default Early signs of gait deviation in Duchenne muscular dystrophy

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Early signs of gait deviation in Duchenne muscular dystrophy.
Doglio L, Pavan E, Pernigotti I, Petralia P, Frigo C, Minetti C.
Eur J Phys Rehabil Med. 2011 Sep 13. [Epub ahead of print]
Quote:
BACKGROUND:
Most analytical studies found in literature only focus on specific aspects of Duchenne muscular dystrophy (DMD) gait and posture (joint range of motion, standing balance, variations of gait spatial-temporal parameters). Some of them analyze single cases and do not provide a comprehensive evaluation of locomotion. There are few studies about DMD gait patterns, most of them concerning small groups of patients, sometimes not homogeneous, in which the clinical manifestations of the next stages of DMD were present.

AIM:
The goal of our study was to analyze the characteristics of gait patterns in early stage patients, when clinical and functional evaluation do not allow to quantify initial walking worsening or to identify the changes adopted to compensate for muscle weakness.

SETTING:
Gait Analysis Laboratory by using a six-camera motion capture system (Vicon, Oxford Metrics, UK), set at a sampling rate of 60 Hz. Subjects were asked to walk barefoot at their usual cadence, along a 10-m walkway, where one force platform (Kistler, Switzerland), embedded in the middle portion of the pathway, measured the foot-ground reaction forces. Retroreflective markers were placed on the subjects according to the protocol described in Davis et al.

POPULATION:
A group of 15 patients aging from 5 to 6.8 years was compared with a similar age control group composed of 9 healthy children.

RESULTS:
Spatial and temporal parameters showed significant differences between the two groups: cadence was increased and step length was decreased significantly in the DMD group. We found a significant increase in the range of anterior-posterior pelvic tilt and in pelvic rotation. In the frontal plane there was a tendency for an increased pelvic obliquity. Dynamic range of motion in sagittal plane showed a significant difference at the ankle, with an increased plantarflexion in swing in the dystrophic patients. Maximum dorsiflexion was reduced in the DMD group. Kinetic analysis showed significant differences in power generation and absorption at the hip joint and at the ankle joint. At knee there was a reduced flexor moment in mid-stance. Ankle showed a reduced dorsiflexor moment in terminal stance and pre-swing with a consequent reduction in the peak-to-peak excursion.

CONCLUSION AND CLINICAL REHABILITATIOIN IMPACT:
It was shown that instrumented gait analysis, being more sensitive than other clinical and functional assessment methods, allowed to quantify the very early modifications characterizing locomotion worsening in the first stage of the DMD.
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Old 15th September 2011, 03:10 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

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Old 7th December 2012, 08:58 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

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Another muscular dystrophy mystery solved; MU scientists inch closer to a therapy for patients
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COLUMBIA, Mo. -- Approximately 250,000 people in the United States suffer from muscular dystrophy, which occurs when damaged muscle tissue is replaced with fibrous, bony or fatty tissue and loses function. Three years ago, University of Missouri scientists found a molecular compound that is vital to curing the disease, but they didn't know how to make the compound bind to the muscle cells. In a new study, published in the Proceedings of the National Academies of Science, MU School of Medicine scientists Yi Lai and Dongsheng Duan have discovered the missing pieces to this puzzle that could ultimately lead to a therapy and, potentially, a longer lifespan for patients suffering from the disease.

Duchenne muscular dystrophy (DMD), predominantly affecting males, is the most common type of muscular dystrophy. Patients with Duchenne muscular dystrophy have a gene mutation that disrupts the production of dystrophin, a protein essential for muscle cell survival and function. Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. While dystrophin is vital for muscle development, the protein also needs several "helpers" to maintain the muscle tissue. One of these "helper" molecular compounds is nNOS, which produces nitric oxide that can keep muscle cells healthy after exercise.

"Dystrophin not only helps build muscle cells, it's also a key factor to attracting nNOS to the muscles cells and helping nNOS bind to the cell and help repair it following activity," said Lai, a research assistant professor in the Department of Molecular Microbiology and Immunology. "Prior to this discovery, we didn't know how dystrophin made nNOS bind to the cells. What we found was that dystrophin has a special 'claw' that is used to grab nNOS and bring it close to the muscle cell. Now that we have that key, we hope to begin the process of developing a therapy for patients."

In their study, Lai and Duan found that two particular sections of the dystrophin gene must be present for nNOS to bind to the muscle cells. The sections of the gene, known as "repeaters 16 & 17," contain a "claw" that can grab nNOS and bring it to the muscle cells so that it will bind and repair any damage from regular use. Without this "claw," nNOS doesn't bind to the cells and the damage is not repaired, leading to further problems associated with muscular dystrophy.

The other key to this puzzle is dystrophin. If the protein is not present in the body, no "claw" exists and nNOS would never make it to the muscle cells. For years, scientists have been attempting to find ways to make the body manufacture more dystrophin, and thus get more nNOS to the muscle cells. Duan and Lai said the answer might lie elsewhere.

"Everybody, including those individuals with muscular dystrophy, has another protein known as 'utrophin,'" said Duan, a professor of molecular microbiology and immunology. "Utrophin is nearly identical to dystrophin except that it is missing repeaters 16 & 17, so it cannot attract nNOS to the muscle cells. In our study, we were able to modify utrophin so that it had the repeaters, and thus, the ability to grab nNOS and bring it to the muscle cells for repair. Our study was completed in mice; if we can do the same thing in larger animals, we could eventually have a significant therapy for humans with this devastating disease."
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Old 7th December 2012, 09:00 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

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Old 12th December 2012, 05:53 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

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Scientists find drug that may help in fight against Duchenne muscular dystrophy
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Drugs that are currently being tested show promise for treating patients with Duchenne muscular dystrophy, an inherited disease that affects about one in 3,600 boys and results in muscle degeneration and, eventually, death.

Now, scientists at UCLA have identified an additional drug — one that is already approved by the U.S. Food and Drug Administration and is being used in humans — that provides a powerful boost to the therapy now being tested in clinical trials. They hope that when used in combination, the drugs will provide a one-two punch that will overcome the genetic mutations that cause Duchenne muscular dystrophy (DMD), restore a missing protein needed for proper muscle function, and allow those affected by the disease to lead relatively normal lives.

The drug, called dantrolene, was found after researchers examined thousands of small molecules using a high-throughput molecular screening technique that allows them to scrutinize many molecules at the same time, said the study's senior authors, Dr. Stanley Nelson, a UCLA professor of human genetics, and Carrie Miceli, a UCLA professor of microbiology, immunology and molecular genetics.

Dantrolene is a muscle relaxant that is used to treat malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia. It is also used in the treatment of severe muscle spasms.

"Dantrolene is such an attractive candidate to test in this disease, as it is already approved and has been used safely in humans for decades, and we won't have to go through the lengthy and costly drug development process," Nelson said. "We were very pleased to find out that this drug seems to work synergistically with the drugs being tested now on boys with DMD."

The study appears Dec. 12 in the peer-reviewed journal Science Translational Medicine.

The research by Miceli and Nelson, who are married, is driven by more than just scientific curiosity. Their youngest son, Dylan, 11, was diagnosed with DMD in 2004. While he's still ambulatory — many DMD patients require the use of wheelchairs by about age 10 — Dylan can no longer run or climb stairs, and he can't shoot a basketball over his head like other boys his age. Despite these challenges, Miceli said Dylan remains a happy, funny and engaged boy, full of life and passion.

"We entered into this field because of the diagnosis of our son, but we hope our research can help many others," she said. "There are drugs that can help manage the symptoms of the disease but nothing that changes its course dramatically. We're trying to correct the defect that causes DMD with highly personalized genetic medicine."

DMD is caused by mutations in the Duchene gene, which is located on the X chromosome and is necessary for correct muscle-cell function. These mutations prohibit production of the protein dystrophin, causing the muscles, as well as the heart and respiratory system, to deteriorate. An exon — a sequence of DNA — or multiple exons are deleted in the mutant gene, causing the cellular machinery to "skip over" the exon; what was once a readable genetic instruction is thus rendered unreadable.

The drugs being tested in boys with DMD now use small pieces of DNA called antisense oligonucleotides that act as molecular "patches," allowing for the production of dystrophin. The trials thus far have shown that the exon-skipping therapy is working. However not enough dystrophin is being produced for fully normal muscle function. Nelson and Miceli sought out molecules that could give a boost to the exon-skipping drugs so that DMD patients could produce enough dystrophin for more normal muscle function.

Miceli and Nelson, members of the Broad Stem Cell Research Center at UCLA, used DMD patient–specific stem cells, reprogrammed them into muscle cells and then treated the cells with the exon-skipping drugs. The molecular screening technique then added the thousands of small molecules to the cells, and the results were analyzed by studying the treated cells to see which cells responded to which molecule. Dantrolene showed promise, Nelson said.

In collaboration with Melissa Spencer, a professor of neurology at UCLA, the scientists tested the combination in a DMD mouse model. The animals were treated with dantrolene in combination with the exon-skipping drugs. The treated mice produced more dystrophin and showed improved muscle function. Tests showed the DMD mice treated with the combination therapy were significantly stronger than those that weren't.

DMD, the most common of childhood's deadly DNA-linked diseases, generally leads to death by respiratory or heart failure in the teens or early 20s. Miceli and Nelson hope that their combination therapy could lead to longer life spans for boys with DMD.

"Our hope is that these boys won't have to die so young and suffer from the progressive muscle degeneration and the loss of mobility that they do now," Miceli said. "We hope to find a therapy that at the least results in much more mild symptoms and delays by many years the onset of this disease."

Going forward, Nelson and Miceli will further their research with the goal of translating their findings from the bench to the bedside. The pair has received a $6 million grant from the California Institute for Regenerative Medicine to do longer-term studies of their drug combination therapy in mouse models to ensure that it can restore dystrophin levels to normal or near-normal levels. They also will explore whether DMD patients with other mutations can benefit from the combination therapy. They hope their work will result in clinical trials testing the exon-skipping drugs together with dantrolene or dantrolene-like drugs togetherin boys with DMD.

"These findings highlight the value of combination therapies and the repurposing of FDA-approved medications as powerful translational strategies," the study states.

The seven-year study, conducted in three UCLA laboratories, was funded by the Foundation to Eradicate Duchenne, the Department of Defense and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. It was performed within the Center for Duchenne Muscular Dystrophy at UCLA.
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Old 14th January 2013, 02:03 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

Press Release:
Stem-cell approach shows promise for Duchenne muscular dystrophy
Quote:
Researchers have shown that transplanting stem cells derived from normal mouse blood vessels into the hearts of mice that model the pathology associated with Duchenne muscular dystrophy (DMD) prevents the decrease in heart function associated with DMD.

Their findings appear in the journal Stem Cells Translational Medicine.

Duchenne muscular dystrophy is a genetic disorder caused by a mutation in the gene for dystrophin, a protein that anchors muscle cells in place when they contract. Without dystrophin, muscle contractions tear cell membranes, leading to cell death. The lost muscle cells must be regenerated, but in time, scar tissue replaces the muscle cells, causing the muscle weakness and heart problems typical of DMD.

The U.S. Centers for Disease Control and Prevention estimates that DMD affects one in every 3,500 males. The disease is more prevalent in males because the dystrophin mutation occurs on the X chromosome; males have one X and one Y chromosome, so a male with this mutation will have DMD, while females have two X chromosomes and must have the mutation on both of them to have the disease. Females with the mutation in one X chromosome sometimes develop muscle weakness and heart problems as well, and may pass the mutation on to their children.

Although medical advances have extended the lifespans of DMD patients from their teens or 20s into their early 30s, disease-related damage to the heart and diaphragm still limits their lifespan.

"Almost 100 percent of patients develop dilated cardiomyopathy," in which a weakened heart with enlarged chambers prevents blood from being properly pumped throughout the body, said University of Illinois comparative biosciences professor Suzanne Berry-Miller, who led the study. "Right now, doctors are treating the symptoms of this heart problem by giving patients drugs to try to prolong heart function, but that can't replace the lost or damaged cells," she said.

In the new study, the researchers injected stem cells known as aorta-derived mesoangioblasts (ADM) into the hearts of dystrophin-deficient mice that serve as a model for human DMD. The ADM stem cells have a working copy of the dystrophin gene.

This stem cell therapy prevented or delayed heart problems in mice that did not already show signs of the functional or structural defects typical of Duchenne muscular dystrophy, the researchers report.

Berry-Miller and her colleagues do not yet know why the functional benefits occur, but proposed three potential mechanisms. They observed that some of the injected stem cells became new heart muscle cells that expressed the lacking dystrophin protein. The treatment also caused existing stem cells in the heart to divide and become new heart muscle cells, and the stem cells stimulated new blood vessel formation in the heart. It is not yet clear which of these effects is responsible for delaying the onset of cardiomyopathy, Berry-Miller said.

"These vessel-derived cells might be good candidates for therapy, but the more important thing is the results give us new potential therapeutic targets to study, which may be activated directly without the use of cells that are injected into the patient, such as the ADM in the current study," Berry-Miller said. "Activating stem cells that are already present in the body to repair tissue would avoid the potential requirement to find a match between donors and recipients and potential rejection of the stem cells by the patients."

Despite the encouraging results that show that stem cells yield a functional benefit when administered before pathology arises in DMD mouse hearts, a decline in function was seen in mice that already showed the characteristics of dilated cardiomyopathy. One of these characteristics is the replacement of muscle tissue with connective tissue, known as fibrosis.

This difference may occur, Berry-Miller said, as a result of stem cells landing in a pocket of fibrosis rather than in muscle tissue. The stem cells may then become fibroblasts that generate more connective tissue, increasing the amount of scarring and making heart function worse. This shows that the timing of stem cell insertion plays a crucial role in an increase in heart function in mice lacking the dystrophin protein.

She remains optimistic that these results provide a stepping-stone toward new clinical targets for human DMD patients.

"This is the only study so far where a functional benefit has been observed from stem cells in the dystrophin-deficient heart, or where endogenous stem cells in the heart have been observed to produce new muscle cells that replace those lost in DMD, so I think it opens up a new area to focus on in pre-clinical studies for DMD," Berry-Miller said.
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Old 15th January 2013, 04:26 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

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A quantum leap in gene therapy of Duchenne muscular dystrophy
Quote:
Usually, results from a new study help scientists inch their way toward an answer whether they are battling a health problem or are on the verge of a technological breakthrough. Once in a while, those results give them a giant leap forward. In a preliminary study in a canine model of Duchenne muscular dystrophy (DMD), University of Missouri scientists showed exactly such a leap using gene therapy to treat muscular dystrophy. The results of the study will be published in the journal Molecular Therapy on Jan. 15, 2013.

Muscular dystrophy occurs when damaged muscle tissue is replaced with fibrous, bony or fatty tissue and loses function. Duchenne muscular dystrophy is the most common type of muscular dystrophy predominantly affecting boys. Patients with DMD have a gene mutation that disrupts the production of dystrophin, a protein essential for muscle cell survival and function. Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. For years, scientists have been working to find the key to restoring dystrophin, but they have faced many challenges.

One of the largest hurdles in DMD gene therapy is the large size of the gene. Dystrophin is the largest gene in the human genome, containing approximately 4,000 amino acids. To fit the dystrophin gene into a vehicle that could deliver the gene to the appropriate site in the body, one has to delete 70 percent of the gene. The highly abbreviated gene is known as the "micro-dystrophin" gene. Previous studies suggest that micro-dystrophin can effectively stop muscle disease in mice that are missing dystrophin. However, mice that are missing dystrophin show minimal DMD symptoms, and results from mice often do not predict what will happen in humans. In contrast to mice, loss of dystrophin results in severe muscular dystrophy in dogs. If micro-dystrophin can work in dystrophic dogs, it will likely work in human patients. Unfortunately, when micro-dystrophin was tested in dogs in previous studies, it was not successful.

To overcome these hurdles, a team led by Dongsheng Duan, the Margaret Proctor Mulligan Professor in Medical Research at the MU School of Medicine, engineered a new micro-dystrophin gene that carries an important functional region missing in previously tested micro-dystrophins.

"We placed the new microgene into a virus and then injected the virus into dystrophic dogs' muscles," Duan said. Following gene therapy, Duan's team examined the dogs for signs of muscle disease and measured muscle force in treated and untreated dogs. After careful evaluation of 22 dogs, Duan and colleagues found that the new version of micro-dystrophin not only reduced inflammation and fibrosis, it also effectively improved muscle strength.

"This is the first time that we have seen positive gene therapy results in large mammals of DMD," said Duan. "We still have a lot of work to do, but we now know that our gene therapy strategy works in large mammals; this is a quantum leap forward in fighting this disease. Our next step is to test our strategy in a large group of muscles in the dogs, and then, eventually, see if 'whole body therapy' will work in the dogs. We are still a long way off before we will have a human treatment, but with this finding, I do see a light at the end of this tunnel."

If additional studies, including animal studies, are successful within the next few years, MU officials would request authority from the federal government to begin human drug development (this is commonly referred to as the "investigative new drug" status). After this status has been granted, researchers may conduct human clinical trials with the hope of developing new treatments for Duchenne muscular dystrophy.
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Old 9th August 2013, 01:13 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

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Combined therapy could repair and prevent damage in Duchenne muscular dystrophy
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New research on two promising gene therapies suggests that combining them into one treatment not only repairs muscle damage caused by Duchenne muscular dystrophy, but also prevents future injury from the muscle-wasting disease. The work, led by a team at The Research Institute at Nationwide Children's Hospital, is the first to look at the approach in aged mice, a key step toward clinical trials in patients. The findings were published in July in Human Molecular Genetics.

"We're excited about the fact that these are older mice and we're still able to see a sustained functional benefit from this combined therapy—this hasn't been shown before," says Louise Rodino-Klapac, PhD, a principle investigator in the Center for Gene Therapy at Nationwide Children's and lead author of the research.

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in children, affecting about one out of every 3,500 to 6,000 male births. Symptoms usually begin between the ages of 3 and 5 years and progress rapidly. Most patients are unable to walk by age 12 and ultimately need a respirator to breathe.

Patients with DMD lack the gene that makes dystrophin, a protein vital for healthy muscle tissue. Dystrophin acts as an anchor to support muscle fiber strength and prevent injury. Without it over time, the muscle degenerates, scar tissue builds up and fat slowly replaces the dead muscle. The gene that produces dystrophin is huge—the largest known gene in the body—so a much smaller version, called micro-dystrophin, has been developed for gene replacement therapeutic studies.

Another gene replacement therapy currently under study in patients with different forms of muscular dystrophy is follistatin 344, which produces a protein that enhances muscle strength and prevents atrophy.

While preliminary studies in animals of each of these therapies suggest they offer some benefit when used individually, the team at Nationwide Children's wanted to see what would happen if the therapies were combined.

Dr. Rodino-Klapac and her colleagues packaged the micro-dystrophin and follistatin therapeutic genes into adeno-associated virus, which doesn't cause disease and isn't absorbed in the genome. The virus and its genetic cargo were delivered via injection to dystrophic mice that were either 6 or 12 months old. The virus "infects" cells, the therapeutic genes are released, and the body ideally begins to produce micro-dystrophin—which prevents future muscle injuries—and follistatin—which repairs existing muscle damage.

The researchers analyzed skeletal muscle strength in the mice at 12 and 20 months of age. Mice that received the combined therapy showed a significant increase in muscle strength compared to mice treated with either the micro-dystrophin or follistatin 344 alone. Equally important, the treated mice also suffered less muscle damage over time.

A clinical trial of micro-dystrophin in patients with DMD will begin at Nationwide Children's this fall. Another trial of follistatin is already under way with support from Milo Biotechnology, a clinical stage startup company whose lead product is an adeno-associated virus (AAV)- delivered follistatin protein. That trial should conclude next year.

If both trials are successful, the next step would be to create a clinical study to look at the use of the combined therapies in patients.

"This study suggests we could do two very important things—repair existing damage and prevent additional damage—and that's key, because when most patients would come in for treatment, they would have already incurred a great deal of muscle damage," says Brian Kaspar, PhD, a principal investigator in the Center for Gene Therapy at Nationwide Children's and co-author of the new study.

This combined therapy may offer greater benefit to patients if we can effectively move this towards clinical trials," says Dr. Kaspar, who also is an associate professor of pediatrics and neuroscience at The Ohio State University College of Medicine. "We've got novel therapeutics moving forward and a number of promising therapeutics in the pipeline. There's excitement in the field right now."

"We're very enthused about this study because of the potential synergistic impact that follistatin could have with dystrophin delivery for treatment of muscular dystrophy," says Al Hawkins, CEO, Milo Biotechnology. "Our follistatin pilot trial at Nationwide Children's is independent and ongoing, but one could someday imagine a combination therapy that could have great benefit to patients."

The number of physician-scientists at Nationwide Children's is one of the reasons these studies seem to move from the lab to clinical trials so quickly, says Jerry Mendell, MD, director, Center for Gene Therapy and professor of pediatrics and neurology at The Ohio State University College of Medicine. Physician-investigators are developing therapies for diseases at the same time they are caring for the patients who have these diseases.

"We are learning more about the disease every day because we see it in the children we treat. You find out the things you need to tweak and go back to the lab and perfect it. This is all part of our basic science process," says Dr. Rodino-Klapac, who also is an assistant professor of pediatrics at The Ohio State University College of Medicine. "We have a unique setting where we can take things from bench to bedside more quickly."
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

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New Muscular Dystrophy Treatment Shows Promise in Early Study Led by Children’s National
September 17, 2013

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WASHINGTON, DC — A preclinical study led by researchers at Children’s National Medical Center has found that a new oral drug shows early promise for the treatment of Duchenne muscular dystrophy (DMD). The results, published in EMBO Molecular Medicine, show that the drug, VBP15, decreases inflammation and protects and strengthens muscle without the harsh side effects linked to current treatments with glucocorticoids such as prednisone.

Duchenne muscular dystrophy results in severe muscle degeneration and affects approximately 180,000 patients worldwide, mostly children. The current standard treatment uses glucocorticoids, but is limited due to serious side effects leading to fragile bones and suppression of both the immune system and growth.

“These findings, while preliminary, are very promising for advancing the treatment of this disease, which causes disability in so many children worldwide,” said Eric P. Hoffman, PhD, director of the Center for Genetic Medicine Research at Children’s National. “The study also suggests the potential for new strategies in very early treatment, which could further benefit patients.”
The Children’s National research team also observed that VBP15 inhibits the transcription factor NF-κB, a key cell-signaling molecule found in most cell types that plays a role in inflammation and tissue damage. The team previously found that NF-κB is active in dystrophin-deficient muscle years before the onset of symptoms, suggesting that very early treatment of Duchenne muscular dystrophy patients with VBP15 may prevent or delay the onset of some clinical symptoms.

“VBP15 has an additional property of addressing membrane defects in dystrophic muscle cells,” remarked Kanneboyina Nagaraju, DVM, PhD, the lead author of the study, and principal investigator in the Center for Genetic Medicine at Children’s National. “It is becoming increasingly clear that membrane integrity and repair are crucial factors not only in muscle, but also in cardiovascular, neurodegenerative, and airway disorders. In-creasing pre-clinical data suggest that VBP15 may show efficacy in these other disorders and in many other indications where steroids are used.” Dr. Nagaraju noted.

Initial clinical trials of VBP15 are planned, pending Food and Drug Administration (FDA) review and approval, anticipated in 2014. ReveraGen Biopharma, Inc., the first Children's National private spin-off company, is working closely with Children’s National investigators to translate the pre-clinical findings to DMD patients. ReveraGen Biopharma collaborated with NIH/TRND on VBP15, which was selected through a national com-petitive process, one of the few inaugural compounds selected through this novel pro-gram.

“The partnership with NIH and support from many others is illustrative of the importance of private-public partnerships that are essential in expediting the development of orphan disease therapeutics,” remarked Edward Connor, MD, CEO, and CMO of ReveraGen Biopharma and Director of Innovation Development at Children’s National. “We are optimistic that the new drug will translate well to patients, and are moving this forward as quickly as possible, while assuring safety.”

In addition to the support from the National Institutes of Health, the VBP15 study was also funded through the U.S. Department of Defense, Muscular Dystrophy Association, Foundation to Eradicate Duchenne, and CureDuchenne Foundation.
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Old 14th October 2013, 11:34 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

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Old 11th February 2014, 12:02 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

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Nanoparticles treat muscular dystrophy in mice
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Researchers at Washington University School of Medicine in St. Louis have demonstrated a new approach to treating muscular dystrophy. Mice with a form of this muscle-weakening disease showed improved strength and heart function when treated with nanoparticles loaded with rapamycin, an immunosuppressive drug recently found to improve recycling of cellular waste.

The study appears online in The FASEB Journal.

The investigators, including first author Kristin P. Bibee, MD, PhD, looked at a mouse model of Duchenne muscular dystrophy, the most severe inherited form of the disease. Duchenne exclusively affects boys who have to rely on wheelchairs by age 12 and die from heart or respiratory failure in their 20s.

The faulty gene that causes the disease prevents the body from producing dystrophin, a protein crucial for maintaining muscle cell integrity and function. The new study demonstrated that mice with muscular dystrophy, in addition to missing dystrophin, also can't recycle cellular waste, a process known as autophagy, or self-eating.

"Autophagy plays a major role in disposing of cellular debris," said senior author Samuel A. Wickline, MD, the James R. Hornsby Family Professor of Medicine. "If it doesn't happen, you might say the cell chokes on its own refuse. In muscular dystrophy, defective autophagy is not necessarily a primary source of muscle weakness, but it clearly becomes a problem over time. If you solve that, you can help the situation by maintaining more normal cellular function."

Though it's not clear how the missing dystrophin protein might be responsible for the muscle cells' poor housekeeping, the study showed that boosting autophagy improved skeletal muscle strength and heart function in these mice.

"Some investigators are looking for ways to replace dystrophin," said co-author Conrad C. Weihl, MD, PhD, associate professor of neurology. "But here we are focusing on the defect in autophagy. What is exciting about our approach is that there are existing drugs that activate autophagy. And by repackaging the drug on nanoparticles, we can target it specifically to muscles and correct the defect in the cells' ability to recycle waste."

When treated with rapamycin nanoparticles, the mice showed a 30 percent increase in grip strength and a significant improvement in cardiac function, based on an increase in the volume of blood the heart pumped.

"An important aspect of our study is that we are treating both skeletal muscle and heart muscle with the same drug," Wickline said. "The heart is a difficult organ to treat in muscular dystrophy. But even in older animals, this regimen works well to recover heart function, and it is effective over a short period of time and after only a few doses."

"Death from Duchenne in many people is due to heart dysfunction," said Weihl, who also treats patients with neuromuscular disorders at Barnes-Jewish Hospital. "So even improving cardiac function by 10 percent in late-stage disease could be very important."

The nanoparticle used in the study consists of an inert core made of perfluorocarbon, originally designed as a blood substitute. The particles are about 200 nanometers in diameter—500 times smaller than the thickness of a human hair. The surface of the nanoparticle is coated with rapamycin, which suppresses the immune system. The drug typically is used to help prevent organ rejection in transplant patients. It is known for its anti-inflammatory properties and, more recently, for its role in activating autophagy.

When injected into the bloodstream, according to Wickline, the nanoparticles accumulate in areas of inflammation, where damaged tissues have leaky blood vessels and are undergoing cell death and repair.

"The nanoparticles tend to penetrate and be retained in areas of inflammation," Wickline said. "Then they release the rapamycin over a period of time, so the drug itself can permeate the muscle tissue."

Compared with oral delivery, the nanoparticle approach also allowed the researchers to give the mice smaller doses of the drug.

"We showed that oral doses of rapamycin, even at 10 times the dose we used in the nanoparticles, were ineffective," Weihl said. "This is important because rapamycin suppresses the immune system, and directly targeting it to muscle in smaller doses would reduce unwanted side effects."

Current treatment for Duchenne involves corticosteroids such as prednisone, which has been shown to extend the time patients are able to walk. But steroids also cause weight gain, brittle bones, high blood pressure and other long-term side effects.

Although it's not clear why steroid treatment helps maintain skeletal muscle strength, Weihl said the study suggests prednisone also may promote autophagy, raising the possibility of combination therapy, in which both steroid treatment and rapamycin nanoparticles could be given simultaneously, each at lower doses.
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Old 20th June 2014, 04:37 AM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

Recent advances in Duchenne muscular dystrophy
Perkins KJ, Davies KE
Degenerative Neurological and Neuromuscular Disease

Quote:
Duchenne muscular dystrophy (DMD), an allelic X-linked progressive muscle-wasting disease, is one of the most common single-gene disorders in the developed world. Despite knowledge of the underlying genetic causation and resultant pathophysiology from lack of dystrophin protein at the muscle sarcolemma, clinical intervention is currently restricted to symptom management. In recent years, however, unprecedented advances in strategies devised to correct the primary defect through gene- and cell-based therapeutics hold particular promise for treating dystrophic muscle. Conventional gene replacement and endogenous modification strategies have greatly benefited from continued improvements in encapsidation capacity, transduction efficiency, and systemic delivery. In particular, RNA-based modifying approaches such as exon skipping enable expression of a shorter but functional dystrophin protein and rapid progress toward clinical application. Emerging combined gene- and cell-therapy strategies also illustrate particular promise in enabling ex vivo genetic correction and autologous transplantation to circumvent a number of immune challenges. These approaches are complemented by a vast array of pharmacological approaches, in particular the successful identification of molecules that enable functional replacement or ameliorate secondary DMD pathology. Animal models have been instrumental in providing proof of principle for many of these strategies, leading to several recent trials that have investigated their efficacy in DMD patients. Although none has reached the point of clinical use, rapid improvements in experimental technology and design draw this goal ever closer. Here, we review therapeutic approaches to DMD, with particular emphasis on recent progress in strategic development, preclinical evaluation and establishment of clinical efficacy. Further, we discuss the numerous challenges faced and synergistic approaches being devised to combat dystrophic pathology effectively.
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Old 18th November 2014, 04:29 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

Effects of AFO Use on Walking in Boys With Duchenne Muscular Dystrophy: A Pilot Study.
Townsend EL, Tamhane H, Gross KD.
Pediatr Phys Ther. 2014 Nov 14.
Quote:
PURPOSE::
Although bracing in the late ambulatory stage of Duchenne muscular dystrophy (DMD) has been described, the effects of ankle-foot orthoses (AFOs) in earlier stages have not been evaluated. The aim of this pilot study was to describe the effects of dynamic response AFO (DR-AFO) use in boys with DMD who are ambulatory.
METHODS::
Using a crossover design, 3 boys were randomly assigned to either a 2-week DR-AFO or a placebo intervention. Phases were separated by a 1-week washout period. Primary outcomes were time to walk 10 m and a 6-Minute Walk Test.
RESULTS::
With DR-AFO use, declines in 10-m walk time (median decline = 0.8 s) and 6-Minute Walk Distance (median = 25.0 m) occurred. Parental report suggested that the use of DR-AFOs increased falls in 2 of 3 participants.
CONCLUSION::
This pilot study does not support the use of DR-AFOs by boys with DMD who are ambulatory.
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Old 1st December 2014, 08:51 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

Gait propulsion in patients with facioscapulohumeral muscular dystrophy and ankle plantarflexor weakness
N.H.M. Rijken, MSc, B.G.M. van Engelen, MD PhD, J.W.J. de Rooy, MD, V. Weerdesteyn, PhD, A.C.H. Geurts, MD PhD
Gait & Posture; Articles in Press
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Highlights
•Evaluation of associations between muscle involvement, kinetics and gait speed.
•Calves are optimally recruited to increase gait speed in persons with FSHD.
•Common compensatory gait strategies are restricted in persons with FSHD.
•Trunk stability may be critical to recruit a successful ‘pull-off’ strategy.
Quote:
Facioscapulohumeral muscular dystrophy is a slowly progressive hereditary disorder resulting in fatty infiltration of eventually most skeletal muscles. Weakness of trunk and leg muscles causes problems with postural balance and gait, and is associated with an increased fall risk. Although drop foot and related tripping are common problems in FSHD, gait impairments are poorly documented. The effect of ankle plantarflexor involvement on gait propulsion has never been addressed. In addition to ankle plantarflexion, gait propulsion is generated through hip flexion and hip extension. Compensatory shifts between these propulsion sources occur when specific muscles are affected. Such a shift may be expected in patients with FSHD since the calves may show early fatty infiltration, whereas iliopsoas and gluteus maximus muscles are often spared for a longer time. In the current study, magnetic resonance imaging was used to assess the percentage of unaffected calf, iliopsoas and gluteus maximus muscles. Joint powers were analyzed in ten patients with FSHD at comfortable and maximum walking speed to determine the contribution of ankle plantarflexor, hip flexor and hip extensor power to propulsion. Associations between muscle morphology, power generation and gait speed were assessed. Based on multivariate regression analysis, ankle plantarflexor power was the only factor that uniquely contributed to the explained variance of comfortable (R2 = 80%) and maximum (R2 = 86%) walking speed. Although the iliopsoas muscles were largely unaffected, they appeared to be sub-maximally recruited. This submaximal recruitment may be related to poor trunk stability, resulting in a disproportionate effect of calf muscle affliction on gait speed in patients with FSHD.
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Old 1st December 2014, 08:57 PM
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Default Re: Early signs of gait deviation in Duchenne muscular dystrophy

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Gait propulsion in patients with facioscapulohumeral muscular dystrophy and ankle plantarflexor weakness
N.H.M. Rijken, MSc, B.G.M. van Engelen, MD PhD, J.W.J. de Rooy, MD, V. Weerdesteyn, PhD, A.C.H. Geurts, MD PhD
Gait & Posture; Articles in Press
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