Scientists Uncover Most Detailed Picture Of Muscular Dystrophy Defect

Scientists from the Florida campus of The Scripps Research Institute have revealed an atomic-level view of a genetic defect that causes a form of muscular dystrophy, myotonic dystrophy type 2, and have used this information to design drug candidates with potential to counter those defects—and reverse the disease.

“This the first time the structure of the RNA defect that causes this disease has been determined,” said TSRI Associate Professor Matthew Disney, who led the study. “Based on these results, we designed compounds that, even in small amounts, significantly improve disease-associated defects in treated cells.”

Myotonic dystrophy type 2 is a relatively rare form of muscular dystrophy that is somewhat milder than myotonic dystrophy type 1, the most common adult-onset form of the disease.

Both types of myotonic dystrophy are inherited disorders that involve progressive muscle wasting and weakness, and both are caused by a type of genetic defect known as a “RNA repeat expansion,” a series of nucleotides repeated more times than normal in an individual’s genetic code. The repeat binds to the protein MBNL1, rendering it inactive and resulting in RNA splicing abnormalities—which lead to the disease.

Many other researchers had tried to find the atomic-level structure of the myotonic dystrophy 2 repeat, but had run into technical difficulties. In a technique called X-ray crystallography, which is used to find detailed structural information, scientists manipulate a molecule so that a crystal forms. This crystal is then placed in a beam of X-rays, which diffract when they strike the atoms in the crystal. Based on the pattern of diffraction, scientists can then reconstruct the shape of the original molecule.

Prior to the new research, which was published in an advance, online issue of the journal ACS Chemical Biology, scientists had not been able to crystallize the problematic RNA. The Scripps Florida team spent several years on the problem and succeeded in engineering the RNA to have crystal contacts in different positions. This allowed the RNA to be crystallized—and its structure to be revealed.

Using information about the RNA’s structure and movement, the scientists were able to design molecules to improve RNA function.

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New muscular dystrophy treatment shows promise in early study

A preclinical study led by researchers in the United States has found that a new oral drug shows early promise for the treatment of muscular dystrophy. The results, which are published today in EMBO Molecular Medicine, show that VBP15 decreases inflammation in mice with symptoms similar to those found in patients with Duchenne muscular dystrophy. The authors found that the drug 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. Treatment with the current standard therapy, glucocorticoids, can only be used for a short time due to serious side effects leading to fragile bones and suppression of both the immune system and growth hormone production.

The researchers also observed that VBP15 inhibits the transcription factor NF-kB, a key cell-signaling molecule found in most animal cell types that plays a role in inflammation and tissue damage.

The study authors previously found out that NF-kB 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.

“It is becoming increasingly clear that membrane integrity and repair are crucial factors in muscle, cardiovascular, neurodegenerative and airway disorders. The chemical properties of VBP15 also suggest potential for the treatment of other diseases.” remarked Kanneboyina Nagaraju, DVM, PhD, the lead author of the study and a principal investigator in the Center for Genetic Medicine Research, Children’s National Medical Center in Washington, DC. The authors conclude that VBP15 merits further investigation for efficacy in clinical trials.

Scientists Can Turn Muscular Dystrophy Defect On, Off In Cells

Scientists at the Scripps Research Institute have discovered molecules that allow control over the most common adult onset form of muscular dystrophy. Their findings were published in the latest issue of the journal Nature Communications.

“This is the first example I know of at all where someone can literally turn on and off a disease,” said TSRI Associate Professor Matthew Disney. “This easy approach is an entirely new way to turn a genetic defect off or on.”

Myotonic dystrophy, an inherited disorder, is the most common form of a group of muscular dystrophies that progressively deteriorate the muscles. It is cause by an RNA defect called “triplet repeat” in which a series of three nucleotides are repeated more times than normal in an individual’s genetic code.

Disney’s team developed three new compounds, looking at their effect on human muscle tissue both with and without the defect. Diseased muscle with the RNA-binding compound caused the disease to go away.

“In complex diseases, there are always unanticipated mechanisms,” he said. “Now that we can reverse the disease at will, we can study those aspects of it.”

FDA seeks more data on Sarepta muscular dystrophy drug

Adithya Venkatesan

(Reuters) – Sarepta Therapeutics Inc said U.S. health regulators have asked for additional information on its experimental drug to treat a rare degenerative disease in boys.

Sarepta shares fell 12 percent in extended trading after closing at $39.24 on the Nasdaq on Monday.

The drugmaker said the U.S. Food and Drug Administration sought more information about the drug, eteplirsen, to consider early approval.

“We do not anticipate that the request for information by the FDA nor the delay of a few months on the definitive decision on the acceptability of an accelerated approval submission will have an impact on our ongoing activities,” Chief Executive Chris Garabedian said on a conference call.

The company said in October that the drug significantly improved walking ability in a mid-stage trial for patients with Duchenne Muscular Dystrophy (DMD).

DMD is caused by mutation of the gene that helps produce dystrophin, a protein that plays a key role in muscle fiber function. The drug enables the production of dystrophin.

Sarepta said it was confident that the consistency of the dystrophin levels will be enough to determine that the drug needs a quicker approval.

The company said the FDA indicated that the safety data from the first few months of a yet-to-be-conducted late-stage study could be used to support approval of the drug.

The company said it intends to continue dosing patients in a late-stage study in the first quarter of 2014.

“The fact that the FDA is just asking for some further clarification which will all occur over the near term, within one quarter or so seems to be a positive,” said William Blair & Company analyst Tim Lugo.

Nine of the 10 brokerages tracked by Thomson Reuters StarMine recommend buying Sarepta shares. Their mean price target is $42; five of the analysts rate the company a “strong buy.

(Reporting By Adithya Venkatesan in Bangalore; Editing by Maju Samuel and Steve Orlofsky)

Copyright © 2013, Reuters

Protein injection holds promise for muscular dystrophy treatment

Injecting a novel human protein into muscle affected by Duchenne muscular dystrophy significantly increases its size and strength, scientists have discovered.

The findings could lead to a therapy akin to the use of insulin by diabetics.

The study was conducted by Dr. Julia von Maltzahn and Dr. Michael Rudnicki, the Ottawa scientist who discovered muscle stem cells in adults.

“This is an unprecedented and dramatic restoration in muscle strength,” said Dr. Rudnicki, a senior scientist and director for the Regenerative Medicine Program and Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute.

He is also a Canada Research Chair in Molecular Genetics and professor in the Faculty of Medicine at the University of Ottawa.

“We know from our previous work that this protein, called Wnt7a, promotes the growth and repair of healthy muscle tissue. In this study we show the same types of improvement in a mouse model of Duchenne muscular dystrophy. We found that Wnt7a injections increased muscle strength almost two-fold, to nearly normal levels. We also found that the size of the muscle fibre increased and there was less muscle damage, compared to mice not given Wnt7a,” he explained.

Duchenne muscular dystrophy is a genetic disorder that affects one of every 3,500 newborn males. In Canada, all types of muscular dystrophy affect more than 50,000 people. The disease often progresses to a state where the muscles are so depleted that the person dies due to an inability to breath. For people with Duchenne muscular dystrophy, this usually happens in their 20s or 30s. “This is also exciting because we think it’s a therapeutic approach that could apply to other muscle-wasting diseases,” said Dr. Rudnicki.

These results were published in the Proceedings of the National Academy of Sciences.

Muscular dystrophy therapy biotech wins $250K JumpStart investment

A clinical-stage biotechnology startup that’s developing a therapy for neuromuscular diseases such as muscular dystrophy has received a $250,000 investment from nonprofit economic development group JumpStart.

Cleveland-based Milo Biotechnology’s drug candidate is based on technology developed at Columbus’ Nationwide Children’s Hospital, and the company has already begun a clinical trial there, according to a statement from JumpStart.

The company’s lead product is a protein that stimulates muscle growth and prevents muscle scarring after injury.

Muscular dystrophy is a group of inherited disorders that involve muscle weakness and loss of muscle tissue, which get worse over time. It’s most frequently found in children.

Milo’s phase 1/2 clinical trial is enrolling patients with two specific types of muscular dystrophy — Becker muscular dystrophy and inclusion body myositis. The trial was funded by a grant from Parent Project Muscular Dystrophy.

In preclinical studies in mice and nonhuman primates, the drug candidate brought about increases in muscle size and strength, according to the statement.

The company’s CEO is Al Hawkins, currently an entrepreneur-in-residence with Cleveland nonprofit BioEnterprise. Previously, Hawkins managed a venture capital fund for Boston University and was a partner with Agave Group New Venture Consulting.

Good-bye, Wheelchair, Hello Exoskeleton

In a warehouse that looks like a cross between a mad inventor’s garage and a climbing gym, a pair of mechanical legs hangs from the ceiling on ropes. With the quiet whir of four motors, one in each hip and knee, the legs take a step, then another and another. This is an exoskeleton walking suit, and it is taking the hundreds of thousands of steps that regulators demand to prove that it’s no mere toy but a reliable medical device, one that just might change the lives of people who thought they’d never again rise from a wheelchair.
graphic link to special report

The Berkeley, Calif., warehouse is the home of Ekso Bionics (formerly known as Berkeley Bionics), a young ­company that’s about to step out onto the world stage. Early this year the company will begin selling its Ekso suit to rehab clinics in the United States and Europe, to allow patients with spinal cord injuries to train with the device under a doctor’s supervision. By the middle of 2012, the company plans to have a model for at-home physical therapy.

User Tamara Mena, who was paralyzed in 2005, gleefully puts her exoskeleton walking suit through its paces.

When you don the Ekso, you are essentially strapping yourself to a sophisticated robot. It supports its own 20-kilogram weight via the skeletal legs and footrests and takes care of the calculations needed for each step. Your job is to balance your upper body, shifting your weight as you plant a walking stick on the right; your physical therapist will then use a remote control to signal the left leg to step forward. In a later model the walking sticks will have motion sensors that communicate with the legs, allowing the user to take complete control.

“We took the idea of the external skele­ton, and we added nerves in the form of sensors and motors that represent your muscles and computers that represent your brain,” says Eythor Bender, CEO of Ekso Bionics.

The company began its evolution in 2005 with the ExoHiker, an exoskeleton that allows able-bodied people to carry 90 kg (about 200 pounds) with minimal exertion. The company’s engineers at first thought it would take 5 kilowatts to power such an exoskeleton, which would have meant bulky batteries and motors. The breakthrough was a redistribution of weight that reduced the power requirements by three orders of magnitude. A later system, the load-carrying HULC (Human Universal Load Carrier), was licensed to Lockheed Martin Corp. for military development in 2009, and Ekso Bionics’ engineers began looking for a new direction. Their energy-efficient devices, they realized, left them with a “power budget” that could be spent on moving the user’s legs. That’s when paraplegic people became the company’s target customers.

A few other companies around the world are bringing out exoskeletons for people with disabilities, but Ekso Bionics’ push in 2012 may give it a market advantage. Ten top U.S. rehab clinics have already signed up for the first batch of production units.

One of the first devices will go to Mount Sinai Hospital, in New York City, where Kristjan T. Ragnarsson, chairman of the department of rehabilitation medicine, has treated spinal cord patients for 40 years. His patients’ priorities have never changed. “The first thing they want to know is whether they will walk again,” says Ragnarsson. “As their physician, I always have to address that question.”

Over the years he has told his patients about the latest inventions, from stiff air-filled garments to devices that electrically stimulate the muscles, but all these contraptions proved too difficult for the patients to operate. “They were completely exhausted after just a few steps,” he says.

Ragnarsson thinks the Ekso can succeed where so many others failed, because the powered device does most of the labor for the patient. “I’m optimistic, actually, that this will work,” he says. “I think my patients will be able to stand up and take a few steps and face the next person directly on!”