Exon Skipping for Duchenne Muscular Dsystrophy

There was some exciting data presented at MDA’s 2014 clinical Conference held this week in Chicago regarding gene therapy for Duchenne muscular dystrophy (DMD).

What is exon skipping?

skimming_stones

Many cases of DMD are caused by small deletions in the dystrophin gene which lead to frame shifts and totally disrupt transcription:

If you imagine that the gene is made up of segments (or exons) which ultimately spliced together to make a recipe or message for producing the protein:

exon-skipping-scheme

A deletion of exon 71 would be considered “in frame” because the 70 and 72 could still joint up and allow transcription.  However, a deletion of exons 48 through 50 would be “out of frame” since 47 and 51 do not splice back together to form the message:

exon

The message would become corrupted and the gene product, in this case dystrophin, would be dysfunctional or even totally absent:

frameshift

The drug Eteplirsen will link 47 and 51 back together again, and in so doing restore the reading frame and facilitate transcription of an altered but hopefully functional gene product:

exon skiip

Does it work?

A clinical study started in August 2011

The preliminary results from this study were very encouraging – the boys who received the drug maintained strength and walking ability and there were no treatment related adverse effects.

What’s the next step?

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BYM338 (Bimagrumab) for Inclusion Body Myositis – New cure or next dud?

Posted by Jeffrey Schneider, MSIV, Drexel University College of Medicine

There has recently been a flurry of news articles about a new treatment in clinical trials for Inclusion Body Myositis. Novartis has announced that BYM338 (Bimagrumab) has recently received FDA breakthrough status for the treatment of inclusion body myositis. What does this mean and what are the implications? Is this a cure or sensationalist hype? What do we need to know about BYM338 other than a sorely needed name change. Before we get to that let’s talk a little about inclusion body myositis.

What is Inclusion Body Myositis?

Inclusion Body Myositis (IBM) is a progressive disease of muscle weakness. Myositis, derived from Greek as many of our beloved medical terms are, is aptly named as it is a disease characterized by inflammation of the muscle. This disease most commonly presents insidiously with weakness of the fingers and quadriceps (thigh). This leads to difficulty with everyday activities like walking or holding objects. Some may also develop dysphagia (difficulty swallowing). The disease may occur sporadically (sIBM) and rarely as Hereditary IBM. It is not a fatal disease but the progressive muscle weakness means that many will rely on assistance for walking and everyday activity within 5 years.  This condition can often be difficult to diagnosis and can be aided with the help of a muscle biopsy.

Epidimiology

IBM is an age related disease that typically affects those 50 and older. Men are more often affected It is the most common of the inflammatory myopathies but is still a relatively rare condition

Differential Diagnosis

A common laboratory finding of myositis is an elevated in Creatine Kinase (CK).  CK, however, is not specific for just Inclusion Body Myositis and many conditions may also have this abnormal laboratory finding. More commonly cholesterol lowering drugs like Statins and Fibrates may lead to myositis. IBM may be mistaken for the other inflammatory myopathies, polymyositis and dermatomyositis. Polymyositis and dermatomyositis are treated with steroids and other immunosuppressive drugs of which have little effect on IBM which can sometimes be the clue that you might be dealing with IBM.

Pathology

The cause of IBM is not fully understood. What is evident is that there is an element of muscle inflammation and an element of muscle degeneration. A muscle biopsy will show the architecture of muscle at the microscopic level. Some of the key features that help to identify IBM are of course the inclusion body itself which are abnormal clumps of protein and tubules. Another feature are rimmed vacuoles which are empty pockets found within the cells. They are found in other inflammatory myopathies but occur in greater numbers in IBM.

Here is another biopsy slide showing some of the characteristic vacuoles and also the inflammatory cells in the endomysium (the layer that surrounds each individual muscle fiber).

Current Treatment

Unlike dermatomyositis and polymyositis there is currently no effective treatment of IBM.  Studies have shown the failure of steroids and other immunosuppressive agents.  Therefore it is approached symptomatically with physical therapy and exercise.

Where does that leave us now?

Novartis’ recent announcement is quite an interesting one. BYM338 (Bimagrumab) is a monoclonal antibody targeted to a very specific receptor on muscles cells. Monoclonal antibody therapy is a very field based on the human body’s own immune system.  B cells, a type of white blood cell, produce millions of variations on a common antibody to target infection. When the right antibody is found to bind to an infectious particle that B cell will undergo a series of interactions leading to cloning of that cell. This is the monoclonal proliferation that leads to a highly specific response. Researchers  have taken advantage of this concept to create highly targeted drugs.

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In the case of BYM338 (Bimagrumab), it is targeted to Type II Activin receptors on muscle tissue. This receptor normally binds an enzyme called Myostatin which inhibits muscle growth. By blocking this receptor the drug is blocking the effect of Myostatin and in theory allowing muscle growth. It is a novel approach to muscle degeneration seen in IBM.An interesting side note is that there is a breed of cattle with a defect in the gene for myostatin. The Breed is called Belgian Blue, their mutation leads to non-functioning Myostatin. They also look like this…

So is this the cure to IBM that we have been looking for. Currently the data has not been published so it is impossible to say. What we do now is that the FDA has approved BYM338 for “breakthrough” status. What this means is that the FDA is going to expedite the review of BYM338 based on what it has seen so far. This does not mean that it is a new breakthrough therapy that has passed all of its tests but rather that the FDA is intrigued by its prospects. It is also important to know that BYM338 has only gone through Phase II of Clinical trials. Phase I assesses the safety of a drug. Phase II trials are compared against placebo with a relatively small sample size (100-300). Phase 3 trials and FDA review will most likely take several more years before we will find out whether BYM338, or rather endearingly BYM338, lives up to its expectations. Could this drug be expanded to treat muscle wasting in cancer patients or the elderly? That is something developers are probably interested in but we currently don’t have the published data to support it. Could this effectively treat IBM? Maybe. Could this be a dud? Possibly. Will it be expensive? Most definitely.

New study compares steroid regimens in boys with Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) affects 1 in 3,600 boys and is caused by a mutation in the dystrophin gene, resulting in progressive muscle weakness.

Affected male children are normal at birth, but develop signs of muscle weakness before age 6, usually first affecting the legs and pelvis, causing difficulty getting up from the floor or a sitting position, and difficulty climbing stairs. Untreated boys are usually wheelchair dependent by age 12.

Ongoing research is leading towards pre-symptomatic diagnosis of DMD, and there has been some progress in genetic therapy for affected boys identified in these early stages of the disease.

However, so far corticosteroid therapy is the only treatment that has been shown to increase muscle strength in boys already affected with symptoms of DMD.

Steroids can cause side effects, and there is wide variability whether doctors doctors prescribe prednisone or deflazacort, as well as the dosing, duration of steroid use or even whether steroids are prescribed at all.

A new study aims to answer some of these questions.

The study is looking to enroll boys aged 4-7 with genetically confirmed DMD who have not taken steroids before.

They will be included in the study for 3-5 years and receive either:
1. Prednisone 0.75mg/Kg/d, or
2. Prednisone 0.75mg/Kg/d 10days on then 10 days off, or
3. Deflazacort 0.9mg/Kg/d

They will need hospital visits every 3 months for the first 6 months, then every 6 months thereafter.

This study is available locally at Penn Sate Hershey Medical Center – parents or physicians of interested patients should contact Beth Stephens at 717-531 0003 extension 283395 or by email for more information.