Isis Pharmaceuticals has announced that it has started a phase 1 clinical trial of ISIS-DMPKRx — a drug designed to reduce the production of toxic molecules in the cells of people with myotonic dystrophy type 1. Previous clinical trials for myotonic dystrophy have only tested drugs aimed at relieving particular symptoms of the condition such as muscle stiffness or heart problems.

This new drug uses so-called “antisense” technology which involves small pieces of genetic material which bind to genetic instructions known as RNA. This approach has been shown to reverse symptoms of myotonic dystrophy in a mouse model of myotonic dystrophy.

How is the drug anticipated to work?
Myotonic dystrophy type 1, the most common type of myotonic dystrophy, is caused by the inheritance of extra DNA code at the end of a gene called ‘DMPK’. A three letter DNA code is repeated many hundreds of times instead of the usual number which is less than thirty.

A molecule called ‘RNA’ is key to causing myotonic dystrophy. RNA is the carbon copy of DNA that carries genetic messages from the centre of the cell (the nucleus) to the rest of the cell in order to build proteins.

In myotonic dystrophy the extra repeats in the RNA copy of the DMPK gene cause it to fold in half into a hairpin shape and get stuck inside the nucleus. This toxic RNA then hooks onto certain proteins trapping them inside the nucleus. The proteins held in the nucleus are then unable to perform their normal functions. For example, the protein known as ‘MBNL1’, which has a crucial role in ensuring that other proteins are properly formed, is trapped by the toxic RNA.

ISIS-DMPKRx is a small piece of genetic material (similar to DNA) designed to specifically bind to the extra repeats in the toxic DMPK RNA. This stops it interacting with proteins and/or leads to the RNA’s destruction. In preclinical studies in a mouse model the drug entered muscle cells and significantly reduced the amount of toxic RNA. This led to a reversal of the disease symptoms that was sustained for up to one year after treatment.

Antisense technology can be used in a variety of ways to treat different genetic diseases. Isis Pharmaceuticals (in collaboration with Biogen Idec) is also developing antisense drugs for two other neuromuscular diseases — spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Promising clinical trial results are also being produced from clinical trials for Duchenne muscular dystrophy using antisense technology called “exon skipping”.

About the clinical trial
Only healthy volunteers are to be included in this trial – this is standard practice for phase 1 trials. The trial will give the first information about the safety of the drug in humans. Healthy volunteers are used in phase 1 studies because if side effects do occur then it is more straightforward to know that it is likely to be caused by the drug, not because of the symptoms of myotonic dystrophy. There is also usually little or no physical benefit for the participants in phase 1 trials because the trials are so short, so it is better to ‘save’ the patients for the phase 2 trial which will be longer and will start to look at whether the treatment works.

Upon completion of the Phase 1 safety evaluation Isis can then proceed with the next clinical trial, which they hope to start before the end of this year (2014). This will be a Phase 1/2a study to evaluate the safety and best dose of ISIS-DMPKRx in patients with myotonic dystrophy type 1. This will be a relatively small study and it is likely that all of the clinical trial sites will be in the USA. Details of this study, including eligibility criteria and location, will be posted on as soon as they become available, which is anticipated to be late in 2014. If all goes to plan and ISIS-DMPKRx proceeds to larger phase 2 and 3 studies international clinical sites will become involved.

What does this mean for people with myotonic dystrophy?
The start of this trial is encouraging news because targeting the root cause of myotonic dystrophy is the ultimate goal for an effective treatment. The condition affects many different systems in the body besides the muscles and it is hoped that a therapy such as this will be able to alleviate many of the symptoms that affect people with myotonic dystrophy.

If this treatment proves to be safe and effective, a similar drug could be designed to treat myotonic dystrophy type 2 which is caused by the inheritance of extra pieces of repeated DNA in a different gene.

We eagerly await the results of this and further clinical trials of antisense drugs for myotonic dystrophy as the results of clinical trials testing similar technology for other conditions are looking promising.

Further information
• Read the Isis Pharmaceuticals press release
• The MDA myotonic dystrophy factsheet contains more information about the condition including a research summary
• For definitions of any terms that you are not familiar with please take a look at our glossary
• More research news
Clinical trials – your questions answered
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Uploaded 12 June 2014