Progress towards a cure for Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a severe inherited muscular dystrophy that causes progressive muscle degeneration which eventually leads to loss of the ability to use muscles and death, and every year tens thousands of children are born afflicted with the disease. It is caused by mutations in the DMD gene that encodes dystrophin, a protein vital to the maintenance of muscle cell structure and function. Not surprisingly there are several charities around the world dedicated to finding a cure, and it looks as if their persistance may soon pay off.

Earlier this week the NIH announced some exciting results from a study (1) of a cocktail of morpholinos, small artificial molecules also called antisense oligonucleotides which mimic DNA and bind to it, that in a process termed exon skipping act as patches to allow the production of dystrophin where it would otherwise fail due to a mutation in the DMD gene. The team lead by Dr. Eric Hoffman found that they when they injected this morpholino cocktail into the bloodstream of dogs that suffer from duchenne muscular dystrophy skeletal muscle degeneration stopped, though the degeneration of cardiac muscle continued. They chose dogs for this experiment because they accurately mimic the physiological effects of human DMD, so the researchers were able to tell if the exon-skipping approach could actually restore enough of the dystrophin function to halt the progression of the disease. Mouse models of DMD, particularly the Mdx mouse which has a mutation in exon 23 that prevents it from making dystrophin, have proved invaluable to research on exon-skipping and other approaches to treating DMD. Their drawback is that the mice only develop a relatively mild version of the disease, and so are not always ideal if you want the determine whether a “patched” dystrophin will actually prevent muscle deterioration. While the truncated dystrophin protein produced as a result of exon skipping does not function as well as normal dystrophin in this study on dogs,  they did demostrate that enough dystrophin function was restored to halt deterioration and make a real difference to patients.

Where this work is an advance on previous research is that it uses an intravenous injection that then relied on the bloodstream to circulate the morpholinos to all muscle groups, rather than directly injecting the morpholinos into each of the muscle that need treatment. This is a significant improvement that will make the technique far more practical in the clinic. The use of a cocktail of morpholinos that each target different mutation sites in the DMD gene is also interesting, many DMD patients have several different mutations in their DMD genes and previous methods using antisense oligonucleotides have only been of potential benefit to a small proportion of patients, whereas the cocktail approach may benefit more that 90% of them.

As I mentioned above a serious drawback with the morpholino cocktail technique was that it failed to restore dystrophin function in the heart, but another recent research paper (2) suggests that this problem can be solved by attaching a cell-penetrating peptide to the morpholino. Using this approach Dr. Qi Lu and colleagues at the McColl-Lockwood Laboratory for Muscular Dystrophy were able to safely restore almost full dystrophin activity in both cardiac and sleletal muscles by intravenous injection of a cell-penetrating peptide linked to a morpholino that patches the exon 23 mutation in the Mdx mouse model of DMD.  This is an excellent result, and if it can be combined with a cocktail approach has great potential for the future treatment of DMD.

All in all morpholinos are looking like an increasingly promising approach to treating DMD, and along with other approaches including the drug PTC124 that is currently in clinical trials* and stem cell transplantation, offer hope to the many thousands of DMD sufferers around the world.

*As you might expect the basic research that underpinned the dicsovery of PTC124 and the subsequent pre-clinical evaluation of its efficacy and safety relied heavily on  mouse models of  Duchenne muscular dystrophy and cystic fibrosis (3).

Regards

Paul Browne

Related posts:

Stem Cell Hope for Duchenne Muscular Dystrophy

Promising Clinical Trial Result for Exon Skipping in Duchenne Muscular Dystrophy

1) Yokota T. et al. “Efficacy of systemic morpholino exon-skipping in duchenne dystrophy dogs” Annals of Neurology Published Online: 13 Mar 2009, DOI:10.1002/ana.21627

2) Wu B. et al. “Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer” PNAS Volume 105(39), pages 14814-14819. DOI:10.1073/pnas.0805676105

3) Hirawat S. “Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers.” J Clin Pharmacol. Volume 47(4), pages 430-444 (2007) DOI:10.1177/0091270006297140

26 thoughts on “Progress towards a cure for Duchenne Muscular Dystrophy”

  1. my brother is one year old and we recently found out that he has DMD.
    we are all very worried about him, and i would like to know any guesses of when the treatment to cure DMD will be available?

  2. I’m a mother of 4 son who is affected by DMD can you please tell me where to find some help because we belong in an indigent family please help us my 2 sons already died of the disease I want to at least make my two other sons happy even in their short stay here on earth.

  3. my son is suffering by DMD.please help me for his treatment. he cant walk and age is 10.I want to know if any clinic for research and treatment is working in India. Is there possibility of treatment. contact no.+919412894003

  5. Pawan, where do you live?

    If you live in the US I would recommend that you contact the Muscular Dystrophy Association http://www.mda.org/research/ who play an important role in supporting patients as well as funding research into treatments, and potential cures, for muscular dystrophy.

  6. my son is suffring by DMD.please help me for his treatmant. he cant walk and age is 16.

  7. My son aged 20 years is suffering from DMD. I want to know if any clinic for research and treatment is working in India. Is there possibility of treatment.

    1. Dear S.K Sharma, I would recommend that you contact the Muscular Dystrophy Association India http://www.mdindia.org/ who are involved with both patient care and research into new therapies.

      Their website also includes links to several other organizations that provide support for people with muscular dystrophy in India, some of which also fund research http://www.mdindia.org/org_india.html

      I wish all the best for you and you son.

  8. my son is four years old and suffered from dmd . I want to know about dmd care center

  12. hi… my son suspected with this disease… had to run other test to confirm.. my heart is broken…

    btw, is there any different between abnormal and no distrophn?

    1. Hi Zach, sorry to hear about your son, and I hope that you will get some good news soon.

      I’ll start by saying that I am not a medical doctor and can’t offer medical advice, you need to discuss this with your doctor and muscular dystrophy specialists who can advise you on what to do next.

      The short answer to your question is that there is a difference between abnormal and no dystrophin.

      Some mutations in the dystrophin gene result in the production of a shortened but still partially function of the dystrophin protein. This usually leads to a syndrome called Becker muscular dystrophy, which can vary in seriousness from very similar to Duchenne Muscular dystrophy (DMD) to almost asymptomatic.

      DMD is caused by a variety of mutations in the dystrophin gene that lead to no dystrophin protein being produced. There are several types of experimental treatment under development and whether a particular therapy will be appropriate for an individual DMD case will depend on the specific mutation that disrupts the dystrophin gene. An exon-skipping therapy appears promising in early clinical trials http://www.muscular-dystrophy.org/news/1771_uk_exon_skipping_clinical_trial_for_duchenne_reports_promising_preliminary_results would only help about 15% of DMD patients, but as I mentioned in my report above other exon-skipping techniques are being developed that may be able to help over 90% of DMD patients.

      These techniques are still at a relatively early stage of development, and more clinical ttrials will need to take place. Doctors are sometimes understandibly reluctant to appear to pressure parents to enter their children into clinical trials, so one thing I will say is that if after reading more about the therapies that are being studied you decide that you would like your son to take part in a clinical trial you should make your wish known to your son’s doctors.

      If you haven’t seen it already the Muscular Dystrophy Campaign website has a lot of useful information and contacts http://www.muscular-dystrophy.org/

  14. Hi
    I am so sorry for your kids. I think they are very lucky to have such devoted parents.
    In the interests of providing information that I found useful, and not suggesting that it is in any way a cure, avoiding additives and natural substances in some foods can help. It is a doctor prescribed diet for allergies but tends to lessen hyperactivity and other problems in children. It’s called Failsafe. fedup.com.au. If you should try it and it helps let us know.

    KR

  16. im andre 17.yrs.old from manila, philippines. Im also suffering the same thing. Just please contact me for any progress of studies of cure…

    I just want you to know ALSO THAT I CAN STILL WALK AT THE AGE OF 17, I CAN STILL MANAGE MYSELF DOING ANY STUFF. I PLAY VOLLEYBALL AND YES, I CAN SPIKE! I CAN STILL MOVE INDEPENDENTLY, but cannot run,jump,go upstairs, etc just by myself

    1. Hi, Andre

      I am looking for people with facial paralysis. I understand you have Duchenne..

      How do we contact you? We’re doing a documentary about people with facial paralysis.

      Pls. call once you receive this message.

      Andrea S. Pineda
      I-Witness Researcher
      Cell: 09177447631

  17. my son is eight and half year old & suffering from D.M.D. if any remeady comes pl. contact me on 9960681246

  19. Please want to know any successfull treatment for
    duchenne muscular dystrophy . As my son of age 7 suffering from the same.
    Please do contact me and inform me if possible.
    I am realy in need for support to help my son.
    please help me.

    1. you got any treatment for your son please tell me because my brother also suffering from same DMD, if you have any possible please try to contact me 09959261271 dis is my contact number .
      please inform me…
      please

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