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| Aim: |
Use drugs to treat the various aspects of disease pathology. |
| Background: |
Due to the loss of dystrophin, patient's muscle fibers are continuously damaged during exercise. Lost muscle tissue is replaced by scar tissue ("fibrosis"). This process is irreversible and is exacerbated by an immune response that is initiated by the muscle damage. Drugs can help to increase muscle growth, to compensate for the lost muscle tissue. Alternatively, they can suppress the immune system or inhibit scar tissue formation. |
| Disadvantage: |
The drugs only treat the symptoms of the disease, not the cause. The vast majority work temporarily to slow down disease progression. |
| Advantage: |
Generally drugs can be taken orally and act on all muscles in the body (no delivery problems as observed for gene and cell therapy). Sometimes drugs already used to treat other diseases can also be used to treat Duchenne patients. This speeds up the transition to clinical application, since a lot of information is already known for the drug (e.g. toxicity, dose etc). |
| There is a vast number of drugs that are reputedly beneficial in Duchenne patients and/or dystrophic mouse models. We here list the ones that have been tested in patients and the ones that gave very promising results in mouse models. |
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Drugs tested in patients
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| Corticosteroids (prednisone, deflazacort etc) |
| Aim: |
To suppress the immune system in order to reduce the formation of scar tissue. |
| Background: |
Corticosteroids are a group of drugs that can suppress the immune system. When muscle tissue is damaged, this will elicit an immune response (the body does not know what causes the damage - it could well be a virus, a bacteria etc). While the immune response has the best intensions (to protect the body from infections), in this case the immune system increases the severity of the disease. Immune cells excrete toxic substances (aimed to kill bacteria etc), which further increase muscle damage and enhance the formation of scar tissue. |
| By suppressing the immune system with corticosteroids, muscle damage will be less severe and less scar tissue will be formed. |
| Clinical trials: |
Not that many trials have been done to compare patients treated with corticosteroids and those without, or to compare one corticosteroid to another (e.g. prednisone to deflazacort), but the general consensus is that corticosteroids do work to delay the disease progression. It will delay wheelchair dependency by ~1-3 years, will temporarily improve muscle strength and function and will delay the loss of respiratory function. Steroids have only been used for several years, so it is not yet known whether they also increase life expectancy. |
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It is very likely that corticosteroids work on other levels than immune suppression as well (it is thought they can increase expression of utrophin and/or stabilize muscle fibers, so they are less sensitive to damage). This is still under investigation. However, the finding that drugs that only suppress the immune system are less effective than corticosteroids, underlines this idea. |
| Challenge 1: |
Corticosteroids have to be taken regularly and chronically. This results in side effects in most patients. The most common are weight gain, depression, behavioral problems, growth retardation, delayed puberty and loss of bone mass but many more have been described. |
| Solution 1a: |
For some patients side effects can be reduced by an "on-off" treatment regime. Steroids are e.g. taken only every other week, or only during weekdays and not weekends. For some patients, less side effects occur when deflazacort is taken. |
| Solution 1b: |
Some patients cannot tolerate chronic treatment with corticosteroids. If the side effects outweigh the benefits (e.g. weight gain to such an extent it impairs rather than enhances muscle functionality) it may be best to stop treatment (this should of course always be done after discussion with the treating clinician). |
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| Cyclosporine |
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| Aim: |
To suppress the immune system in order to reduce the formation of scar tissue. |
| Background: |
Cyclosporin is a drug that suppresses the immune system. When muscle tissue is damaged, this will elicit an immune response (the body does not know what causes the damage - it could well be a virus, a bacteria etc). While the immune response has the best intensions (to protect the body from infections), in this case the immune system increase the pathology. Immune cells excrete toxic substances (aimed to kill bacteria etc), which further increases muscle damage and enhances the formation of scar tissue. |
| By suppressing the immune system with cyclosporin, muscle damage will thus be less severe and less scar tissue will be formed. It is thought to induce less side effects than corticosteroids. |
| Clinical trial: |
A clinical trials was performed in Germany (Korinthenberg) to assess whether cyclosporine treatment indeed is beneficial for patients. Unfortunately, no difference was observed between patients treated with and without cyclosporine. |
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| Idebenone |
| Aim: |
To reduce scar formation primarily in heart tissue. |
| Background: |
Due to the loss of dystrophin, skeletal and heart muscle of Duchenne patients is under continuous stress (oxidative stress), which is yet another process that leads to the formation of scar tissue. In muscle this leads to loss of muscle function. In heart, it results in a reduced pump function (the heart becomes "stiffer"). Idebenone aims to reduce oxidative stress (it is an antioxidant), primarily in heart, to prevent scar tissue formation. Thus, the heart pathology that is seen in many adolescent patients could be delayed or even prevented. |
| Clinical trials: |
Santhera (Thomas Meier, Switzerland) has tested idebenone in Duchenne patients and has shown it is safe. A Phase II extension trial where the effect (safety and efficacy) of longer treatment was tested is now fully recruited and ongoing whilst a Phase III study has also been initiated and is currently recruiting patients. |
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Drugs still under development
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| Utrophin upregulation |
| Aim: |
To increase the levels of the dystrophin homologue utrophin in muscle. |
| Background: |
Utrophin is a protein that is very similar to dystrophin and forms the same link between cell skeleton and connective tissue dystrophin does, but primarily in non muscle tissues. In muscles it is expressed at very low levels and mainly located at the transition of nerve to muscle (neuromuscular junction). In Duchenne patients and animal models, however, utrophin is expressed in muscles. In patients these increased levels are still to low to be beneficial. Mice studies have revealed that higher levels of utrophin can functionally compensate for lack of dystrophin and delay disease progression. |
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Genes have a volume switch, which is regulated by special proteins that can turn a gene off, or set it to low or high in different tissues (resulting in low or high levels of protein, respectively). The utrophin gene switch is set to a very low volume in muscle. Thousands of drugs are screened in order to find those that can increase the volume of the utrophin gene. |
| Clinical trials: |
Drugs to enhance utrophin expression in cultured cells and animal models have been identified by Summit PLC (John Tinsley and Kay Davies, UK), BioMarin Pharmaceutical Inc. and PTC Therapeutics. BioMarin has recently initiated a phase 1 clinical trial where the BMN-195 compound is tested in healthy volunteers. |
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| Myostatin inhibition |
| Aim: |
To increase muscle mass by reducing the levels of the muscle growth inhibitor myostatin. |
| Background: |
There are factors that enhance the formation of muscle and factors that inhibit muscle formation (not all tissues have to be muscle and because muscles use a lot of energy, they should not be bigger than necessary). Myostatin is one of the factors that inhibit muscle growth (it lowers the volume of many muscle related genes). When the gene for the myostatin protein is mutated and no myostatin is made, this leads to increased muscle formation in animals (Belgium blue cattle, Texel sheep, greyhounds, mice) and humans. Thus, if it is possible to prevent myostatin from doing its job, this should enhance muscle formation. This could compensate for the loss of muscle tissue in Duchenne patients and can be achieved by antibodies for myostatin (proteins that can specifically bind to other proteins). These bind to myostatin and prevent it from reaching the gene switches and turning down the volume. |
| Clinical trials: |
Myostatin antibodies have been tested in healthy volunteers and were deemed safe. They were consecutively tested in adult patients with muscle diseases. While treatment was safe, it did not result in an increase in muscle mass in the patients. However, patients were only treated for 28 days, which might not have been long enough. |
| Future: |
The company Acceleron has identified a new myostatin antibody (ACE-031) that outperforms the old one in Duchenne mouse models. This antibody has been tested in healthy volunteers. This was well tolerated and led to increased muscle mass in a dose dependent manner, with an increase of ~1 kg for the highest dose in a period of 2 weeks. A trial with ACE-031 in Duchenne patients has recently started. |
| Challenge: |
Myostatin inhibition will lead to expansion of muscle stem cells (satellite cells, see cell transplantation). Due to the continuous muscle damage in Duchenne patients, the number of these muscle cells is reduced and myostatin inhibition may further deplete the pool of muscle stem cells (i.e. the point where no stem cells are left and muscles can no longer be repaired is reached earlier). However, it has not yet been proven that this is indeed the case. |
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Mutation Specific Approach > |
