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| Aim: |
To deliver muscle cells from a healthy donor (containing a healthy gene) to Duchenne muscles to compensate for lost muscle tissue and to allow normal dystrophin production by the donor cells. |
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| Background: |
Muscle consists of muscle fibers, which do not divide and muscle stem cells that lay on top of the fiber (Figure 4). When the muscle fiber is damaged, these muscle stem cells (also called satellite cells or myoblasts) will start dividing and will fuse with the damaged muscle to repair it. These stem cells can be isolated from a muscle biopsy and expanded in the lab and then transplanted into Duchenne muscle. |
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| Challenge 1: |
Muscle stem cells are unable to travel from the bloodstream into muscle. |
| Solution: |
Local injection into affected muscles. |
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| Challenge 2: |
Even muscles injected directly into muscles do not migrate beyond 1-2 mm from the needle tract. |
| Solution: |
Perform multiple injections (e.g. 100 in a square cm). This has been tested in Duchenne patients (see also here) and dystrophin positive cells were indeed observed at the injection sites. |
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| Challenge 3: |
Nevertheless, it is unfeasible to use this form of treatment to deliver muscle cells to all muscles in the body. |
| Solution: |
There are other stem cells present in blood, blood vessel walls and fat tissue that can also participate in muscle formation. These cells can be isolated and expanded in the lab. An advantage is that these cells are probably able to travel from the bloodstream into muscles, thus allowing body wide treatment. |
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| Challenge 4: |
Although these cells are able to participate in muscle formation the efficiency is at the moment very low (<1% of the transplanted cells ends up in muscle). |
| Future: |
Ways to increase the efficiency of this approach are currently under investigation. Promising results have been obtained in mouse and dog models with "mesangioblasts" (group of Giulio Cossu) and "CD133+" cells (group of Ivan Torrente). |
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| Challenge 5: |
Transplantation of donor muscles will elicit an immune response (like the transplantation of any tissue into another person). |
| Solution a: |
Administration of drugs that suppress the immune system. This is standard treatment for individuals receiving donor tissue. Unfortunately, chronic treatment with these drugs is not without side effects (e.g. one is more prone to infections). |
| Solution b: |
Isolate muscle cells from the patients, expand them in the lab and treat them (e.g. with gene therapy) in the lab. Then transplant the patient's own cells back (autologous transplantation). Gene therapy is much more efficient in cells (in the lab) than in tissue (in a person). In addition, because the patient's own cells are transplanted, immune suppression is not necessary. |
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| Challenge 6: |
It is possible the immune system will still respond to the transplanted cells even though they are from the patient: due to the manipulation in the lab, the cells are likely changed and the immune system may pick up on this. In addition, for this to work, ways to efficiently deliver muscle cells or other stem cells to muscle first have to be optimized (see challenge 1-4). |
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| Clinical trials: |
A clinical trial where muscle stem cells were injected with 100 injections in a small area of muscle (0.25-1 cm2) has been completed in Canada (Tremblay and Skuk). The treatment was safe and dystrophin positive fibers could be detected in a biopsy taken from the treated area. |
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A trial where CD133+ cells were obtained from Duchenne patients (isolated from blood), expanded in the lab and then transplanted back into hand muscles of patients has been completed in Italy (Torrente). |
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Preparations for clinical trials with donor mesangioblasts are ongoing (Cossu). |
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Drug Therapy > |
