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Prof Dickson and his team have produced a series of different micro-dystrophin genes which they will test for their ability to produce protein effectively and safely in the muscle cell. The researchers will also be exploiting a natural process that occurs in cells to try and deliver a full-length dystrophin gene to the muscle.


Using a full-length dystrophin gene could have advantages over micro-dystrophin as they can then be certain that all of the parts important for the correct functioning of dystrophin are present. This process, called trans-splicing, involves using three different AAV-vectors. Each vector carries a different, but overlapping piece of the dystrophin gene. When the muscle cell begins processing the information contained in the gene pieces, it is thought that the cell will assemble them together. This will create one single messenger molecule with all the instructions for a full-length dystrophin protein.

Gene Therapy - Muscular Dystrophy News

Prof Dickson will use a mouse model of Duchenne muscular dystrophy to test the different micro-dystrophin genes and trans-splicing AAV vectors. He will study how efficient they are at producing dystrophin in the muscles as well as determining which is the best at delivering dystrophin to all of the muscles of the body. An important aspect of this will be assessing how well they restore muscle function as well as whether they cause an immune response. Prof Dickson is aiming to address the three main challenges that have prevented gene therapy such as this from being used to treat Duchenne muscular dystrophy.

These are the size of the dystrophin gene, delivering enough of the gene to the muscle to alleviate symptoms, and the immune response that is often generated as a reaction to gene therapy. The main problem, which researchers have been working to overcome, is the size of the dystrophin gene — it is very large. The AAV virus can only carry a limited amount of information and the full dystrophin gene is too much information for it to hold. In order to halt the progression of Duchenne muscular dystrophy the viral vector must be able to deliver large enough quantities of the dystrophin gene to all the affected muscles.

Making a small change to the micro-dystrophin gene can increase its efficiency at producing dystrophin protein in the muscle. Combining this approach with testing different types of AAV vector, Prof Dickson hopes to optimize delivery of the dystrophin gene to the muscles. Finally, it is known that gene therapy can elicit an immune response. This can either by triggered by the viral vector or the newly introduced dystrophin protein itself. The body will see proteins that it does not recognise as foreign. Since boys with Duchenne muscular dystrophy do not produce the dystrophin protein, it is thought that the body sees the newly produced dystrophin as a foreign protein and can mount an attack against it.

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In order to get around this problem Prof Dickson will be investigating ways to make the immune system ignore the dystrophin protein and AAV-vector so that when the muscle cells produce the dystrophin protein they will not be attacked by the immune system. By addressing these problems, Prof Dickson may speed up the translation of this technology from the bench to the bedside.

This is pre-clinical research, a crucial stage in getting a treatment into clinical trial. Animal models will be used to try to optimize the safety and efficiency of this particular gene therapy. If these researchers can show it is possible to deliver sufficient quantities of the dystrophin gene to muscle, while minimizing or preventing an immune reaction, these studies may provide a gene therapy agent that can move forward into clinical trial.

Several of the therapies that are currently under investigation and in clinical trial, such as exon skipping and Ataluren formerly PTC can only be applied to boys with specific types of mutation and so they would not be of benefit to all boys with Duchenne.

AAV6 Vector Production and Purification for Muscle Gene Therapy.

This gene therapy approach is not dependent on the type of mutation and so could potentially be used to treat all boys with Duchenne. The aim of gene therapy is to compensate for faulty genes by introducing a normal copy of the gene back into the cell. The trial reinitiated in June To Consider: A recent safety study in dogs and monkeys shows that high doses of AAV vectors can lead to liver and brain problems. Note that the vector type used in this study differs from the ones that will be used for microdystrophin trials. Skip to content Aim: To deliver a healthy gene to Duchenne muscles, to allow normal dystrophin production.

Background: Genes consist of DNA and are located on chromosomes, which are present in the nuclei of all cells. The dystrophin gene contains the genetic code for dystrophin, which can be read by the cell and translated into the dystrophin protein. The healthy gene has to be delivered to a significant portion of the cell nuclei of all muscles. Solution: Fortunately, there is an organism that is quite good at injecting genes into cells: the virus. Thus, the gene therapy field has developed viral vectors, where the viral genes are removed, so there is room for the new gene and the modified viruses are no longer pathogenic.

Challenge 2: Most viruses like to infect dividing cells. Muscle tissue hardly divides and thus is a poor target. In addition, muscle fibers are enveloped by layers of connective tissue, which trap viral particles, so the virus cannot reach the muscle fiber to inject its dystrophin gene.

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  8. Solution: There is a virus that is relatively good at infecting muscle cells, the so called AAV virus. This virus can infect human cells but is not pathogenic it does not cause a disease. Solution: Scientists have attempted to create the smallest possible dystrophin, containing only the bare essential domains micro-dystrophin. The genetic code of this micro-dystrophin is small enough to fit into the AAV vector.

    In the Duchenne mouse model mdx mouse treatment with microdystrophin containing AAV viruses resulted in an improved muscle quality and function.

    Consequently, cells infected with the AAV containing microdystrophin were destroyed by the immune system. From clinical trials in humans with other genes e.

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    The immune response will attack all foreign intruders viruses, bacteria, parasites and has no way of knowing this time the virus carries a good gene. Solution: Ways to reduce the immune response are currently under investigation. This can be done by suppressing the immune response with high doses of corticosteroids. These individuals have antibodies against AAV that would preclude them from receiving viral vectors of that specific subtype.