Micro dystrophin and full-length dystrophin play crucial roles in treating Duchenne muscular dystrophy (DMD), a genetic disorder that causes progressive muscle weakness. While full-length dystrophin is the protein missing in individuals with DMD, micro-dystrophin therapy is emerging as a promising alternative, offering potential benefits for those with the condition.
With 79 exons—the sections of DNA that provide your cell the instructions to make a protein—the dystrophin gene is the largest gene in the body. Currently, it is not feasible to deliver the full dystrophin gene to a cell because of the size of the gene and the small size of the vectors used to transfer transgenes to cells. In order to create a functionally shorter protein, researchers have created micro dystrophin transgenes that preserve essential genetic information. – Read more: O Gene da Distrofina: Função, Distúrbios e Avanços Terapêuticos
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Mechanism of Micro Dystrophin
The dystrophin gene mutation that causes Duchenne muscular dystrophy results in little to no functional dystrophin protein synthesis. Making a functioning copy of the dystrophin gene available to muscle cells so they can start producing the dystrophin protein is one possible treatment for Duchenne. This is the concept underlying using a gene therapy product to replace cells.
It is possible to start the production of the missing protein by introducing a transgene, which are DNA instructions for the body to manufacture a protein. People with Duchenne who have a wide variety of genetic variants are expected to have the option of gene therapy using a micro-dystrophin since it replaces the gene rather than correcting a genetic defect.
Micro Dystrophin Transgenes
The fact that the vector, or transporter, required to deliver the transgene into cells is too small to package the complete dystrophin gene, which is required to produce a full-length dystrophin protein, is a significant obstacle for existing gene replacement techniques. As a result, researchers developed what are known as micro dystrophin transgenes. The cells are instructed to produce a truncated but functional form of the protein by these micro-dystrophin transgenes.
Micro Dystrophin in Becker Muscular Dystrophy
The functioning but truncated dystrophin proteins observed in certain Becker muscular dystrophy patients served as inspiration for the invention of these micro dystrophins. It is difficult to compare people with Duchenne who receive gene replacement with a micro-dystrophin to those who have Becker, even though these micro-dystrophins are similar to the proteins produced in some Becker individuals. This is because those individuals have been producing those proteins in all of their muscle cells since birth. People with Becker are unlikely to benefit from or be suitable for gene therapy using micro-dystrophin because they normally produce a tiny, semi-functional dystrophin on their own. – Read more: Quais são as diferenças entre DMD e BMD?
Challenges of Micro Dystrophin
There are new difficulties brought forth by the protein’s shortening. For example, these micro dystrophins require the exclusion of numerous exons that are a component of the dystrophin gene. One of the many vital functions of the dystrophin protein in the body is to stabilize the membrane of muscle cells. Interactions between the dystrophin protein and a number of other advantageous proteins on the muscle cell membrane stabilize the membrane.
Certain sections of the dystrophin gene that interact with other proteins will eventually be absent from a micro-dystrophin transgene, despite researchers’ best efforts to be judicious about which bits are included. Having a micro-dystrophin protein will therefore not be as beneficial as having the full-length dystrophin protein, but it will still probably be better than having no dystrophin on hand.
Unknown Answers About Micro Dystrophin
How long the muscle cells will continue to generate the micro dystrophin, or the endurance of the transgenic, is another unknown in the replacement of the micro-dystrophin gene. An individual’s DNA does not incorporate the transgene.
Animal research has been done, but in order to determine how long the transgene remains in cells, we must assess its endurance over time in humans.
There are several factors that could affect durability. Dilution, for example, may result in transgene loss. As a person ages, their body will gain more muscle than it did as a youngster. The micro-dystrophin transgene or protein may not be present in newly formed muscle cells, which could cause them to behave like normal dystrophic muscle.
Muscle injury could be another constraint on durability. Cells carrying a micro-dystrophin transgene may be lost as a result of physical activity that uses or damages muscles. Understanding durability and determining whether and when redosing is necessary will depend on patient monitoring for those who underwent micro-dystrophin gene substitution.
The Problem of Reaching All Cells
It’s also crucial to remember that a microdystrophin would only be produced by living muscle cells that carried the transgene. This implies that the microdystrophin transgene will not help any muscle tissue that has been replaced by fibrosis or fat. People shall discover whether there is a perfect time to administer this specific gene replacement technique as more patients at various phases of the illness are exposed to microdystophin gene therapy.
Relationship between Micro Dystrophin and CK, AST and ALT
Does Micro Dystrophin Gene Therapy Reduce CK, AST and ALT to Normal Levels? Results of the EMBARK phase 3 randomized trial of delandistrogene moxeparvovec (Elevidys) revealed that CK, ALT and AST did not decrease to accepted normal levels. – Read more: EMBARK phase 3 randomized trial
