Duchenne muscular dystrophy is caused by a variant in the dystrophin gene leading to little or no production of functional dystrophin protein. One potential way to treat Duchenne is to provide muscle cells with a functional copy of the dystrophin gene so the cells can begin to make the dystrophin protein. This is the idea behind gene replacement with a gene therapy product. By delivering a transgene, which are DNA instructions for the body to produce a protein, the body could begin producing the missing protein. Because it is gene replacement rather than fixing an error in the gene, gene therapy with a microdystrophin is expected to be an option for people with Duchenne who have many different types of genetic variants.
One major challenge facing current gene replacement strategies is that the vector, or transporter needed to get the transgene into cells, is too small to package the entire dystrophin gene which is needed to make a full-length dystrophin protein. Therefore, scientists have created what are called microdystrophin transgenes. These microdystrophin transgenes provide the cells with instructions to make a shortened, but functional, version of the protein. The design of these microdystrophins have been informed by looking at the functional, but shortened, dystrophin proteins seen in some people with Becker muscular dystrophy. While these microdystrophins are similar to protein produced in some people with Becker, it is important to remember that those individuals with Becker have been producing those proteins in all their muscle cells since birth so it is challenging to compare people with Duchenne receiving gene replacement with a microdystrophin to people with Becker. Because people with Becker typically make a smaller, semi-functional dystrophin on their own, people with Becker are unlikely to benefit from or be eligible for gene therapy with microdystrophin.
We are still learning about how gene replacement with a microdystrophin impacts disease progression in Duchenne. Delivery of a microdystrophin is expected to provide benefit to skeletal and cardiac muscles. This may delay the loss of ambulation, and could slow the decline of lung function and provide benefit to the heart, but all of these outcomes require further study to truly understand the impact of gene replacement with a microdystrophin.
While there are many approaches to treating Duchenne with gene therapy, the strategy that is most prevalent in Duchenne is gene replacement with a micro-dystrophin. The idea behind this strategy is to provide cells with a modified, but functional, version of the dystrophin gene which is responsible for producing dystrophin.
In this gene replacement strategy, the genetic variant that is responsible for causing Duchenne hasn’t been altered, but a new gene has been delivered to the cell to help produce a functional dystrophin protein to protect the cells.
While it would be ideal to be able to deliver a full-length version of the dystrophin gene to the cells, our current vectors, such as adeno-associated virus (AAV), are too small to contain that much genetic information. The Duchenne gene is the largest gene in the human body, so researchers have had to develop smaller versions of the dystrophin gene that can be packaged in the vectors, called micro-dystrophins.
The design of the micro-dystrophins has been informed by looking at the smaller, but functional, versions of dystrophin seen in some people with Becker. It is important to note that all people with Becker don’t produce the same kind of dystrophin, which is why we see variation in disease progression in Becker. While these micro-dystrophins don’t contain all of the information coded by the dystrophin gene, they have been designed to maintain key information to produce a functional dystrophin protein that can provide some benefit.
While these micro-dystrophins are modeled after proteins seen in people with Becker, it is important to note some key differences. People with Becker who have highly functional dystrophin proteins have been producing those proteins in all their muscle cells since before birth. People with Duchenne who receive a gene therapy will likely have had some amount of muscle tissue replaced by fibrosis, and it is unlikely that the gene therapy will occur in every single muscle cell.
