ETHAN , living with Duchenne.
Research Strategies Targeting Dystrophin Production
What Is Gene Therapy?
One treatment option for Duchenne currently in development is called gene therapy. The goal of gene therapy is to deliver a new version of the dystrophin gene into cells that are affected by the disease.
When designing a gene therapy, researchers need a way to get the new gene into the target cells. They do this by developing three main components of gene therapy: the vector, promoter, and transgene. Scientists carefully select each of these components and then test to determine if their gene therapy is working as intended.
What Are the Key Components of Gene Therapy?
Each gene transfer therapy is composed of three key components—the vector, promoter, and transgene
Antibodies and Gene Therapy
Prior to receiving gene therapy, individuals must be assessed for eligibility based on factors such as age, type of genetic mutation, baseline mobility and function, and prior exposure to an investigational or commercially available therapy. Patients must also be tested for preexisting antibodies to understand if they have previously been exposed to the virus being used as the gene therapy vector.
Individuals may develop preexisting antibodies that recognize a gene therapy vector even if they have never received a gene therapy before. Some viruses naturally present in the environment are similar to vectors used in gene therapy, and if exposed, an individual’s immune system can make antibodies against the virus that also recognize the vector.
Currently, there is no way to prevent the development of these naturally occurring antibodies or to know if an individual has been exposed to one of these viruses without an antibody test.
Scientists are working to carefully select vectors that will help the transgene and promoter get into the correct cells, reducing the risk of an immune response. At this time, antibody testing is the only way to determine if an individual has preexisting antibodies that may prevent a gene therapy from working as intended.
Gene editing is an experimental technique in the very early stages of development. The goal of this research is to change specific building blocks in the dystrophin gene, like changing letters in an instruction manual, so that cells can produce dystrophin. These strategies use a technique called CRISPR/Cas (also called CRISPR/Cas9 or simply CRISPR) gene editing.
One way that researchers are using CRISPR is to cut out “errors” in the dystrophin gene in heart and muscle cells so that the cells can now read the gene and make dystrophin protein. Another potential strategy uses CRISPR to replace the errors in the dystrophin gene with parts from a healthy gene, with the goal of restoring the cell’s ability to produce dystrophin.
CRISPR gene editing is also being explored in muscle stem cells in Duchenne. Researchers are editing the dystrophin gene in muscle stem cells and investigating whether they can develop into new muscle cells that produce dystrophin. The ultimate goal is to regenerate healthy muscle to replace the weakened muscle in Duchenne.
Emerging Exon-Skipping Approaches
Phosphorodiamidate morpholino oligomers, or PMOs, are synthetic molecules modeled after the natural framework of RNA. Today, there are four FDA-approved PMOs. These PMOs address deletions in three exons that are common deletions in Duchenne. Additional PMO therapies are being developed to address deletions in other exons.
Investigational peptide phosphorodiamidate morpholino oligomers (PPMOs) are similar to PMO exon-skipping approaches but have an added element—a peptide (small protein) that may help the exon-skipping therapy get into cells.