Researching 3 treatment approaches
Gene therapy, RNA technologies, and gene editing are 3 approaches being explored for the treatment of rare genetic conditions. Sarepta research focuses on the potential of each of these approaches to develop products that may impact conditions such as Duchenne muscular dystrophy and the limb-girdle muscular dystrophies.
Learn about genes and gene therapy
What is a gene?
Genes are made up of DNA, which is the code that determines how people are “built.” Each of us has between 20,000 and 25,000 different genes, which determine everything from our hair color to whether we may develop certain health conditions. Every cell in our body contains these genes.
Each gene tells your body how to make a certain protein. Proteins have several important jobs, from making up the structure of tissue to helping with food digestion and the ability to fight infections. They are needed for all of your body systems to work properly.
What is gene therapy?
The goal of gene therapy is to affect the root causes of an illness. Genes are like the blueprints for our body, and gene therapy aims to fill in missing parts or correct errors in the plans. These investigational products show great promise because they could potentially:
- target any of the thousands of genes in your body
- slow down or stop a disease from getting worse
- stop damage before it occurs, if treatment is given early (this is one reason why an early diagnosis is so important)
Research in gene therapy has led to breakthroughs in the treatment of cancer and of rare conditions that are caused by changes in a single gene. These advances inspire us to move forward in our quest for new investigational products for rare genetic diseases.
Creating new genes to meet different needs
If you or your child is a candidate for gene therapy, your healthcare team can help you understand what’s involved, and what type of approach might be best for you.
There are 3 main gene therapy approaches:
Gene addition, also known as gene replacement, is a one-time procedure that adds a new gene that contains the instructions for a cell to make the kind of protein that is needed
Gene silencing tells cells to decrease the amount of a protein that is being made
Gene editing uses very precise technology to change or remove information within a particular gene
How is gene therapy intended to work?
The role of proteins
Proteins are essential to help your body work, and genes provide instructions for how to make the proteins you need. For example, a protein called dystrophin is needed by muscles to protect them as they contract and relax. Changes in genes, called mutations or variants, can alter these instructions—and this can affect your body in different ways and cause diseases such as Duchenne.
Gene mutations can be passed from parents to a child, which is called inheritance. Mutations can also occur by chance, from aging, or from exposure to certain chemicals or radiation in the environment. Mutations can cause illness by changing how the affected proteins function.
Gene therapy uses genetic material, such as DNA or RNA, to treat or prevent conditions caused by mutations. Each gene therapy is made of 3 main parts:
Any change in the DNA sequence of a cell.
The vector aims to deliver the transgene and promoter to the correct cells
The promoter’s job is to turn the transgene “on” only when it’s in the correct cells
The transgene is the new gene delivered to cells. It is intended to provide the instructions needed to make the new, working version of a protein
How gene therapy is intended to work in the body
- The vector aims to deliver the transgene and the promoter to target cells (like muscle cells in Duchenne).
- The goal of the promoter is to “turn on” the transgene.
- The transgene is designed to instruct the cell to create a different version of a protein.
- The vector is expected to leave the body after delivery is complete.
Each gene therapy is unique, even when it is designed to treat the same condition as another gene therapy. Which vector, promoter, and transgene the scientists choose can impact how well the gene therapy might work, and the side effects a person might have.
Special delivery: AAV vectors
Viruses have a natural ability to deliver genetic material into cells. This ability is harnessed in many types of gene therapy. Sarepta uses adeno-associated virus (AAV) vectors, which have been used to target muscle and nerve cells, and are preferred for their safety and efficacy features.
In addition to gene therapy, Sarepta is also exploring how other investigational products based on RNA may be able to help people living with rare diseases.
RNA: delivering the “how-to” instructions
When the body needs to make a protein, instructions are provided by DNA, which is housed in a part of the cell called the nucleus. These instructions are passed to a similar molecule, RNA. Both DNA and RNA are made up of nucleic acids and are the main information-carrying molecules of the cell that direct the process of protein creation.
Exploring new possibilities
A structure within each cell that carries the genes, and controls the activities of the cell.
Messenger RNA (mRNA) allows the instructions from DNA to be translated in the cell, outside the nucleus, where the new shortened protein is assembled. Sarepta is interested in the possibilities of using mRNA technologies to create new products.
When there is a mutation in DNA, it gets passed on to the mRNA. The error in the instructions provided by the DNA can prevent the protein from working as it should. The goal of gene therapies based on mRNA technology is to modify the instructions to help cells make a new kind of shortened protein that replaces the non-working protein.
Sarepta has multiple RNA-based research programs, and we are working to optimize these approaches on an ongoing basis.
Exon skipping: making new connections
Exons are segments of genes that are linked together in a string to provide the instructions for making proteins. For example, a large string of 79 exons provides the instructions for making dystrophin, a protein that muscles need to work properly. If a mutation occurs, such as when one or more exons in the string are missing, the body can’t read the genetic instructions to make dystrophin. Without this protein, muscle development and function can be affected.
By “skipping” over certain exons, new connections can be made that enable the body to make a shortened version of the missing or non-functional protein. Exon-skipping therapies are the cornerstone of Sarepta’s current RNA technologies.
Exon deletion tool
A genetic test can reveal a missing exon—known as an exon deletion. If a genetic test reveals an exon deletion, use the Exon deletion tool at Duchenne.com to help prepare for a discussion with your doctor or genetic counselor.
ASOs: targeting single genes
Exon-skipping therapies are sometimes referred to as ASOs (antisense oligonucleotides), which are short molecules that can zero in on specific sections of RNA that may be carrying incorrect instructions to cells. They make up a broad category of investigational products that use synthetic nucleic acid sequences for therapeutic purposes. ASOs can alter RNA and reduce, restore, or modify protein expression through different mechanisms. They are especially promising for rare conditions that are caused by mutations in single genes.
PMOs: researching RNA technology
There are multiple FDA-approved PMOs (phosphorodiamidate morpholino oligomers), and additional research is ongoing to investigate others. PMOs are man-made ASO molecules modeled after the natural framework of RNA. A clinician would use the results of a genetic test to determine if a patient is amenable to exon skipping and if a PMO is an option for treatment, because each PMO is specific for a range of deletions that may be found in a gene.