The human body is made of trillions of cells that work like small factories. These cells do important jobs, using materials and energy, to make products and help the body work like it should. Like a factory, most cells have a headquarters, called the nucleus, which controls the main operations of that cell.
The nucleus is also where important information is stored. This important information is a person's unique genetic formula, which is called deoxyribonucleic acid or DNA. DNA is organized into pairs of thread-like structures called chromosomes. Usually, every cell has 23 pairs of chromosomes.
Genes are pieces of DNA in the chromosomes that are responsible for determining everything from physical traits, like eye color, to how our bodies work every day.
One important role of genes is to serve as instruction guides that tell cells how to make specific products such as proteins. Proteins perform many tasks to help bodies work properly, such as building and maintaining structures that make up the body, fighting off infections, and transporting materials across cells.
Genes are passed down, or inherited, from parents, so a person typically has two copies of each gene - one from their father and one from their mother.
It is believed that humans have between 20,000 and 25,000 genes!
There are two ways genes can play a role in causing or increasing risk of developing a disease:
Sometimes, a change can happen in a gene, which may cause it to give different instructions – affecting how the protein is made and works. These changes are called variations or mutations. Gene variations can be inherited, occur as people age, or be caused by the environment.
The effects of variations can vary widely: some variations may not lead to any noticeable differences or problems, while other variations can cause or heighten the risk of developing genetic diseases. These types of disease-causing variations or mutations are called pathogenic variants.
Some genes have isoforms, or subtypes, that are associated with different outcomes. Depending on the isoform a person inherits, they can be at an increased risk of developing a disease or having a worse outcome with a disease. These negative outcomes are not due to a pathogenic variant.
The goal of gene therapy is to help treat, prevent, or cure genetic diseases that people inherit or acquire by focusing on the root cause. Some of the ways gene therapy can be used to achieve this goal is by:
For gene therapy to be effective, the gene must reach the cells that need it (target cells). Once inside the cells, the gene can give the instructions to make the right protein necessary to help treat, prevent, or cure the disease.
The gene is delivered using a vector, which is a small vehicle designed to go to specific cells in a particular part of the body.
Viral vectors are commonly used in gene therapy because they are good at entering target cells.
In the case of viral vectors, the viral genes are removed and replaced with the gene intended for delivery. These modified vectors cannot cause a viral infection on their own as the virus-causing genes are not inside them anymore.
You can think of them like different vehicles – a truck, a car, a boat, etc. Each vehicle has different characteristics that make them good for delivering different cargo. The most widely used viral vector in gene therapy is called an adeno-associated viral vector (AAV).
Something important to note about AAVs is that they are typically “non-integrating.” This means the gene that is delivered to cells does not change a person's genetic formula, and therefore will not be passed down from parents to children.
Just like there are different models of cars, there are also different types of AAVs. The different types of AAVs have signals that help direct them to specific areas of the body.
Something important to note about AAVs is that they are typically “non-integrating.” This means the gene that is delivered to cells does not change a person's genetic formula, and therefore will not be passed down from parents to children.
Adeno-associated viral vector (AAV) is the standard viral vector used in gene therapy today. Why is that? Well, they have been studied the most in gene therapy clinical trials. In fact, many FDA-approved gene therapies use AAV vectors, meaning there is real-world experience with them in people.
Just like other evolving therapies, there are risks and challenges associated with gene therapy as well. These include off-target effects and immune response:
More information about the risks and challenges associated with viral vectors can be found on the ASGCT patient education website under gene therapy 101: Vectors 101
Lexeo's gene therapy candidates are investigational and safety and efficacy has not yet been established. These investigational therapies have not been approved by the U.S. Food and Drug Administration or any other country's regulatory agency.
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