Gene therapy is designed to insert functional copies of a faulty gene that is not working properly. Genes are the genetic blueprints for proteins and sometimes a mutation can result in a non-functioning or missing protein, which causes a particular disease. Gene therapy can potentially restore the production of a needed protein within a patient’s cells.

Certain types of gene therapies that could treat or potentially cure disease rely on something you might not expect: Inactivated viruses engineered to be delivery vehicles, which are also known as “viral vectors.”

What is a viral vector?

While there are many ways to deliver a needed gene, nature has provided one of the most efficient modes of transportation—viruses. The viruses we encounter in everyday life have evolved to efficiently enter our body and pass genetic material into our cells during an infection.

Over the last 25 years, researchers have identified ways to inactivate specific viruses so that they are incapable of causing disease and then engineer them to deliver needed genetic material into human cells. Removing the infection-causing parts of a virus leaves enough space, or capacity, to make the engineered virus into an effective gene delivery vehicle.

How are viral vectors used in our gene therapy approach?

Orchard’s approach to gene therapy is designed to deliver a functional version of the mutated gene, or transgene, to a patient’s own blood stem cells—called hematopoietic stem cells or HSCs—to produce the desired therapeutic protein. The process begins by collecting and isolating a person’s own HSCs. Then, in a specialized laboratory facility, the patient’s HSCs are combined with the viral vector carrying the functional transgene that encodes the needed protein. The vector enters the cell in a process called transduction and introduces the transgene to produce the needed protein.

What are lentiviral vectors, and why are they well-suited for HSC gene therapy?

Not all viruses—and viral vectors—are alike. Different types of viral vectors are used in gene delivery. The viral vector used is largely dependent on the disease and cell type that needs correcting. Lentiviral vectors, the type of vector that Orchard uses, are particularly well-suited for our HSC gene therapy approach.

Lentiviral vectors are derived from viruses that integrate the transgene into the DNA genome of the target cells. This is important because HSCs divide often in order to produce all the blood cells needed throughout a person’s lifetime. When gene-modified HSCs divide, the DNA with the integrated transgene is passed on to the new blood cells, offering a potentially stable and lasting supply of gene-corrected cells capable of producing the needed protein. For this reason, lentiviral vectors are typically used to target rapidly dividing cells, such as HSCs.

Once a patient’s cells are isolated and transduced with the viral vector, the patient is conditioned with agents that prepare the bone marrow to receive the gene-corrected cells, which are then infused back into that individual. Once infused, the gene-corrected HSCs embed—or engraft—in the patient’s bone marrow. After engraftment occurs, the gene-corrected HSCs self-replicate and produce gene-corrected blood cells of all types that circulate throughout the body while producing the needed protein. Furthermore, specialized blood cells called macrophages also embed in all tissue types, including the brain, and produce the therapeutic protein.

Are lentiviral vectors and AAVs similar?

Another type of viral vector is based on the adeno-associated virus and is called AAV. Generally, AAV is delivered directly into the body to transduce cells where they are located. Similar to lentiviral vectors, AAV also delivers the transgene to the nucleus of the target cell, but unlike lentiviral vectors, the transgene is not integrated into the target cell’s DNA genome, so it is not passed on to future generations when those cells divide. Therefore, AAV is typically used to gene-correct non-dividing cells, such as cells in the liver, nervous system, eyes and skeletal muscles.

Are all lentiviral vectors used in gene therapy the same?

Most of the lentiviral vectors used for gene therapy by Orchard, and others, have a common viral backbone. This generation of vectors has been engineered to be self-inactivating, so the vectors have less influence on nearby genes. This generation of lentiviral vectors also allows for customizing the way the transgene is regulated so that therapeutic protein production is matched with the needs of the cell or the surrounding tissue.

Learn more about our HSC gene therapy approach here.