Gene therapy

The goal of gene therapy is to provide a long-term treatment for genetic conditions by modifying the DNA in a person’s cells. In the case of primary immunodeficiency (PI), gene therapy focuses on hematopoietic stem cells in the bone marrow, which make all of a person’s immune system cells. By altering these stem cells, gene therapy can provide people with PI with a working immune system.

Currently, gene therapy for primary immunodeficiencies (PIs) is mainly available through clinical trials in the United States. There are two exceptions: 

1. Etuvetidigene autotemcel (trade name Waskyra), which is approved by the U.S. Food and Drug Administration (FDA) to treat Wiskott-Aldrich syndrome (WAS) [1]. 
2. Marnetegragene autotemcel (trade name Kresladi), which is approved to treat leukocyte adhesion deficiency type I (LAD1). 

However, several research groups are actively working toward FDA approval, and there may be FDA-approved gene therapies for additional types of PI in the near future. Additionally, the European Medicines Agency (EMA) authorized Strimvelis, a gene therapy for a type of severe combined immune deficiency caused by adenosine deaminase deficiency (ADA-SCID), in Europe [2].

How gene therapy works

Strategies for correcting cells

Researchers have developed several approaches for gene therapy. The two main strategies used for treating PI are gene addition and gene editing.

Gene addition involves adding a working copy of a gene to cells and was the first type of gene therapy researchers developed. Gene addition is typically used to treat autosomal recessive or X-linked forms of PI. Once inside cells, the working gene copy becomes part of the cells’ DNA, and it is passed on to all future cells produced by the corrected cell. In the case of PI, this means that all blood and immune system cells made by the modified hematopoietic stem cells carry the extra working copy of the gene. Waskyra for WAS and Kresladi for LAD1 both use the gene addition strategy.

In contrast, gene editing directly targets and repairs the genetic variant causing the condition. This type of gene therapy is generally more precise and can treat a broader range of genetic variants. Once the pieces of the gene editing system are delivered to cells, they locate the PI-causing gene variant in the DNA and correct it, restoring the gene’s function. As with gene addition, the correction is permanent and all future cells produced by the corrected cell carry the edited, working version of the gene.

For both gene addition and gene editing, the therapy has to get inside of cells. Most gene therapies use viral vectors—virus shells that cannot cause infections—to get the therapy into the cells. Viral vectors can’t cause infections because the virus' genes are replaced by the gene therapy cargo, which is the working gene copy that will be added into an individual’s DNA (gene addition) or used to correct a disease-causing variant (gene editing).

To date, most FDA-approved gene therapies for non-PI conditions use gene addition rather than gene editing. However, in 2023, FDA approved the first gene editing therapy for treating sickle cell disease [3]. Gene editing is also being tested in clinical trials for several conditions, including hereditary angioedema (HAE), which is a deficiency of C1 inhibitor [4], and chronic granulomatous disease (CGD) [5]. Gene editing technology continues to advance, offering potential treatments for a broader range of genetic disorders.

Receiving gene therapy

Gene therapy is either ex vivo (outside the body) or in vivo (inside the body), referring to the location of the person’s cells when they are treated. 

Waskyra for WAS and Kresladi for LAD1 are both ex vivo gene therapies. For ex vivo gene therapy, the person with PI serves as both the donor and recipient in a process similar to hematopoietic stem cell transplantation (HSCT). Doctors first collect hematopoietic stem cells from the individual's bone marrow, peripheral blood, or umbilical cord blood (in the case of a newborn). The laboratory then grows the cells, typically with proteins called growth factors that tell the cells to grow and divide. During this time, the cells are modified either by gene addition using a viral vector or gene editing using a system like CRISPR/Cas9 combined with a viral vector. Once the cells are modified, they are typically infused into a large vein in the same way that someone receives a blood transfusion or stored for later use.

Before the modified hematopoietic stem cells can be infused, the individual often receives conditioning with chemotherapy or immunosuppressive drugs. This conditioning, usually at a lower dose than with HSCT, helps create space in the bone marrow for the corrected stem cells to grow. Since ex vivo gene therapy uses the individual’s own stem cells, there is no risk of graft rejection or graft-versus-host disease (GVHD), which can occur with HSCT. After conditioning, the corrected stem cells are infused through an IV line, where they travel to the bone marrow and begin producing a healthy immune system. Healthcare providers monitor the individual closely for signs of new immune cells or infection during recovery in a hospital setting.

In vivo gene therapy treats individuals without removing cells from the body. The key advantage is that in vivo gene therapy eliminates the need for cell collection, which could expose the cells to factors that interfere with their growth and overall health. However, a major challenge of in vivo gene therapy is making sure that the gene therapy cargo reaches the correct cells, while minimizing effects on other cells. Currently, in vivo therapies often involve direct injections into specific areas, such as the eye, which is a self-contained environment that helps minimize the risk of impacting other cells.