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Young child's arm with IV tubing.

Gene therapy

Gene therapy is in clinical trials for several types of primary immunodeficiency (PI) and offers an alternative to hematopoietic stem cell transplantation when a suitable donor is not available.

Gene therapy is not yet a Food and Drug Administration (FDA)-approved treatment for any PI and is only available through enrollment in a clinical trial in the U.S. However, gene therapies have been FDA-approved for other conditions like hemophilia B and spinal muscular atrophy.

If approved in the future, gene therapy will offer an important alternative to hematopoietic stem cell transplantation (HSCT) with a partial-match donor, such as a parent or unrelated donor. Partial-match HSCT carries a high risk of graft rejection, where the body tries to reject or fails to accept the new cells, and acute graft versus host disease (GVHD), where the new cells attack the recipient’s body. In contrast, because gene therapy uses a person’s own stem cells, there is no risk of graft rejection or GVHD.

How gene therapy works

For gene therapy, individuals with PI are both the donors and recipients in an HSCT-like process—their own hematopoietic stem cells are collected, the PI-causing gene variant is either corrected or a functional copy of the gene is introduced into the stem cells, and then the modified stem cells are given back to the individual by an intravenous infusion.

A graphical illustration of ex vivo gene therapy.
In ex vivo gene therapy, stem cells are collected from the individual’s body, modified in cell culture, and then returned to the individual via infusion.

First, stem cells are taken out of the individual's bone marrow, peripheral blood, or in the case of a newborn, umbilical cord blood, just as they would be from an HSCT donor. The cells are then cultured in the laboratory for a few days, usually with proteins called growth factors to encourage the cells to grow and divide. During this time, the cells are modified to either add a functional copy of the gene of interest or to edit the PI-causing gene variant directly.

To add a functional copy of a gene to the cultured cells, it is first packaged within a viral vector. Viral vectors are "shells" that have been modified so that the virus' genes are replaced with a human gene. These viral vectors keep their ability to insert genetic material into human cells but are no longer able to cause infection. Most gene therapies use one of three types of viral vectors: adeno-associated-virus (AAV) vectors, adenovirus vectors, or lentivirus vectors.

The viral vector carrying the functional gene is mixed with the cultured stem cells and injects the functional gene into the cells. Genes carried by lentiviral vectors integrate into the stem cells' chromosomes, whereas genes carried by AAV or adenoviral vectors do not integrate into the stem cells’ chromosomes—they remain outside of the chromosomes as tiny circles of DNA called episomes. Once inside the stem cell, the functional gene becomes a permanent part of the cell's genetic material and is copied and passed on to all blood cells that stem cell makes in the future.

To directly fix PI-causing gene variants, instead of inserting a functional copy of the gene into the cultured stem cells, the viral vector delivers protein, RNA, and/or DNA pieces of a gene editing system like the CRISPR/Cas system. The components of the gene editing system find the PI-causing genetic variant in the DNA of each stem cell and correct it so that the gene is now functional. As with adding a functional copy of the gene, the correction is permanent and all future blood cells that stem cell makes will have it as well.

At this time, all FDA-approved gene therapies for non-PI conditions add a functional copy of a gene of interest to cells rather than directly editing gene variants. However, gene editing therapies are in clinical trials for several conditions, including hereditary angioedema (HAE), which is a complement deficiency.

After being modified, the stem cells can then either be infused back into the individual directly, or frozen and given back later.

Before the corrected hematopoietic stem cells are infused into the individual, they may or may not receive conditioning, such as chemotherapy or other immunosuppressant drugs. This is sometimes needed to make sure the corrected hematopoietic stem cells have enough space in the bone marrow to grow and divide normally. However, in general, less chemotherapy is necessary for gene therapy than for HSCT from an unrelated donor.

After any conditioning, the corrected hematopoietic stem cells are taken out of storage and given back to the individual in a simple IV infusion. In two to three months, the corrected hematopoietic stem cells spread throughout the individual’s body, which results in a new, healthy immune system with functional T cells. As with HSCT, individuals who are treated with gene therapy are watched closely by doctors for any complications and for evidence that the new cells are working.

History of gene therapy to treat PI

Gene therapy has been used to treat individuals with several types of severe combined immunodeficiency (SCID), hereditary angioedema (HAE) type 1, X-linked chronic granulomatous disease (X-linked CGD), leukocyte adhesion deficiency-1 (LAD-1), and Wiskott-Aldrich syndrome (WAS).

Gene therapy for ADA-SCID

The first clinical trial for gene therapy was at the National Institutes of Health in 1990 and treated a 4-year-old girl with ADA-SCID. The design of this first trial did not attempt to correct her stem cells, only her T cells. This patient is still clinically well and has about 25% of her circulating T cells carrying the corrected ADA gene more than 30 years after her treatment.

After this initial clinical trial demonstrated that gene therapy could be carried out safely and that gene-corrected T cells could survive for years and function normally, follow-up trials were initiated attempting to treat other children with ADA-SCID by targeting stem cells from the bone marrow. In terms of providing a functioning immune system, the results have been excellent, with most of the nearly 100 individuals treated for ADA-SCID attaining a significant, long-lasting increase in T and B cell counts and a remarkable improvement in immune function.

In 2016, the European Medicines Agency (EMA) approved an ADA-SCID gene therapy product called Strimvelis that uses a gammaretroviral vector. Thirty-three patients were treated with Strimvelis before reports in the fall of 2020 that one patient developed leukemia four years after treatment due to insertional oncogenesis. Insertional oncogenesis is a known risk with gammaretroviral vectors. These vectors carry DNA sequences that can activate other genes near where the new functional gene is integrated into the stem cell’s chromosome and, depending on which genes are nearby, can make a stem cell more likely to become cancerous. EMA issued a direct healthcare professional communication in early 2021 advising clinicians to follow patients closely for signs of leukemia. Strimvelis remains authorized in the European Union.

An ongoing clinical trial for ADA-SCID gene therapy using a different viral vector is active in the U.S. at the University of California, Los Angeles.

Gene therapy for other PIs

The first gene therapy trials for X-linked SCID, X-linked CGD, and WAS also used gammaretroviral vectors to introduce functional versions of the affected genes into individuals' hematopoietic stem cells. While these trials resulted in restored immune function for the majority of treated individuals, a substantial number of them went on to develop leukemia in the years following treatment due to insertional oncogenesis caused by the viral vector.

More recent trials for several types of PI have used viral vectors designed to avoid the risk of insertional oncogenesis and have led to similar, if not better, immune benefits as in the early trials. No cases of leukemia have yet been tied to any gene therapy using a non-gammaretroviral vector. 

Limitations of gene therapy

Some of the limitations of gene therapy are similar to those of HSCT.

  • Gene therapy "fixes" only the cells that develop directly from hematopoietic stem cells. The new or edited gene is not introduced into any other cells of the body, so conditions that affect non-blood cells may not be treated completely.
  • An individual treated with gene therapy can still pass their PI-causing genetic variant on to their future offspring because their egg or sperm cells do not receive the extra, functional copy of the gene.
  • Gene therapy cannot undo or erase damage already caused by PI, such as lung damage from severe respiratory infections.

Compared to HSCT, which can be used to treat any PI, gene therapy is more specialized and requires the development of a specific viral vector or editing system to treat each different type of PI. This specialization makes gene therapies some of the most expensive medications on the market. Gene therapy is also limited to treating PIs caused by variants in a single, known gene.

Overall, the growing experience with gene therapy has demonstrated that it is possible to successfully treat PI by inserting a functional copy of the gene into the individual's stem cells. It is likely that many severe types of PI will be treated by gene therapy in the future.

This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice.

Adapted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition 
Copyright ©2019 by Immune Deficiency Foundation, USA