Gene therapy

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.

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.