Behind the Headlines—Developing Gene Therapy for Infants with a Rare, Fatal Disease

NIAID Now | December 19, 2019

Overview of the X-SCID gene therapy developed by NIAID and St. Jude scientists. 1: Blood-forming stem cells (blue) are taken from the patient and purified in the laboratory. 2: Stem cells are treated with a lentivector (green) bearing a healthy copy of the IL2RG gene (orange). 3: The patient receives a low dose of busulfan to help make room in the bone marrow for the gene-corrected stem cells. 4: The corrected stem cells are returned to the patient.

Credit: NIAID

Earlier this year, international news outlets reported that an experimental gene therapy had successfully rebuilt the immune systems of eight infants with a rare, life-threatening genetic immune deficiency disease. The findings, published in the New England Journal of Medicine, offer hope for fully restoring immunity to those born with X-linked severe combined immunodeficiency, or X-SCID. Recently, the Smithsonian presented an American Ingenuity Award to representatives from the team of scientists—at NIAID, St. Jude Children’s Research Hospital in Memphis, and the University of California, San Francisco—who collaborated on this advance.

Prior to 1975, most infants with X-SCID died from severe infections in the first year of life. The condition sometimes is called “bubble boy disease” after the highly publicized case of David Vetter, who was born with X-SCID in 1971 and spent most of his life in a plastic isolation bubble to avoid infections. Today, widespread implementation of a newborn screening test has made it possible to detect and treat X-SCID before infections become overwhelming. 

X-SCID is caused by mutations in the IL2RG gene on the X chromosome and primarily affects males. Babies born with X-SCID are highly susceptible to infections because they have low numbers of infection-fighting T cells and natural killer (NK) cells, and their antibody-producing B cells do not function.

The standard treatment for X-SCID is a transplant of blood-forming stem cells, ideally from a genetically matched sibling donor. However, most infants with X-SCID lack such a donor and receive a half-matched transplant from a parent, a life-saving treatment that restores their T cells. Many of these children experience chronic medical problems and require antibody replacement therapy. The amount and function of their T cells also may wane over time.

Early gene therapy trials yield success, but also safety concerns

To develop improved X-SCID treatments, scientists turned to gene therapy. The principle is simple—insert a healthy copy of the IL2RG gene into the patient’s immune cells—but accomplishing this task is complex. The new IL2RG copy must be integrated into the DNA of the patient’s blood-forming stem cells. Researchers selected retroviruses—a class of viruses that survives and spreads by inserting their genes into the host’s DNA—as a carrier, or “vector,” to deliver the gene into cells. The procedure involves removing stem cells from the patient’s bone marrow, using the vector to insert the corrected gene, and returning the corrected cells to the patient.

In the early 2000s, researchers from Paris reported that gene therapy with a mouse gamma retroviral vector restored T cells, but not B or NK cells, in infants with X-SCID. Not long after, a group of scientists from London, also using a mouse gamma retrovirus, reported similar results.

But a few years after the first patients had received the gene therapy, a problem surfaced. Of 20 X-SCID patients treated with gene therapy, six developed leukemias, one of whom died as a result. Retroviruses insert genes at random locations in a cell’s DNA and sometimes can activate nearby genes. Scientists suspect that the vectors used in these early studies may have activated genes that control cell growth, contributing to leukemia.

While this was a major setback, scientific advances have since made it possible for researchers to modify retroviral vectors to greatly reduce or eliminate their ability to activate cancer genes. In fact, NIAID-funded scientists in 2014 reported using a so-called “self-inactivated” mouse gamma retroviral vector to treat nine infants with X-SCID.  Analyses of the children’s T cells suggested that this engineered vector caused fewer genomic changes that could be linked to leukemia. As in the earlier studies, transfusion of gene-corrected stem cells was performed without any chemotherapy. With this approach, the gene therapy restored only the infants’ T cells, not their B or NK cells.

A new gene therapy provides unprecedented immune reconstitution

Back in 2007, NIAID’s Harry Malech, M.D., had started a collaboration with Brian Sorrentino, M.D., at St. Jude to develop a novel X-SCID gene therapy using a different type of retrovirus—a lentivirus. They engineered a “lentivector” that incorporates the self-inactivating element, as well as additional modifications to further reduce the potential for causing cancers. 

The researchers decided to first test the lentivector in older children and young adults with X-SCID who had received life-saving transplants from a parent but experienced chronic medical problems and waning immunity. Dr. Malech proposed adding a low dose of chemotherapy with the drug busulfan prior to returning the gene-corrected stem cells to the patient. He hypothesized that busulfan chemotherapy would help make room in the bone marrow for the corrected stem cells to take hold. 

In July 2012 at the NIH Clinical Center, a team led by Dr. Malech and Suk See De Ravin, M.D., Ph.D., treated their first young adult patient with this new approach. Gratifyingly, the strategy not only boosted the patient’s T cell numbers and function, but also restored his B and NK cells. As a result, he was able to stop the monthly antibody injections that he had required since infancy. His newly strengthened immune system cleared his chronic infection with norovirus, a pathogen best-known for causing epidemics of vomiting and diarrhea on cruise ships and other environments with close contact. He later discussed his experiences in a NIAID video.

By 2015, the NIAID team had treated five older children and young adults with X-SCID. Although the second patient to receive the therapy later died of a pre-existing lung condition, the other four continue to benefit.

Based on these promising results, the researchers deemed the lentiviral gene therapy plus busulfan chemotherapy safe to assess as a treatment for newly diagnosed infants with X-SCID who lacked a matched sibling donor. A clinical trial began at St. Jude and UCSF Benioff Children’s Hospital in San Francisco, with the first infant treated in 2016. As reported this spring, the first eight infants to receive the therapy experienced substantial, broad improvements in immune system function and were growing normally up to two years after treatment. 

Both the trial in infants and the NIAID trial in older children and young adults are ongoing. The NIAID trial has now treated 13 patients, ranging from 3 to 37 years of age. Over the course of their study, the NIAID team has improved the step in which stem cells are treated with the lentivector. They hope that these methodological improvements will accelerate and further improve the level of immune correction in patients. Researchers at NIAID, St. Jude, and UCSF continue to monitor those who have received the gene therapy to assess the long-term effects of the treatment.

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