The Salk researchers, led by Inder Verma, Ph.D., a professor in the Laboratory of Genetics, discovered that the healthy copy, which replaces the defective gene can itself promote cancer development. Their findings appear in this week’s issue of the journal Nature.
Niels-Bjarne R. Woods, Ph.D., a post-doctoral researcher in Inder Verma’s team followed mice treated with the IL2RG gene three times longer than any study had ever before, and found that one-third of the animals developed lymphoma later in their life. This is the same gene being given to patients with X-linked severe combined immune deficiency (X-SCID) – commonly known as the "bubble boy" syndrome – in small clinical trials being conducted in France, the United States, the United Kingdom, and Australia.
Although replacement of IL2RG can cure X-SCID, the Salk scientists urge caution in the use of such therapy on the basis of their new findings.
"We were surprised by the strength of the association between IL2RG gene therapy and development of lymphoma," says Woods. "These results suggest that curing X-SCID by replacing IL2RG in the manner it is currently being done puts patients at an increased risk of developing cancer."
Woods adds that the study could explain why one of three children in the French trial developed T-cell leukemia. Two developed the disease because IL2RG inserted itself into the cellular genome next to a known cancer-causing gene and activated it, but the cause of the third cancer case had not been solved.
The French trial is the largest to date to test IL2RG gene therapy, and of the 10 children treated, nine were successfully cured of X-SCID, although cancer was diagnosed in three of the children. Halted for a time, the trial is now continuing on a case-by-case basis, according to Woods.
In the studies leading up to the human clinical studies, mice were studied post-transplant for less than 6 months, which is a traditional research protocol. The Salk research team, however, allowed the mice to live through their natural life span, which is about one-and-a-half years. Mice that developed lymphoma did so at an average of 10 months of age.
In the human gene therapy trials, leukemia did not appear until 2-3 years after treatment, Woods says.
"This indicates that preclinical experimental treatments involving transgenes should include long-term follow-up before entering a clinical trial," says Woods.
But, more fundamentally, the Salk study suggests that replacement of a gene that serves multiple functions in the body may be much more problematic than therapy to replace a gene that serves a single function, says Verma.
"The bottom line here is that if you replace a gene that has multiple effects, you have to know more about its regulation and its ability to affect other genes, and that requires extensive preclinical work and a much more careful analysis," he says.
X-SCID is caused by mutations in IL2RG, which provides instructions for making the common gamma chain protein. This powerful protein, found on the surface of immature blood cells in the bone marrow, works with other proteins to direct the growth and maturation of a number of different immune system cells, including T cells, B cells, and natural killer cells. These immune system cells that kill invading viruses and bacteria, produce antibodies as well as help regulate the entire immune system. Without the common gamma chain, these cells cannot develop normally, and are unable to protect the body.
Researchers who also contributed to this paper include Virginie Bottero, Ph.D., in the Laboratory of Genetics at the Salk Institute, as well as Manfred Schmidt, Ph.D., and Christof von Kalle, Ph.D., both at the Cancer Research Center in Heidelberg, Germany.
Gina Kirchweger | EurekAlert!
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Earth Sciences
17.01.2017 | Machine Engineering
17.01.2017 | Physics and Astronomy