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!
Scientists unlock ability to generate new sensory hair cells
22.02.2017 | Brigham and Women's Hospital
New insights into the information processing of motor neurons
22.02.2017 | Max Planck Florida Institute for Neuroscience
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
22.02.2017 | Power and Electrical Engineering
22.02.2017 | Life Sciences
22.02.2017 | Physics and Astronomy