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Primary Immune Deficiency Diseases

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A Step Closer to Personalized Medicine: Improving Gene Therapy to Treat a Devastating Genetic Disease

Recent advances in adult stem cell research could change the way doctors treat a host of debilitating diseases. At NIAID, scientists are exploring novel ways to convert adult tissue into more primitive stem cells and then use these cells to treat chronic granulomatous disease (CGD), an inherited disease of the immune system. The most exciting part of NIAID's research? The treatment cells come from the patient. No donors are necessary.

micrograph of Neutrophil
Neutrophil from a blood smear magnified 100X
Credit: Wikimedia Commons

Background

CGD is caused by an inherited mutation that reduces the infection-fighting ability of immune cells called neutrophils. Neutrophils are supposed to make a microbe-killing molecule called superoxide. People with CGD produce little or no superoxide, making them more susceptible to bacterial and fungal infections; abscesses in their lungs, liver, spleen, bones, or skin; and even masses of cells, called granulomas, which can obstruct the bowel or urinary tract.

The majority of people who have CGD inherit it as an X-linked disease, meaning that the mutated gene is located only on the X chromosome. People with X-linked CGD have a mutated CYBB gene, which is required to make superoxide.

People with CGD take lifelong regimens of antibiotics and antifungals, but this does not fix the defect in superoxide production. A bone marrow transplant can cure X-linked CGD, but suitable donors are hard to find and not all transplants are successful. Gene therapy holds promise for curing X-linked CGD, but current approaches have failed to achieve substantial permanent benefit and, in some cases, the therapy has activated cancer genes.

Looking for a potentially safer type of gene therapy to treat CGD, Harry Malech, M.D., chief of the NIAID Laboratory of Host Defenses, and his colleagues turned to a promising new field of research in which primitive stem cells are created from a patient's own tissue.

In 2007, researchers from Japan demonstrated that it is possible to reprogram cells from adult tissue into pluripotent stem cells. These reprogrammed adult cells are called induced pluripotent stem (iPS) cells. Similar to embryonic stem cells, iPS cells can grow indefinitely in a lab environment and differentiate into any cell type in the body.

diagram of the development of iPS cells
 

Results of Study

In a study published in March 2011, Dr. Malech's lab reprogrammed adult bone marrow cells from a patient with X-linked CGD into iPS cells. Exposing the iPS cells to specific growth factors for 30 days caused 30 to 40 percent of the cells to become mature neutrophils. Similar to neutrophils found in the patient's circulating blood, the iPS cell-derived neutrophils failed to generate superoxide.

Investigators then used a zinc finger nuclease, a synthetic protein that precisely targets a specific location in the genome, to insert a functioning CYBB gene into the patient-derived iPS cells. In traditional gene therapy methods, lab-engineered viruses insert synthetic copies of the normal gene at random into the genome of stem cells. Using a zinc finger nuclease allowed Dr. Malech's team to insert the functioning CYBB gene at an exact location in the iPS cell genome and correct the mutation causing X-linked CGD.

After selecting the iPS cells with only the desired gene insertion, investigators differentiated the selected cells into neutrophils that could now produce superoxide. 

Significance

Performing gene therapy on the patient's cells means that there is no need to search for a matching donor; patients provide their own means for treatment. Using zinc finger nucleases to insert the normal gene also improves control and testing of the gene correction process, leaving no new genetic materials or changes to the iPS cell's genome except for the desired repair.

As the field of iPS cell research progresses, it may become possible to use only a small sample of a patient's blood to make iPS cells that scientists can correct and then give back to the patient to cure disease.

Next Steps

For patients with X-linked CGD, repaired iPS cells could be differentiated into large numbers of mature functional neutrophils and given to patients to help manage infections. The repaired cells also could be differentiated into adult blood stem cells and used as a transplant.

Although successfully using the repaired iPS cells to permanently restore the patient's immune system is still many years away, Dr. Malech's efforts are a step in the direction of truly personalized medicine.

References

Zou J, Sweeney CL, Chou BK, Choi U, Pan J, Wang H, Dowey SN, Cheng L, Malech HL. Oxidase deficient neutrophils from X-linked chronic granulomatous disease iPS cells: functional correction by zinc finger nuclease mediated safe harbor targeting. Blood. 117(17): 4434-4441 (2011).

NIH's Stem Cell Information

NIAID's CGD and Dr. Malech's lab

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Last Updated May 20, 2011

Last Reviewed May 18, 2011