"This is encouraging news for people born with CGD," says
NIAID Director Anthony S. Fauci, M.D. "While other therapeutic
advances have improved the prognosis for CGD patients in recent
years, the development of effective gene therapy would represent a
big step forward."
One of more than 70 different inherited disorders known
collectively as primary immune deficiencies, CGD is caused by a
defect in an enzyme called phagocyte NADPH oxidase, or phox.
White blood cells use this enzyme to generate hydrogen peroxide,
which the cells need to kill bacteria and fungi. Mutations in one of
four different genes can cause this defect, which leads to frequent
and often life-threatening infections of the skin, lungs and bones with
localized, swollen collections of inflamed tissue called granulomas.
Approximately four to five of every million people worldwide have
CGD, including about 1,000 people in the United States.
In the study reported in PNAS, researchers led by Harry L.
Malech, M.D., deputy chief of NIAID's Laboratory of Host Defenses
(LHD), removed stem cells, the ancestral immune cells that give rise
to white blood cells, from five people with CGD. The researchers
inserted the correct form of the phox gene into the stem cells and
then transfused the corrected cells back into each patient. Dr.
Malech and his colleagues sampled the patients' blood at regular
intervals to see if the stem cells were producing white blood cells with
functional phox genes.
"We detected phox activity in white blood cells from each
patient for an average of three months after the gene-corrected stem
cells were transfused," explains Dr. Malech. "In one patient, phox
activity was still present six months after transfusion. On average,
the corrected phox gene was present in one out of every 5,000 cells.
While the numbers of gene-corrected cells were small, the study
demonstrates unequivocally that gene therapy of stem cells can
produce functionally normal blood cells in patients for a prolonged
The finding could have important clinical implications for the
treatment of CGD. "Since life-threatening infections caused by CGD
may require many weeks or months of therapy and relapses are
frequent, use of gene therapy to provide even short- to medium-term
production of phox-positive cells may be clinically beneficial," says
Studies suggest that people having 3 to 5 percent phox-positive
cells in their blood might be protected from infections
associated with CGD, he notes. Although those levels are at least
150-fold higher than levels attained in the current study, Dr. Malech
predicts that they might be achieved within the next five to 10 years.
"Until the tools are developed to achieve higher levels of
permanent gene transfer to stem cells, our studies suggest that an
achievable intermediate goal of gene therapy for CGD might be to
augment white blood cell function in the treatment of severe
infections," says Dr. Malech.
In addition to advancing the development of gene-based
therapy for CGD, Dr. Malech notes that some of the techniques used
in this study could have broad application in gene therapy protocols
for other diseases. Designed to enhance the safety of gene therapy
procedures involving stem cells, these techniques included the use of
cell culture media containing no non-human proteins and a closed
system of gas-permeable flexible plastic containers for culture and
Animal proteins are widely used in most cell culture media.
However, animal proteins taken up by human cells during prolonged
culture can stimulate an immune response when the
cells are transfused back into a patient undergoing gene therapy.
The closed system of flexible plastic containers, similar to those used
in blood banks, reduces the contamination risk associated with
procedures where cells and culture media are transferred among
"To our knowledge, this is the first human gene therapy trial
targeting stem cells in which animal proteins were eliminated and
stem cells were grown in sealed gas-permeable flexible plastic
containers," says Dr. Malech. "We showed that it is possible to
incorporate these safety features without compromising stem cell
viability or gene transfer efficiency."
In addition to Dr. Malech, investigators involved in the study
included John I. Gallin, M.D., chief of LHD and director of the National
Institutes of Health (NIH) Clinical Center; other LHD and Clinical
Center staff; as well as investigators at Baxter Healthcare, Inc., who
contributed stem cell technology, and Cell Genesys, Inc., who
contributed gene transfer technology.
NIAID, a component of the National Institutes of Health (NIH),
supports research on AIDS, malaria, tuberculosis and other infectious
diseases, as well as allergies and immunology. NIH is an agency of
the U.S. Department of Health and Human Services.
Reference: Malech HL, Maples PB, Whiting-Theobald N, Linton GF,
Sekhsaria S, Vowells SJ, Li F, Miller JA, DeCarlo E, Holland SM,
Leitman SF, Carter CS, Butz RE, Read EJ, Fleisher TA,
Schneiderman RD, Van Epps DE, Spratt SK, Maack CA, Rokovich
JA, Cohen LK, Gallin JI. Prolonged production of NADPH oxidase-
corrected granulocytes after gene therapy of chronic granulomatous
disease. PNAS 1997;94:12133-8.
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