WASHINGTON, MD -- October 28, 1997 -- Gene therapy in patients with
chronic granulomatous disease (CGD) can result in prolonged production of
genetically corrected cells, according to a study by scientists at the
National Institute of Allergy and Infectious Diseases (NIAID). A hopeful
advance in the treatment of this rare immunologic disorder, the finding is
reported in today’s issue of the Proceedings
of the National Academy of Sciences (PNAS).
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 researchers, led by Harry 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," Dr.
Malech explained. "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 period."
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," Dr. Malech said.
Studies suggest people having three to five percent phox-positive cells in
their blood might be protected from infections associated with CGD, he
added. Although those levels are at least 150-fold higher than levels
attained in the current study, Dr. Malech predicts 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," Dr. Malech
explained.
In addition to advancing the development of gene-based therapy for CGD,
Dr. Malech said 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 gene transfer.
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 flasks.
"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," Dr. Malech said . "We showed that it is possible to
incorporate these safety features without compromising stem cell viability
or gene transfer efficiency." |