Study Provides Key Safety Data For Human Trials
Article Date: 07 May 2008 - 4:00 PDT
A new study by UC Davis researchers provides evidence that methods
using human bone marrow-derived stem cells to deliver gene therapy to
cure diseases of the blood, bone marrow and certain types of cancer
do not cause the development of tumors or leukemia. The study was
published online in the May 6, 2008 issue of Molecular Therapy.
"The results of our decade-long study of adult human stem cell
transplantation shows that there is little risk of adverse events
caused by gene transfer, and that adult human stem cells do not pose
a cancer risk when implanted into different organs," said Jan Nolta,
senior author of the study and director of the UC Davis Stem Cell
Program.
Nolta and her colleagues tested the safety of gene transfer into bone
marrow stem cells from human donors in more than 600 mice. None of
the transplanted mice developed leukemia or solid tumors caused by
the gene therapy treatment, during the evaluation period of up to 18
months.
"These data are critical for advancing stem cell research leading
toward therapies," Nolta said. "We've shown that adult stem cells
follow natural cues to reach target locations, they function normally
when they get there and do not exhibit the unchecked cell growth that
is the hallmark of cancer."
Gene therapy trials using human bone marrow cells began in the early
1990s and have since included roughly 1,000 patients worldwide. In
2000, a leukemia-like condition emerged in three participants in a
clinical trial in France, halting the trial and calling into question
the safety of the method. Researchers suspected that the gene
transferred in this trial gave the transplanted cells an enhanced
growth capacity that led to the cancers.
"After those studies in France, the gene therapy community felt that
further biosafety testing was warranted," explained Gerhard Bauer,
lead author of the study and an assistant professor of hematology and
oncology. "Due to the significantly large number of study animals,
our investigation further illuminates the safety of gene therapy
using hematopoietic stem cells. It allows us to rest easier with the
knowledge that if we insert corrective genes into human bone marrow
stem cells and administer those cells to human patients, we are
providing a relatively safe therapy."
Today, gene therapy using the adult blood-forming cells found in bone
marrow (known as hematopoietic stem cells) is normally done in an
autologous transplant setting. The therapy involves taking
hematopoietic stem cells from a person who needs treatment,
genetically modifying the cells - perhaps by adding a missing gene -
and then re-inserting the cells back into the same person. This
treatment eliminates the complications of graft-versus-
or host rejection that can occur in allogeneic transplants (therapy
where the cell donor is different from the recipient).
In the current study, 630 immunodeficient mice received mesenchymal
stem cells from one human bone marrow donor and hematopoietic stem
cells from another. Mesenchymal stem cells are a type of cell found
in bone marrow that support the function of hematopoietic stem cells,
and can give rise to bone, cartilage, fat, and muscle. Genes were
inserted into the hematopoietic stem cells using one of two viral
vectors - either a retrovirus or a lentivirus - before they were
transplanted into the mice, along with genetically modified
mesenchymal stem cells.
Of the mice used in the long-term study, four developed human
leukemia. None of those mice, however, were found to have vector DNA
present in the malignant cells.
"This is evidence of a natural tendency for human bone marrow stem
cells to develop leukemia in long-term studies, not that the leukemia
was caused by the genetic modification,
good statistical control for our method."
Bauer noted that while the current study results are important for
use with adult stem cells, they are not applicable to human embryonic
stem cells, which have completely different properties.
"Our experiments did not involve human embryonic stem cells, so we
have a lot of stringent work to do to ensure that those types of stem
cells can be used safely for human clinical trials," said Bauer. "It
certainly is possible, and we are working hard to establish safe and
effective human embryonic stem cell-based cures for patients as
well."
Nolta and Bauer have worked on eighteen cell and gene therapy
clinical therapy trials during their 12 years as colleagues,
including stem cell gene therapy trials for adenosine deaminase
deficiency, also known as the "Bubble Boy Disease," and stem cell
gene therapy for HIV, with colleagues from Children's Hospital Los
Angeles, who are also co-authors on the current report.
Bauer is the director of UC Davis' Good Manufacturing Practice (GMP)
laboratory in Sacramento. Upon its completion, UC Davis will be one
of the few universities with a large GMP facility where scientists
will work in an ultra-clean environment to derive cellular products
that, after certification and extensive testing, will be used to
treat patients. The California Institute for Regenerative Medicine
(CIRM) has recommended funding for this new facility to help bring a
wide range of stem cell therapy cures to patients throughout
California.
According to Nolta, the results of the current study will allow UC
Davis to move forward with increased certainty as it prepares for
clinical trials.
"We are ready to further develop and test this safe approach to
creating effective therapies, and are also using the same model to
test the safety of embryonic stem cell-based therapies to fulfill the
promise of regenerative medicine." she said.
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Article adapted by Medical News Today from original press release.
------------
This work was supported by the National Institutes of Health through
the National Heart, Lung and Blood Institute/National Institutes of
Diabetes and Digestive and Kidney Diseases; The John Connell Gene
Therapy Foundation; a Career Development Award from the Children's
Hospital of Los Angeles Research Institute, and UC Davis Stem Cell
Program start-up funding.
About UC Davis Stem Cell Research
UC Davis has more than 125 basic, translational, and clinical faculty
members working together on a variety of adult and embryonic stem
cell investigations in both Davis and Sacramento. The university is
currently renovating a 100,000 square foot stem cell research
facility on its campus in Sacramento, where researchers will have
access to state-of-the-
testing rooms. That project, along with its Translational Human
Embryonic Stem Cell Shared Research Facility in Davis complements the
university's Clinical and Translational Science Center, which is
supported by the National Institutes of Health (NIH). In 2005, the
NIH awarded $6 million to fund a Center of Excellence in
Translational Human Stem Cell Research on the Davis campus. One of
only two such centers in the nation, it is focused on exploring stem
and progenitor cell therapies for the treatment of childhood
diseases. The California Institute for Regenerative Medicine (CIRM)
has awarded more than $14 million to researchers at UC Davis, to
develop stem cell cures. The programs are designed to expedite the
translation and integration of scientific research into discoveries
and treatments that benefit society.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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