April 8, 2008
Stem cell research leads to potential new therapy for rare blood
disorder
A unique partnership between industry and academia has led to human
clinical trials of a new drug for a rare class of blood diseases
called myeloproliferative disorders (MPD), which are all driven by
the same genetic mutation and can evolve into leukemia.
In just one year, collaborative discoveries by stem cell researchers
from the University of California, San Diego, Dana-Farber Cancer
Institute, the Mayo Clinic and a San Diego pharmaceutical company,
TargeGen, moved from identification of the most promising drug
candidate to clinical trials for a new drug to fight this
degenerative blood disorder, which affects more than 100,000
Americans.
A study headed by Catriona H.M. Jamieson, M.D. Ph.D., assistant
professor of medicine at the University of California, San Diego and
Director for Stem Cell Research at Moores UCSD Cancer Center, found
an inhibitor that can stop the over-proliferation of blood cells that
results in problems with blood clotting, heart attacks and, in some
cases, leukemia. Funded in part by a grant from the California
Institute for Regenerative Medicine (CIRM), the study will be
published in Cancer Cell on April 8, 2008. A parallel study at
Harvard Medical School, headed by D. Gary Gilliland, Ph.D., M.D.,
yielded similar results which will appear in the same issue of Cancer
Cell.
"As a clinician, I asked myself who is going to get this disease, and
what can we do to stop its progression, instead of waiting until it
evolves into a deadly cancer?" said Jamieson. "This project has been
so extraordinary, because a small pharmaceutical company took a big
chance on a rare disease."
With major contributions from collaborators Jason Gotlib at Stanford
University and Ayalew Tefferi at the Mayo Clinic, the research
findings led to development of the inhibitor by TargeGen. That drug
is currently being tested in human clinical trials at the UC San
Diego School of Medicine, the Mayo Clinic, M.D. Anderson Cancer
Center, and the University of Michigan, Stanford and Harvard
University Schools of Medicine.
A patient with MPD makes too many blood cells, caused by a mutation
expressed in the stem cell, the early stage cell that goes on to
differentiate to become either red or white blood cells. In 2006,
Jamieson was first author on a paper published in PNAS, outlining the
discovery that a mutation in the JAK2 signaling pathway in patients
with a type of MPD called polycythemia vera (PV) allows cells to
bypass the process which would normally regulate the production of
red blood cells. As a result of this defect, the bone marrow produces
excessive numbers of red blood cells.
In the current research described in Cancer Cell, the UCSD School of
Medicine researchers and collaborators transferred human cord blood
stem cells, engineered to contain the mutant JAK2 gene, into mouse
models with a suppressed immune system to find whether over-
expression of a single gene could drive, or initiate, the disease.
These stem cells were introduced directly into the liver, the main
site of blood development in the newborn mouse. As a result, the stem
cells over-expressing the mutant gene led to overproduction of human
red blood cells, and the mice developed a disease that looked like
PV.
The researchers corroborated these results by injecting actual stem
cells from patients with PV into the same mouse model, achieving
similar results. "We found that the JAK2 mutation was necessary and
sufficient, by itself, to drive the disease," Jamieson said.
Theorizing that blocking this mutation would prevent overproduction
of red blood cells, TargeGen developed a selective JAK2 inhibitor
called TG101348. This therapy was shown in animal studies to halt
over-expression of the gene and reverse excessive production of red
blood cells. Because TG101348 selectively targets the JAK2 protein
that causes the disease, side effects have been minimized.
"Pre-clinical testing at the UCSD and Harvard University Schools of
Medicine confirmed the therapeutic potential of TG101348. The
compound was rapidly advanced into the current, ongoing human
clinical trials being conducted at major research institutions across
the country," said John Hood, Ph.D., Director of Research for
TargeGen. "This unique industry-academia collaboration has helped
guide a new drug from bench to bedside, from evaluating the
compound's efficacy on cancer stem cells to its evaluation in
patients bearing a disease which otherwise has very limited treatment
options."
Contact
Debra Kain
ddkain@ucsd.
619-543-6163
University of California - San Diego
Source: University of California - San Diego
http://www.checkbio
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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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