Skip Ribbon Commands
Skip to main content
Translate
Translate
menu iconMenu
search iconSearch

From Bench to Bedside in One Year: Stem Cell Research Leads to Potential New Therapy for Rare Blood Disorder

 

April 07, 2008  |  

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.

Catriona Jamieson
Catriona Jamieson, M.D., Ph.D.

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.”

Under the auspices of Jamieson, co-first authors Ifat Geron, M.S., and  Annelie Abrahamsson, M.S., worked in close collaboration with Kenneth Kaushansky, M.D., chair of the UCSD Department of Medicine; Jason Gotlib, M.D., M.S., at Stanford University School of Medicine; and Ayalew Tefferi, M.D., Department of Medicine at the Mayo Clinic in Minnesota.

Additional contributors to this study include Charlene Barroga, Ph.D. and Edward Kavalerchik, M.D., UCSD Department of Medicine; John Hood, Ph.D., Chi Ching Mak, Glenn Noronha and Richard Soll, Ph.D., TargeGen Inc., San Diego; and Jeffrey Durocher, PH.D., Transgenomic Inc., Gaithersberg, MD.  The study was funded in part by the California Institute for Regenerative Medicine and the Mizrahi Family Foundation, the National Institutes of Health (K23HL04409) and an unrestricted gift from TargeGen Inc.

# # #

To read Governor Schwarzenegger's statement on the significance of this discovery and the state's commitment to stem cell research click here

Media Contact:  Debra Kain, 619-543-6163, ddkain@ucsd.edu




Media Contact

Related News

4/22/2015
UC San Diego Health System and Scripps Health are partnering to provide improved continuity of patient care, fellowship training and research in hospice and palliative medicine. Under a new five-year ...
4/20/2015
Researchers at the University of California, San Diego School of Medicine and Moores Cancer Center have discovered a molecular mechanism that connects breast tissue stiffness to tumor metastasis and p ...
4/20/2015
A decrease in the amount of time spent eating and an increase in overnight fasting reduces glucose levels and may reduce the risk of breast cancer among women, report University of California, San Die ...
4/20/2015
The threat of falsified medications, also referred to as counterfeit, fraudulent, and substandard, can be quite real, yet the full scope and prevalence of the problem is poorly understood, say researc ...
4/17/2015
Researchers at the University of California, San Diego School of Medicine have created an in vitro, live-cell artificial vessel that can be used to study both the application and effects of devices us ...
4/16/2015
The increase in use of e-cigarettes has led to heated debates between opponents who question the safety of these devices and proponents who claim the battery-operated products are a useful cessation t ...
4/16/2015
An international team of scientists, led by researchers at University of California, San Diego School of Medicine, have found genetic overlap between Alzheimer’s disease (AD) and two significant cardi ...
4/13/2015
About one quarter of all atrial fibrillation patients at the lowest risk for stroke receive unnecessary blood thinners from cardiology specialists, according to a new study by researchers at Universit ...


Share This Article



Follow Us: