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Science Study Holds Implications for Gene Therapy and Stem Cell Biology


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A study in the May 20 issue of Science holds mixed blessings for scientists who follow research in gene therapy and stem cell biology. The study, conducted by scientists from Cincinnati Children's Hospital Medical Center, and Hannover Medical School and Hamburg University in Germany, reveals important information about how blood forming stem cells regenerate. In addition, the findings offer caution in regards to the side effects associated with genetic engineering of stem cells.

The study, whose lead author is Christopher Baum, MD, an adjunct associate professor of pediatrics in the Division of Experimental Hematology at Cincinnati Children's, is one of a family of studies reporting on the side effects of using disabled retroviruses as gene transfer vectors to genetically engineer hematopoietic stem cells. To date, disabled retroviruses have mostly been tested experimentally in laboratory settings but are also being tested in well-controlled clinical trials to treat severe inborn diseases or cancer in humans.

Retrovirus-based gene transfer vectors are partially defective retroviruses that integrate into the genome of a cell, which can correct specific genetic defects in blood cells but also can potentially increase the expression and / or activity of neighboring genes.

A previous study by Dr. Baum and team revealed that the insertion of several such retrovirus vectors into a single blood-forming stem cell can lead to leukemia in mice, because several "signaling" genes were activated that worked in concert to cause disease.

The question that was left from this and other previous studies: What happens if only one of these genes is activated in a stem cell?

This question is addressed in the newly published Science study. Dr. Baum and colleagues found that they could use the random genome insertion of disabled retroviruses as a tool to discover genes that enhance the fitness of stem cells. Such genes are of great interest for regenerative medicine because they can improve the prospects of stem cell-based therapies.

Stem cells are very rare in the body and typically need to be multiplied for medical use. The genes the researchers found to be marked and activated by the random insertion of a disabled retrovirus appear to have exactly this property: they can increase the multiplication rate of stem cells. While this may put these cells at risk to cause uncontrolled proliferation or even leukemia, the majority of mice that were investigated in this study showed no signs of such side effects.

"This is a step forward in our research because it helps us understand which genes are involved in regulating blood stem cell growth," Dr. Baum said. "This is frontier research. In other words, to date, scientists know little about stem cells, particularly how they grow and what factors cause them to compete with other stem cells or generate more stem cells versus differentiating into different kinds of blood cells.

"The next step would be to increase the availability of genes that enhance stem cell fitness using this novel approach. Simultaneously, we need to study whether similar genes regulate the behavior of human stem cells, because so far our insights are limited to mouse models," Dr. Baum said.

Scientists, in general, experiment with related gene vectors to treat severe inborn genetic disorders or cancer in gene therapy trials. There continues to be an increasing interest in gene therapy research with blood stem cells because these cells can be extracted and manipulated and then reinserted to repopulate the entire blood system, as in leukemia treatment.

The process has the potential to successfully treat inherited blood disorders and immune deficiencies, as demonstrated in an increasing number of patients. The new study published in Science suggests that enhanced fitness of stem cells could be a welcome side effect of current gene-based therapies, but also a potential risk factor for leukemia later in life.

"We still need to learn how many risks we can tolerate in gene therapy, just as in other forms of experimental medicine," Dr. Baum said.

In 2003, Dr. Baum established a research team in the Molecular and Gene Therapy Program in the Division of Experimental Hematology at Cincinnati Children's under the direction of David Williams, MD, and in collaboration with Christof von Kalle, MD, PhD, a physician / researcher also noted for achievements in gene therapy. The team interacts closely with colleagues from the Laboratory for Experimental Cell Therapy, which Dr. Baum founded in 2001, and still supervises, at Hannover Medical School in Hannover, Germany.

Cincinnati Children's is a 423-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to transforming the way health care is delivered by providing care that is timely, efficient, effective, family-centered, equitable and safe. It ranks third nationally among all pediatric centers in research grants from the National Institutes of Health. The Cincinnati Children's vision is to be the leader in improving child health.

Contact Information

Amy Caruso, amy.caruso@cchmc.org, 513-636-5637