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by Carol Morton

Three years ago, a study showed that a bone marrow transplant performed in pre-symptomatic male mice models of Rett Syndrome substantially extended their lives and reduced symptoms of disease. The unexpected findings caught the attention of Rett researchers, physicians, and parents.

Seeking to validate the results and therefore strengthen the case for clinical studies, four other research groups launched their own mouse studies. In independent experiments, each lab was unable to replicate the original findings.

The researchers combined their results into a single paper, published May 20 in Nature, the same journal that published the original positive results. The new study is posted online only as a “brief communication arising,” a category for new scientific data that challenge the findings of an original research paper in the journal, according to Veronique Kiemer, executive editor of the Nature Publishing Group.

The new paper means that bone marrow transplants may not be a viable therapeutic option, but the pair of papers could point the way to new insights into Rett and ways to fix it, said Monica Carson, a neuroimmunologist at the University of California, Riverside, who was not involved in any of the studies.

“The key is that both answers are possible,” Carson said. “ It’s important to figure out the differences between the papers.”

The original paper came from the lab of Jonathan Kipnis, a neuroimmunologist at University of Virginia in Charlottesville. Kipnis and his colleagues explore the role of the immune system in healthy and diseased brains. No stranger to controversial findings, he has shown that T cells closely surrounding the brain are somehow crucial to normal cognitive function.

In fact, the team first conducted the transplants to test the idea that inadequate T cells in Rett mice might explain their cognitive impairment. “We proved our original hypothesis wrong,” Kipnis said. But with new immune cells, the mice lived much longer. Most cases of Rett can be traced to a malfunctioning gene on the X chromosome called methyl-CpG-binding protein 2 (MeCP2). A transplant fixed the faulty gene in the mice’s immune cells.

How was a new immune system exerting a protective effect? A clue came from stem cell transplant studies for Alzheimer’s disease, where another kind of circulating immune cell, called monocytes or macrophages, lodge in the brain and clear away debris that may cause neurodegeneration. After further experiments, Kipnis and his co-authors proposed that monocytes with good MeCP2 genes also migrated to the brain in the Rett models and helped their brain-dwelling microglia cousins in some unknown way.

Last month, the Kipnis team reported the first molecular and cellular evidence that MeCP2 controls gene expression in macrophages and that some types of macrophages in the brain and throughout the body may be especially vulnerable early in disease. “This work is a beautiful example of how the immune and nervous systems are intimately associated, sharing common molecular pathways and potentially affecting the function of one another in many dynamic ways,”  according to a commentary published with the paper.

The original paper was funded by RSRT. Given the serious nature and risk of a bone marrow transplant, RSRT felt it was crucial to reproduce the findings before supporting any clinical trials. RSRT awarded funding to Andrew Pieper, now at the University of Iowa, who had provided the original mice for the Kipnis study, and Antonio Bedalov, at the Fred Hutchinson Cancer Research Center, a scientist and oncologist, who works with bone marrow transplant patients.

Independently, Peter Huppke, at University Medical Center Gottingen in Germany, and Jeffrey Neul, now at University of California, San Diego, also attempted replications. None of the four labs saw the significant effects seen by Kipnis.

For his part, Kipnis interprets the new paper differently. “Most importantly, it confirms our initial findings, although not as dramatically,” he said, pointing to a small increased lifespan effect that could be seen if two figures were combined. He and two lead co-authors of the original paper have written a detailed response in the comment section for the paper. It outlines suspected issues with the new paper, including mice that may have inadvertently acquired a mixed genetic background and may therefore have a version of graft versus host disease (GVHD) which would have confounded the results. This would be analogous to a person receiving bone marrow that was not a tissue match. Bedalov denied that possibility, saying GVHD would be obvious because the mice would have additional symptoms.

The first mouse study had prompted clinical investigators to add boys with Rett to a hematopoietic stem cell transplant protocol last year. Boys with classic Rett mutations have more severe disease and usually die by age 2. Based on the new findings, the trial has withdrawn Rett as a disease eligibility, wrote principal investigator Weston Miller at the University of Minnesota in an email. No boys with Rett had enrolled in the trial.

Other researchers contacted by RSRT applaud the attempt to replicate the bone marrow transplant findings before considering clinical trials, but they see a more important unfolding story is the role of the immune system in Rett disease biology.

Looking ahead, “discrepancies between labs do occur,” Kipnis and his co-authors wrote, “and understanding the cause of varying results can ultimately lead to an even better understanding of the scientific or disease-related process in question.”



One approach to treating Rett Syndrome is to identify existing drugs that improve any of the symptoms. The advantage of this approach is that any drug found to be helpful can be fast-tracked to clinical trials, bypassing the many years involved in drug development.

Andrew Pieper, M.D., Ph.D.

RSRT funded investigator Andrew Pieper, M.D., Ph.D. at the University of Texas Southwestern Medical Center in Dallas is currently screening drugs of interest in the Rett knockout mice.

The idea for the Rett screen came from a bold project begun a handful of years ago in the lab of RSRT Scientific Advisory Board member, Steve McKnight and Pieper who was, at the time, a post-doc in the lab. The goal of the screen was to identify compounds able to enhance the production of neurons. The laborious and risky project has yielded a compound, called P7C3, which protects newly created neurons and improves learning and memory. The study was published last week in the high profile journal, Cell.
We congratulate Drs. McKnight and Pieper and hope for similar results in the ongoing Rett screen.

Small molecule boosts production of brain cells, protects new cells from dying

DALLAS – July 8, 2010 – UT Southwestern Medical Center researchers have found a compound that preserves newly created brain cells and boosts learning and memory in an animal study.

The study of this compound, which appears in the July 9 issue of Cell, springs from a $2.5 million National Institutes of Health Director’s Pioneer Award to Dr. Steven McKnight, chairman of biochemistry at UT Southwestern and senior author of the study.

Over a three-year period, the research team led by Dr. McKnight and Dr. Andrew Pieper, assistant professor of psychiatry and biochemistry at UT Southwestern, screened 1,000 individual molecules to see which ones might enhance the production of neurons in the adult mouse hippocampus, a region of the brain critical to learning and memory. The scientists found that one of the compounds, called P7C3, achieved this by protecting newborn neurons from dying.

The researchers then administered P7C3 to “knockout” mice lacking a gene that controls the generation of new neurons in the hippocampus. Humans who lack this gene have a variety of learning disabilities, and the “knockout” rodents show related abnormalities as well as a poorly formed hippocampus. When the “knockout” mouse received P7C3, however, normal structure and function of the hippocampus were restored.

In elderly rats, which characteristically show a decline in the birth and formation of hippocampal neurons, the researchers found that P7C3 increased both the birth and survival of new neurons, and the memory and learning capability of the aged rats.

“It’s been a wonderful experience,” Dr. Pieper said. “At first there was a lot of doubt, because we could have gone through the whole screen and found nothing.”

The researchers currently are studying the mechanism by which P7C3 protects cells from dying, and whether it might have any protective effect in other models of neurodegenerative disease.

“We don’t know yet whether P7C3 can block the death of mature nerve cells, which is what occurs in humans with these conditions,” Dr. McKnight said.

Dr. McKnight was one of the first 12 recipients of the NIH Director’s Pioneer Award, which is designed to allow researchers to pursue risky experiments that have the potential for producing highly innovative results.

“When I received the award, I thought ‘I’m not going to waste it on something safe – I’m going to go for it. That’s what the NIH expected of me and my team,'” Dr. McKnight said. “I’d like to give the NIH credit for betting on ‘cowboy’ science. If this pans out, it will be the most useful contribution of my career.”

Dr. Francis Collins, director of the NIH, said Dr. McKnight’s results exactly fit the award’s purpose.

“The NIH Director’s Pioneer Award gives highly innovative investigators the freedom to pursue bold new avenues of research. Such approaches can yield substantial payoffs, as in the case of the exciting clinical implications of Professor McKnight’s basic neurobiological research discovery,” Dr. Collins said.

Other press releases on this discovery

Mental decline thwarted in aging rats
A chemical to make brain cells grow