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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.”


by Monica Coenraads

Variations in our genome are what make us unique. It’s also what predisposes or protects us from disease.  For example, you may know people who eat high fat diets and yet have low cholesterol or people who, although they have never smoked, succumb to lung cancer, like Christopher Reeve’s wife, Dana.

I’ve had the opportunity to meet girls with MECP2 mutations and normal X chromosome inactivation that are too high functioning to be diagnosed clinically with Rett Syndrome. These are girls who may walk, run, speak, write, draw, and in some rare instances even speak multiple languages and play an instrument. So what is protecting these individuals from having full-blown Rett?  You guessed it: modifier genes.

Those of you familiar with RSRT’s efforts know that we have been funding a project in the lab of Monica Justice aimed at identifying protective modifiers in mice.  This past summer the Justice lab published the first modifier that suggests that statins (drugs that lower cholesterol) may be treatment options for Rett.   More modifiers are likely to follow.

In the last few years a number of factors have coalesced to make the hunt for modifiers possible in people: 1) the identification of a growing number of individuals with MECP2 mutations who are too high functioning to fit the criteria for a clinical diagnosis of Rett  2) dropping costs for exome sequencing  3) improved bioinformatics which allow for better analysis and interpretation of the vast quantify of data generated from sequencing.

In light of these developments RSRT has awarded $314,000 to Jeffrey Neul at Baylor College of Medicine to sequence the exomes (the protein producing portion of the genome) of high-functioning kids/adults in the hopes that some common variables may point to modifiers which can then become drug targets.

Importantly, the sequencing and phenotypic data will be a valuable resource as it will be deposited into the National Database for Autism Research and available to the scientific community.

We need the Rett community’s help to identify high-functioning individuals who Dr. Neul may not be aware of.
If you think your child may qualify please contact me at

Watch the interview below with Dr. Neul to learn more about this project.

[video transcript]
[video transcript – Chinese]