One out of about every 10,000 girls is born with a mutation that causes autism-like behavior, stunts growth, and impairs the ability to think, sleep, and even breathe. There is currently no cure for the disorder, known as Rett syndrome, but a new study of mice suggests that bone marrow transplants that bolster the ranks of a certain type of immune cell in the brain can reduce some symptoms. Researchers say the findings may be an important clue to the biology of the disease, but they caution that a great deal of additional work is needed to assess the treatment potential.
Rett syndrome results from mutations in a gene on the X chromosome called MECP2, which regulates the activity of other genes. Until recently, researchers assumed that the damage to the nervous system was irreversible because it happens so early in life. But that began to change 5 years ago, when a team led by molecular biologist Adrian Bird of the University of Edinburgh in the United Kingdom published a paper in Science showing that reversing the gene mutation in mice improved movement, breathing, and communication between neurons. Encouraging as the findings were, Bird's team had created a new strain of genetically engineered mice that were born with a reversible mutation—a strategy that could not be used for people.
The new study hints at a very different approach. A team led by neuroimmunologists Noël Derecki and Jonathan Kipnis of the University of Virginia in Charlottesville set out to explore a hypothesis that had received little if any previous consideration: that immune cells called microglia might play a role in Rett syndrome.
To test this idea, the researchers used radiation to wipe out the immune systems of mice that carried a mutation in the rodent equivalent of MECP2. Then they injected bone marrow from genetically normal mice into the mutants. Bone marrow gives rise to all cells of the immune system, so this treatment essentially gave the mutant mice a brand-new immune system that was genetically normal.
Untreated mice invariably got sick within a few weeks of birth. They were underweight, wracked by tremors, had irregular breathing, and could barely move, Derecki says. Most of them died within 8 to 10 weeks. But these problems were reduced dramatically in mice that received the bone marrow transplants when they were 4 weeks old, the researchers report today in Nature. The oldest of the treated mice has now lived almost a year, Derecki says. "This seems to stop the disease in its tracks."
Exactly how isn't clear, but Derecki and Kipnis think it has to do with introducing genetically normal microglia, the immune system's cellular sentries in the brain. Microglia swallow dead cells and other debris in the brain. When the researchers injected transplanted mice with a drug that prevents microglia from engulfing cellular garbage, the benefits of the transplant disappeared. Taken together, the findings suggest to Kipnis that MECP2 mutations render microglia unable to do their custodial duties, resulting in a buildup of debris that interferes with the function of neurons. Other studies suggest that neurons, too, are addled by the Rett mutation. "Our work shows that if you can make their environment healthier, even sick neurons can function better," Kipnis says.
Kipnis and Derecki think it's conceivable, at least in principle, that bone marrow transplants might help girls with Rett syndrome. Fixing MECP2 mutations with gene therapy is well beyond current technology, Kipnis notes. "But if we can improve the environment by adding microglia, which is feasible, we may be able to attenuate some aspects of the disease." He's not advocating clinical trials anytime soon, though. Although bone marrow transplants are already performed on children with leukemia and other cancers, the procedure carries a high risk of serious, and even fatal, side effects.
Gail Mandel, a neurobiologist at the Vollum Institute in Portland, Oregon, cautions that it's premature to think about human therapies based on these findings until much more is known about how the microglia restore neural function, and for how long. In the meantime, however, she thinks the paper will stimulate researchers to think more about the roles that microglia and other types of glial cells play in Rett syndrome. These support cells have been implicated in a wide range of neurological conditions in recent years, she notes, but they haven't received much attention in Rett syndrome until recently. "It's important to appreciate that these disorders are complex and involve non-neuronal cells."