Reversing a severe brain disorder in adult mice

Mice with an artificially disabled gene (MECP2) developed a severe autism-like disorder. After the mice became adults researchers reactivated the gene. The disorder largely resolved...

Progress Is Reported on a Type of Autism - New York Times

Researchers have found that Rett syndrome, a severe form of autism, may not be so entirely beyond repair as supposed. In mice that carry the same genetic defect as human patients and have similar symptoms, the disease can be substantially reversed, even in adult mice, by correcting the errant gene.

.... Rett syndrome strikes mostly girls, who around the age of 3 start to lose their speech and movement faculties. It is one of the spectrum of autistic disorders, but unlike most of the others it is caused by mutations in a single gene. [jf: in the last few days there's a suggestion that other forms of autism maybe associated with up to 6 single gene defects.]

The gene, known as MECP2, was identified in 1990 by Adrian Bird, a molecular biologist now at Edinburgh University. In 1999, Ruthie Amir and Huda Zoghbi at the Baylor College of Medicine discovered that mutated forms of this gene are the cause of Rett syndrome.

Dr. Bird, as part of his continuing study of what the gene does, engineered a strain of mice whose MECP2 genes had been inactivated with the insertion of an extra block of DNA. When the mice were several weeks old, they started to develop the symptoms of Rett syndrome, including the loss of movement control seen in human patients.

Dr. Bird and his colleague Jacky Guy had engineered a second gene into the mice, one with the ability to snip out the interfering block of DNA in MECP2. The second gene could be activated at will by dosing the mice with the drug tamoxifen. When the stricken mice were fed tamoxifen, even at quite advanced ages, they lost the symptoms of Rett syndrome, Dr. Bird and his colleagues reported last week in the journal Science.

A similar finding was published this month in The Proceedings of the National Academy of Sciences by Dr. Rudolph Jaenisch and colleagues at the Whitehead Institute, though in this study the mice’s recovery was not as complete.

Dr. Bird believes that the mice’s symptoms are reversible because the MECP2 gene is not involved in any of the steps that lead neurons to grow and make the right connections among themselves. The gene comes into play only afterward, in maintaining the genetic decisions the developing neurons have made. Among the most important of these are steps to permanently switch off many genes that the neurons will no longer need. Each of the various symptoms of Rett syndrome presumably arises because a specific gene that should have been shut down is left on, causing havoc.

The MECP2 gene plays a central role in this silencing process. Its job is to recognize chemical tags called methyl groups that get added to DNA at what are called CpG sites, and to recruit proteins that silence or switch off the genes at these regions. “What MECP2 does is to go where the methyl groups tell it to go,” Dr. Bird said. “So when you put it back, normal service is resumed.”

Dr. Bird believes that this is the first time a neurological disease has been corrected by restoring a missing component of cells, and that researchers should now reconsider the view that little can be done to repair the brain after birth. “Our result shows it’s not too late,” he said, “so there’s no excuse for not going hell-for-leather to find some sort of therapy.”

The reconsideration could extend to other neurological diseases in which the neurons appear to be intact. “Given that features of Rett can be reversed in a mouse model,” Dr. Zoghbi said, “one would predict that postnatal disorders like autism and schizophrenia might be reversible.

It's hard not to think of Flowers for Algernon reading this. However, I believe most forms of "schizophrenia" and "autism", both of which are probably collections of nameless diverse disorders do show some structural changes on brain imaging, so it is unlikely they could be fully reversed. We should note that two experiments are described, and in the second the mice did not fully recover. Also mice are far better at healing themselves than humans are. Lastly, and most importantly, this only worked because the gene knockout was designed to be readily reversible. Gene therapy in adult humans has been a miserable failure.

And, of course, the hero of Flowers for Algernon had only a short lived response to treatment.

Even so, it is a stunning result. I imagine that funding agencies and researchers are frantically rewriting grants and guidelines. Now that we know this is conceivable, we will be looking for medications that may alter the expression of defective genes, such as medications used to treat sickle cell anemia.

I suspect any possible therapeutic measures for humans that would do something like this are 20-30 years away. Even so, that is well within the lifespan of today's autistic children.