It's odd that all of a sudden, more information on Autism is springing up suddenly. Studies concluding at once perhaps?
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Progress is Reported on a Type of Autism
By NICHOLAS WADE
Published: February 20, 2007
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.
Partial Rescue of MeCP2 Deficiency by Postnatal Activation of MeCP2 (PNAS)This is a surprising result for a neurological disease. Biologists generally assume that if the brain does not wire itself correctly at specific stages of development, the deficit can never be corrected.
The treatment for the Rett mice would not work in people because it involved genetically engineering the mice before conception. But by showing that the neurons are intact, except for the stricken gene, the finding may encourage new approaches. “It gives renewed hope that Rett syndrome will be a treatable disorder, and maybe autism as well,” said Monica Coenraads, co-founder of the Rett Syndrome Research Foundation.
Fred Gage, a brain expert at the Salk Institute, said, “A renewed optimism for finding a therapy for these types of diseases is warranted, I believe.”
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.
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.”
But it is not so easy to correct a mutated gene in people, and gene therapy has seldom worked. The problem in Rett syndrome is that the father’s copy of MECP2 gets damaged in the course of generating sperm. The gene is carried on the X chromosome, of which women have two copies in each cell. But one copy, the one bequeathed by either the mother or the father, is randomly inactivated in each cell so as to keep dosage levels the same in women’s cells as in men’s, which possess only one X chromosome. Males with a defective MECP2 gene mostly die before birth, whereas in affected women half the cells will have a good copy, half a bad one.
Could the good copy be restored in cells where it is silenced? Some biologists are thinking of ways to reawaken genes on the inactivated X chromosome in women, Dr. Gage said. Another approach, Dr. Zoghbi and Dr. Jaenisch suggested, would be to figure out the target genes that MECP2 is supposed to keep silenced and whose improper activation presumably causes the various symptoms of Rett syndrome. Drugs that suppressed each of these target genes might alleviate the symptoms of disease.
