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The more we learn about Rett Syndrome and MECP2 the more we are humbled by the complexities. A main function of MECP2 is to silence other genes. However, the search for these target genes, which began in earnest almost a decade ago, has yielded a paucity of candidates. The most likely, and interesting, candidate, BDNF (brain derived neurotrophic factor), has been implicated in a myriad of neurological disorders. Yet attempts to deliver this trophic factor to the brain have, to date, stumped academic labs as well as pharmaceutical and biotech firms. MECP2 deficiency seems to create havoc among many neurotransmitter systems (norepinephrine, acetycholine, dopamine, serotonin, substance P) as well as growth factors. Furthermore, MECP2 mutations may change the expression of perhaps thousands of downstream genes.
Despite these challenges the 2007 reversal experiments of Adrian Bird remind us that restoring normal levels of the MeCP2 protein makes the symptoms go away. Therapeutic approaches aimed at fixing the underlying genetic problem are therefore quite attractive. We don’t necessarily need to understand what MECP2 does in order to explore ways to normalize its expression.
One such approach is to explore turning on the silent MECP2 gene on the inactive X chromosome. All girls have two X chromosomes and they inactivate one very early in development (as the embryo implants into the uterus). Therefore girls with Rett Syndrome have, in every cell in their body, an X chromosome with the mutated MECP2 gene and an X chromosome with the healthy MECP2. And in every cell one of the two X’s is shut down. In some cells the X chromosome with the healthy MECP2 is activated and the one with the mutated MECP2 is shut down and in other cells it’s the opposite.
Activating the MECP2 on the inactive X could, in theory, cure Rett Syndrome. RSRT is currently supporting a project in the lab of Antonio Bedalov at Fred Hutchinson Cancer Research Center which will attempt to identify either drugs/compounds or genes that will activate the silent MECP2. RSRT is now adding a synergistic project to its portfolio. Marisa Bartolomei, PhD of the University Of Pennsylvania School Of Medicine was awarded funding from RSRT to identify the mechanisms that keep the MECP2 gene silent on the inactive X chromosome.
Dr. Bartolomei discusses this new effort in her lab in a conversation with Monica Coenraads.
I begin each morning by pouring through the day’s newly published scientific papers. I relish this part of my day as I scour the titles and abstracts looking for any that may have relevancy to Rett Syndrome and MECP2. I am rarely disappointed.
Papers of interest are compiled and distributed to the Rett Syndrome scientific community via RTT Science Watch, an electronic newsletter with a subscribership of a thousand researchers and clinicians. I follow up with the authors of these papers of interest via email or phone. Some of these scientists will attend one of our think-tanks, or participate in conference calls, and wind up becoming Rett researchers.
Today I’d like to share a few of the papers that I’ve come across recently that are not specific to Rett Syndrome but demonstrate, instead, evidence of the natural healing powers of the central nervous system. We saw that healing power at work in Adrian Bird’s 2007 Rett reversal experiments and these papers provide further encouraging examples.
A study published a few days ago in the Proceedings of the National Academy of Sciences showed a surprising ability of cats to restore previously damaged myelin – the fatty insulator or nerves (think of it as the plastic coating around electrical wiring) which is damaged in many neurological disorders including multiple sclerosis.
Another encouraging study was just published in the Journal of Neuroscience and shows evidence that individuals who had lost vision due to a stroke can recover their sight through intense daily visual exercises.
Both of these studies show the remarkable healing ability of the brain, even a severely damaged older brain. They bode well for Rett Syndrome.
A third study that recently caught my attention was published in late February in Nature and identifies a gene called IFRD1, that modifies the severity of cystic fibrosis. By analyzing the genetic makeup of 3000 individuals suffering from cystic fibrosis the scientists found that small alterations in this gene correlated with lung disease severity. Scientists will now determine whether IFRD1 is a reasonable drug target. IFRD1 interacts with a class of drugs called histone deacetylases (HDAC) that are also of interest for neurological diseases, including Rett Syndrome.
It is becoming a well accepted fact that the genetic background of individuals may contain small differences that either protect or worsen an existing condition. In Rett Syndrome, for example, there are patients with common MECP2 mutations and normal X inactivation skewing who, in fact, do not have the disorder. These individuals may walk, talk (some in multiple languages), and have normal hand function. They do have some symptoms that are reminiscent of Rett, like anxiety. Efforts aimed at identifying genetic modifiers of MECP2 are ongoing at RSRT. You can read more about this initiative on our website.
I will continue to share examples of studies that fill me with excitement and optimism. It’s important to note that progress in many areas of science will have direct impact on Rett Syndrome. Following these developments, promoting interactions among scientists and facilitating synergies with Rett Syndrome are vital components of RSRT’s work.
Executive Director – RSRT