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.