Rett syndrome is usually not diagnosed until the characteristic difficulties set in in childhood. People with Rett syndrome typically will experience difficulty to perform motor functions, trouble walking, and often have intellectual disabilities, slowed brain growth, and an inability to speak. The syndrome affects girls almost exclusively, and this is because of how it impacts the X chromosome. Females have two X chromosomes, but in each cell only one is activated. During embryonic development the decision is made, one chromosome is activated and the other is inactivated. In people with Rett syndrome, once this selection has been made around 50% of the genes expressed are defective. The reason that men don’t suffer with the syndrome is because they only have one X chromosome, and therefore with no healthy gene on the other chromosome to compensate they usually die before birth. A team headed by Dr. Vincent Pasque at his Lab at KU Leuven alongside researchers from the Jean-Christophe Marine lab and the Edith Heard lab have made a significant step towards developing a treatment for Rett syndrome and other X chromosome linked disorders. In their research, the team demonstrate a method for X chromosome reactivation, which has significant implications for the development of therapeutic interventions for illnesses linked to malfunction of X chromosome linked genes. The mechanism the team has brought to light is that of how genes can be reactivated once they are switched off during embryonic development. The work may one day help to treat Rett syndrome, a severe cognitive disorder, that impairs quality of life, as well as reducing their life expectancy, and for which there is no cure.
Pasque’s team of scientists recognized that in people with Rett syndrome, the cells which use the defective gene still have healthy copies, but they are just switched off. Their aim was to uncover the mechanism for successfully switching these genes back on, in order to develop treatments from the understanding of how to achieve this. Disorders caused by expressions of faulty genes could theoretically be counteracted by switching the healthy ‘back-up’ genes back on. The team decided to first gain a thorough understanding of how X chromosome reactivation works. It’s understood that usually, X chromosome reactivation can only occur in very specific circumstances, and this is during very early stages of embryonic development. Instead of studying embryos, the team decided to use a cell reprogramming technique, where they reprogrammed cells taken from adult female mice into cells that resemble embryonic stem cells. These are known as induced pluripotent stem cells or iPS cells. Once reprogrammed into iPS cells, the team observed that both X chromosomes became active once more. Around 200 different X-linked genes were monitored throughout the duration of the study, and the results revealed that this reactivation is a gradual process. It was also found that the speed of reactivation was different depending on the gene being studied. For some genes significant amounts of time were necessary for reactivation, and others happened more instantly. The team theorized that this difference in reactivation speed is related to the location of the gene on the X chromosome, as well as the role of enzymes and proteins. With this revolutionary understanding gained of how X chromosome reactivation works, there is great potential for developing therapies for X chromosome linked disorders.
This is not he only attempt to rescue the clinical and biological set of Rett syndrome. One year ago, a team led by Dr. Przanowski from the Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine in Charlottesville, after first trials in 2014, they published attempt to reactivate incative X chromosome by means of durgs or drug-like molecules called “XCIF inhibitors” which sould act on the main protein studied for this syndrome, the MeCP2 protein. This team identified thirteen potential XCIFs, two of them being potentially druggable: the PDK-1 protein kinase, between the PI-3K and c-Akt kinases; and the activin receptor A (ACVR1), a member of the bone morphogenetic proteins involved in embryonal development. Inhibition of XCIFs reactivates Xi-linked genes in cultured cells, indicating the therapeutic potential of these targets for treating X-linked diseases such as Rett syndrome itself. To date, however, pharmacological reactivation of Xi-linked genes such as MeCP2 has been demonstrated only in cultured cells, primarily in dividing cells such as mouse and human fibroblasts and differentiated embryonic stem cells. In terms of the next steps to developing a cure for Rett Syndrome, the team of Dr. Pasque, instead, have stated that they need to next figure out how the mechanism could work for a single gene, they also need to develop a method for safely doing this in patients, and it is also essential to develop a method for targeting the right brain cells. At this point, three factors involved in X chromosome reactivation have been highlighted, and the team will continue their work by running experiments to understand their precise role. This means it will take a few years before we see possible therapies being trialed in humans.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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