MECP2 reactivation research hit a new milestone recently with the publication of a paper in the journal Science Translational Medicine. Shawn Liu, PhD; Rudolf Jaenisch, PhD; and and one student and one postdoctoral fellow from Dr. Liu’s lab at Columbia University Medical Center demonstrated that they can reactivate healthy copies of MECP2 in Rett syndrome neurons in the laboratory – and that this reactivation can effectively restore neuronal function.
MECP2 reactivation is one of six genetic-based strategies that RSRT is pursuing to cure Rett syndrome. As we know, Rett syndrome is caused by mutations in the MECP2 gene on the X chromosome. All females have two X chromosomes, one active and one inactive. In every cell where the mutated gene is active there is a healthy backup gene on the inactive X chromosome. The goal of MECP2 reactivation is to awaken the healthy, silenced gene.
In the study the successful reactivation of the healthy copies of MECP2 was accomplished using tools to edit the epigenome, molecules that modify DNA and determine which genes get turned on and which get turned off by adding or removing chemical tags. If you think of DNA (the genome) as a charm bracelet, the epigenome is the charms on the bracelet that can be added and removed. For example, methyl tags on DNA keep genes silent and acetyl tags keep genes active.
The researchers used modified CRISPR technology that was newly developed in Dr. Liu’s laboratory at Columbia. CRISPR typically edits DNA, but in this case the tools edited the epigenome by removing the methyl groups silencing MECP2. The researchers are hopeful that this strategy could be developed into a genetic medicine to treat Rett.
Dr. Liu originally used the modified tool to restore neurons affected by Fragile X syndrome, a neurodevelopmental disorder that causes intellectual disability primarily in boys. When this approach was successful Dr. Liu set his sights on Rett syndrome because, like Fragile X syndrome, Rett is a neurodevelopmental disorder caused by loss-of-function mutations in a single gene. He then contacted RSRT, which has been supporting his research ever since.
Dr. Liu’s lab is now testing the tools in a mouse model of Rett syndrome to see if they can restore normal behavior. The researchers are also working on how to make the tools deliverable in humans, so that they could one day be used to treat patients.
Rett syndrome isn’t the only disorder that could benefit from the lab’s efforts. The epigenome editing tools that have been developed are essentially a toolkit that can be used to tackle other X-linked diseases.