Our initial efforts at MECP2 reactivation were focused on finding small molecule drugs that could achieve the desired effect. Scientists designed cell lines that could detect MECP2 gene reactivation, then tested hundreds of thousands of compounds using high-throughput robotic equipment. RSRT-funded scientists involved in this effort include Benjamin Philpot, Bryan Roth and Terry Magnuson at the University of Carolina at Chapel Hill; Jeannie Lee at Harvard; Antonio Bedalov at the Fred Hutchinson Cancer Research Institute; Michael Green at the University of Massachusetts; Joost Gribnau at Erasmus in the Netherlands; and Andrea Cerase from the Queen Mary University of London.
What it is
MECP2 is on the X chromosome and all females have two Xs, one active and one inactive. In every cell where the mutated gene is active there is a healthy backup gene on the inactive X. The goal of this strategy is to awaken the healthy silenced gene.
Why it matters
What if we could mitigate the flawed gene by reawakening its silenced counterpart? Activating MECP2 in enough cells could conceivably reverse Rett symptoms. RSRT has been championing this strategy from the very beginning.
RSRT has been funding two general paths to reactivation. The first is a drug intervention that would need to be given on an ongoing basis. The second is a biologic one that would be more selective and a one-and-done intervention.
While the end goal of their work is the same — MECP2 reactivation — the scientists employed different strategies. For example, the types of cells the labs use are different. Ben Philpot and colleagues used mouse neurons, Antonio Bedalov and Jeannie Lee used fibroblast cells, while Joost Gribnau a human line. Each cell type has its own set of advantages and disadvantages.
The labs also used different “reporters” – meaning how the cells are designed to detect activation of MECP2. Finally, different classes of small molecule drugs were screened.
Antonio Bedalov and Joost Gribnau importantly developed novel mouse models ideally suited for reactivation experiments.
Unlike the MECP2 Consortium and Gene Therapy Consortium, this group of researchers did not start out as a formal consortium. However through conference calls and in-person meetings this group of researchers has evolved into an effective and productive collaboration. One immediate advantage of the consortium approach is that discoveries in any of the labs can rapidly be validated in the other labs.
MECP2 reactivation is an approach championed by RSRT from the very beginning. Our support, financial and otherwise, has put this strategy on the scientific map.
A cure for Rett.
You want it.
We want it.
Great achievements happen when people stand up and say I’m in. I will be part of the solution!
Rett may be a rare disorder but together we are powerful.