MECP2 Reactivation

This promising strategy aims to cure Rett by activating a backup copy of MECP2 present in all female cells.

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.

MECP2 Reactivation
mecp2-reactivation.svg

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.

Status

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.

Collaborative Approaches

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.

Alcyone Therapeutics

In March 2021 Alcyone Therapeutics announced their lead program, ACTX-101, a unique genetic strategy to reactivate the silenced MECP2 on the inactive X chromosome. Alcyone is actively collaborating with two scientists, Sanchita Bhatnagar and Kathrin Meyer, who began their Rett efforts with RSRT funding. Dr. Bhatnagar first started working on Rett as a post-doc in the RSRT funded lab of Michael Green at University of Massachusetts Medical School. She continued that work when she began her independent career at University of Virginia School of Medicine. Dr. Bhatnagar has discovered that inhibiting certain microRNAs can lead to activation of the silenced MECP2 gene.

Dr. Meyer is a principal investigator at Nationwide Children's Abigail Wexner Research Institute and serves as chief scientific advisor of Alcyone. Previously, she was a senior post-doc in the lab of Brian Kaspar who was part of the original RSRT Gene Therapy Consortium. When Dr. Kaspar left his academic post Dr. Meyer took over his lab and continued working on Rett with RSRT funding.

RSRT introduced Drs. Bhatnagar and Meyer in 2018 and they developed a dynamic collaboration which has led to the Alcyone partnership in Rett gene therapy development. Furthermore, Alcyone has a novel proprietary precision CNS delivery approach that should increase distribution of the therapeutic across the central nervous system and potentially increases the effectiveness and safety of the treatment.

Biologic Solutions to
Reactivation

Several years ago we began funding the lab of Rudolf Jaenisch to pursue a novel approach to reactivation that leverages CRISPR technology to deliver certain epigenetic molecules to the inactive MECP2. The epigenome controls when genes are turned on or off by adding or removing chemical tags. One can think of the genome (DNA) as a charm bracelet and the epigenome as charms that can be added and removed. Methyl tags on DNA keep genes silent and acetyl tags keep genes active. The video below explains the experiments being pursued in the Jaenisch lab.

It’s important to note that biologic therapeutics will need to be delivered to the brain and therefore our ongoing delivery efforts will be highly relevant to our reactivation program.

Herophilus

In January 2021, Herophilus, Inc. announced its SB-9 program, a small molecule therapy designed to reactivate silent MECP2 on the inactive X chromosome. The SB-9 program was discovered using Herophilus’ AI-driven brain organoid drug discovery platform (the “OrCA Platform”) and Rett patient-derived stem cells provided by RSRT. By combining the biological richness of human brain organoid models, industrial automation, and advanced analytical techniques, Herophilus has demonstrated that the SB-9 molecule is able to both reactivate MECP2 at safe levels and reverse disease biology in human in vitro models of Rett Syndrome.

cta-09.jpg

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.