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Those of you who follow the efforts of RSRT know that one of the treatment strategies we are pursuing is the reactivation of the MECP2 gene on the inactive X chromosome.

A quick refresher for those in need of one: mutations in MECP2 cause Rett Syndrome (and a host of other disorders as well). MECP2 is on the X chromosome. Males have one X (and one Y) and females have two X’s, but in order to prevent duplication of genetic material randomly inactivate one of the X’s in every cell. This means that in females with Rett about 50% of cells have the normal MECP2 gene expressed and 50% have the mutated gene expressed. In theory, if we can find a way to reactivate the normal MECP2 gene on the inactive X chromosome, we may cure the disease.

RSRT funded investigators currently pursuing this line of inquiry include Antonio Bedalov of the Fred Hutchinson Cancer Research Center in Seattle, Marisa Bartolomei of UPenn and Ben Philpot and Bryan Roth of UNC.

The reactivation effort now has a new player – Jeannie Lee, M.D., Ph.D. of Harvard University. She is a leader in the X chromosome field and we welcome the significant intellectual and technological resources that she will bring to this endeavor.

MC: Congratulations Dr. Lee on receiving RSRT funding. Tell us a bit about yourself and how you came to be interested in Rett Syndrome.

JL: Growing up I dreamed of being a physician. While I was in college I got involved in undergraduate research and I realized that I really enjoyed doing research. During my senior year I couldn’t decide whether to become a physician or pursue my new-found interest – science, so I decided to keep my options open and enrolled in an MD/PhD program at Penn. By my third year I realized I wasn’t going to practice medicine and would instead hope to make contributions to medicine via science. My interest in X chromosome inactivation (XCI) began as a graduate student in the lab of Robert Nussbaum.

MC: Dr. Nussbaum was actually one of the first scientists that I connected with in 1998 when my daughter was newly diagnosed. He was very kind and offered lots of practical and helpful advice as I started the Rett Syndrome Research Foundation (which later merged with IRSA to become IRSF).

JL: He was a great mentor. In his lab I worked on Fragile X. While attending various genetics meetings I heard some interesting talks on XCI that really caught my attention. I chose to do my post-doc in Rudolf Jaenisch’s lab at MIT and that is when I began working on XCI. Although the Jaenisch lab was not an XCI lab, all the necessary tools were there. Jaenisch was very well versed in knockout technology and transgenics and the lab was full of very bright people. So for me, it was the perfect place to be.

I set up my own lab at Harvard in 1997 and have been working on XCI ever since. To better understand the mechanics of XCI, I incorporated more molecular biochemistry-driven approaches to the mouse system. During the past few years I’ve been thinking more and more about how to apply the lab’s experience, tools and resources to a clinical problem and Rett is the perfect choice.

MC: Why Rett and why now?

JL: Combination of two things. One, the realization that Rett is curable. There is the beautiful mouse model work of Adrian Bird that shows us that you can be born with this deficiency and be cured through gene therapy or reactivation of the normal copy of MECP2. That is profound. How many congenital diseases can we say that about? Rett is one of those congenital genetic diseases for which a cure could actually happen.

And two, the tools are in place to do the necessary experiments. I feel the time is right to take the platform technologies we’ve developed and use them to identify potential therapeutics for diseases. Rett is definitely one of the targets. I’ve been interested all along in applying knowledge of basic principles to cure disease but needed to develop the tools first. We’d rather start simple and Rett gives us this chance.

MC: I don’t think I’ve ever heard Rett referred to as “simple” but I’m sure glad you think so.

JL: Simple from a mechanistic standpoint because Adrian has already shown us that it can be reversed, and that, together with the fact that Rett is a single gene disorder, which is a huge advantage, gives us hope that we’ll succeed, that we won’t be working in vain. There is actually a huge amount of interest in Rett from the scientific community.

MC: Let’s talk about the experiments you are proposing. Your plan is to develop an assay using mouse cells that will glow when the inactive MECP2 gene is activated. You’ll be using the screening facilities of the Broad Institute in Cambridge, MA, which are quite impressive.

The Broad is really a unique facility – an experiment of sorts about a new way to tackle science. It brings together an eclectic group of scientists from its partner institutions that include MIT, Harvard and the affiliated major teaching hospitals (Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Children’s Hospital, Dana-Farber Cancer Institute, and Massachusetts General Hospital). The combination of some of the best minds, unprecedented technological resources and some pretty deep pockets makes for a fertile working environment.

JL: Yes, that’s right. We are quite excited about the project and our ability to leverage the resources of the Broad. We will work with Stuart Schreiber and Nicky Tolliday and others who run the high-throughput screening group within the Broad Institute Chemical Biology platform. They have the know-how and the necessary robotic devices. We simply would not be able to conduct this screen without the Broad.

MC: Just this week an interesting paper was published in Nature describing a class of cancer drugs called topoisomerase inhibitors that have the ability to activate the silent UBE3A gene in Angelman Syndrome. The work was spearheaded by Ben Philpot and Bryan Roth who now have RSRT funding to pursue a similar approach for MECP2. This work provides strong proof-of-concept that these screens can work.

JL: The paper is exciting and promising. I do believe our screen is going to work.

MC: Dr. Lee, we wish you the best of luck as you begin this project and look forward to hearing about your progress. Happy holidays to you, your family and your lab.

Below is a short video of Nicky Tolliday explaining the Broad’s high-throughput screening capacity.


by Monica Coenraads

Many of you know that my involvement in Rett Syndrome is personal. I have a daughter who suffers greatly from every Rett symptom in the book. She is now 15 years old and every year brings new challenges. In the last six months she has developed severe Parkinsonian symptoms: violent tremors, increased rigidity, difficulty initiating movement.

Despite the increased hardships I cannot help but be optimistic. The news from the scientific community continues to be encouraging and I have not heard one shred of data to dampen my optimism. As I reflect on the state of the current research I am particularly struck by one thing: the number of potential treatment approaches that we are pursuing in parallel.  From gene therapy and exploration of modifier genes to repurposing of drugs, there is certainly no lack of ideas about how to reverse Rett Syndrome or modulate symptoms. That simple fact lifts me up even on those dark “Rett days.”

Today RSRT is pleased to announce that we are adding to our portfolio of potential treatment options with $515,054 of new funding for Huda Zoghbi and her lab. Dr. Zoghbi needs no introduction to anyone familiar with Rett Syndrome. She identified MECP2 mutations as the cause of Rett Syndrome in 1999 and has consistently added to our body of knowledge about the disorder, the animal models and the protein in the years since then. Simply put, the field of Rett would look very different without Dr. Zoghbi.

This latest award, entitled “Investigating Novel Therapeutic Approaches for Rett Syndrome” includes three separate objectives, each of which has potential clinical relevance.

The first objective tests a pharmacological intervention while the other two are aimed at altering the activity of the neural network.

1)   Test drugs on Rett mouse models to enhance the cholinergic pathway.
This neurotransmitter pathway is critical for learning, memory and regulation of the autonomic nervous system. Drugs exist that can be used alone or in combination. If we find the data from mouse models encouraging, then the findings could be immediately transitioned into clinical trials.

2)   Explore deep brain stimulation (DBS) as novel treatment strategy.
DBS has revolutionized the treatment of Parkinson’s and is now also used for depression, OCD, Alzheimer’s and more recently in pediatric disorders such as dystonia and Tourette. The availability of Rett mouse models allows us the opportunity to explore potential benefits of this procedure for Rett. Again, encouraging data can be quickly moved to the clinic.

3)   Boosting Mecp2 levels in normal cells.
Girls with Rett have approximately 50% normal cells and 50% cells which lack the MeCP2 protein. Dr. Zoghbi will explore whether boosting MeCP2 levels in the cells that already have normal amount could enhance the overall neural network activity even though the other 50% have no protein. If boosting levels in normal cells rescues some of the symptoms this would set the stage for a large scale effort to identify targets that can modulate MeCP2 levels.

Please join me in congratulating Dr. Zoghbi on this award and wishing her the very best as she pursues these new lines of inquiry. I’d also like to take this opportunity to congratulate her once again on being awarded the prestigious 2011 Gruber Neuroscience Prize which was presented during last month’s annual meeting of the Society for Neuroscience.