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Housed in the nucleus of every cell in the body is 6 feet of DNA.  The nucleus is so small that 10,000 of them with a combined total of 11 miles of DNA would fit on the tip of a needle.  The video below explains how the unimaginable feat of coiling this amount of DNA is accomplished.

 

Today the journal, Cell, published research from the lab of Gail Mandel showing that the Rett protein, MeCP2, plays a role in how DNA is packaged into the nucleus. This research was funded, in part, by RSRT through the MECP2 Consortium. Using a technology called array tomography the Mandel lab found that in cells that are missing MeCP2 the DNA is more tightly compacted.

Increased compaction “hides” genes from the cellular machinery needed for protein production. So genes that are compacted are less likely to be producing protein.

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Imagine DNA as a slinky with genes along the coils. In a compressed state it is difficult for these genes to be accessed by the necessary molecules that facilitate protein production.

 

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However when the slinky is stretched out the genes become very accessible for protein production.

 

 

The scientists also found that the degree of DNA compaction was correlated to the degree of MeCP2 requirement in a given cell type. For example, cells that typically require large amounts of MeCP2 (eg. Purkinje cells) will suffer a greater change in compaction when MeCP2 is missing than cells who normally have a smaller requirement of MeCP2 (eg. astrocytes).

The video below shows normal nuclear compaction in Purkinje cells of female mice on the left and Rett mutant mice on the right.

The person responsible for this work, Mike Linhoff of the Mandel lab, describes the video, “The white shows DNA, while the green shows DNA sequences where MeCP2 binds. Red shows a particular protein modification that promotes DNA compaction. In the absence of MeCP2 this compacting modification invades the DNA sequences where MeCP2 usually binds.”

“The clinical relevance of the work is to point towards cures that will take into account neuronal-specific effects of MeCP2 loss. Once such strategy, which RSRT is already pursuing, is to reactivate the silent MECP2 on the inactive X. Other strategies might include identifying factors that can titrate gene therapy levels of MeCP2 in different neuronal types, or identifying a druggable common downstream consequence that occurs in all neuronal types,” shares Gail Mandel.

 

 

by Monica Coenraads

Chelsea is 18 years old today. It’s a milestone birthday that parents of special needs children face with mixed emotions. My heart is full with love and pride for the beautiful, emotive, tender yet determined young woman that Chelsea has become. But today I am also mourning. Mourning for a childhood never lived and forever lost.

Chelsea beach

When Chelsea was a toddler I made her a promise – that I would do everything in my power to heal her. With little science background, zero drug development knowledge and no fundraising experience I did not appreciate the enormity of my promise. Ignorance, at times, can be a blessing.

The Rett research landscape in the year Chelsea was diagnosed, 1998, was dismal. The disorder was practically unknown in medical and scientific circles, there was no known gene and therefore no diagnostic blood test, there were no animal models, and there was little research beyond trying to pinpoint the genetic cause.

My conviction that treatments and a cure for Rett were possible came from both visceral intuition and a mother’s love. Today that conviction is based on science.

But when will that cure come? Is it really “around the corner” as I so often read on facebook and other social media? I do not know the timeframe associated with “around the corner” (is it weeks, months, years?) but I am confident that a number of treatments will become available to our children in the coming years that will improve certain symptoms. The Potential Rett Syndrome Therapeutics chart on the RSRT website provides insight into the numerous interventions currently being pursued.

As parents we will take any improvement in our children’s symptoms that we can get. But what about the “like it never even happened” cure? (My all-time favorite catchphrase from the disaster restoration company, SERVPRO) For now we do not know whether the cure will be gene therapy, or protein replacement or activating the silent MECP2 (or the entire X chromosome) or a drug that modulates a modifier gene or perhaps a combination of some or all of these approaches. And we don’t know what a cure for someone like my daughter, who is now an adult, will look like. Will she be able to speak, to walk, to use her hands?

I do not focus on these questions because they are, for now, unanswerable. I concentrate only on the facts and these include:

  • The reversal experiments originally done in Adrian Bird’s lab and repeated over and over again in many labs gives us solid proof-of-principle that dramatic reversal of symptoms should be possible. I have yet to hear one piece of scientific data that would dampen my optimism that a cure is possible.
  • Scientists are making progress on many fronts including gene therapy.
  • Rett researchers are collaborating and sharing information in real-time in a way that is unprecedented. Examples include the MECP2 Consortium, the Gene Therapy Consortium, and researchers focused on reactivating the silent MECP2.
  • Technologies exist today that are enabling experiments that only a few years ago would be impossible.
  • Rett has become a high-profile disorder in scientific circles.
  • Biotech and big pharma, for the first time, are showing an interest in Rett Syndrome.
  • Science is not linear. We do not know what might lie around the corner that can dramatically accelerate the development of a cure.

Those of you who know me will know that I am aggressive when it comes to pushing the science forward but I am conservative in how research progress is relayed to families. I prefer facts over hype.

Could a cure for Rett be around the corner?  The answer to that question will come when we have a clearer picture of what form that cure will take.  I can assure you that I will not rest until we accomplish that.

Love alone cannot cure Rett but love and research will. It’s been 16 years and I am more than ready to deliver on my promise.

To profoundly impact a disorder with as many varied and debilitating symptoms as Rett Syndrome, it is likely that intervention must be directed toward the very root of the problem. There are several ways to do this: activate the silent back-up copy of the Rett gene; target modifier genes; explore gene therapy.

Today, we announce a study funded through the MECP2 Consortium suggesting that gene therapy may indeed provide a feasible approach to treat Rett Syndrome.

The work was led by Gail Mandel at Oregon Health and Sciences University in collaboration with Adrian Bird of the University of Edinburgh and Brian Kaspar of Nationwide Children’s Hospital.

Gail Mandel with lab members Dan Lioy and Saurabh Garg

Gail Mandel with lab members
Dan Lioy and Saurabh Garg

Adrian Bird and post-doc Hélène Cheval

Adrian Bird and post-doc
Hélène Cheval

In the past sixty days, four key papers have been published detailing research advances supported financially and intellectually by RSRT. Three of those papers are funded through the MECP2 Consortium, a unique alliance launched by RSRT in 2011 among three leading labs: Bird, Greenberg (Harvard) and Mandel. If you are a donor to RSRT, the accelerated research these projects represent is the result of your money at work.

We wish to express our gratitude to all of our generous supporters and the parent organizations that make this progress possible. Special thanks to our funding partners, the Rett Syndrome Research Trust UK and the Rett Syndrome Research & Treatment Foundation.

Below are some resources to help you understand today’s announcement.

Press Release [Spanish Translation] [German Translation]


Video interview with Dr. Mandel & lab members