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Monica Coenraads interviews Michael Green, MD, PhD of the UMASS School of Medicine about his newly published paper in Proceedings of the National Academy of Sciences.  The work was funded, in part, by RSRT.  He has identified a number of genes that when disrupted can reactivate the silenced X chromosome in females. Some of these genes lie in pathways that are druggable which makes this work potentially clinically relevant not only for Rett Syndrome but also for other X-linked disorders.

Prof. Green’s paper was covered by SFARI.org. in an article written by Jessica Wright.


Rousing silenced X chromosome may treat Rett syndrome

Drugs that activate the silent copy of the X chromosome in women may be able to undo the damage from mutations in genes located there. The study, published 2 September in Proceedings of the National Academy of Sciences, offers hope for treating Rett syndrome and other disorders linked to the chromosome1.

One copy of the two X chromosomes women carry is randomly silenced in each cell of the body. This occurs when the chromosome makes small pieces of RNA, called X-inactive specific transcript, or Xist. A cloud of Xist coats the chromosome and blocks its expression.

Female mice lacking Xist die in utero, so X inactivation was thought to be required for survival. The new study suggests otherwise.

The researchers identified 13 genes required for X inactivation. Female mice missing STC1, one of these genes, show expression of genes from both copies of X and have no obvious symptoms.

“The mouse findings suggest that you might be able to survive without X chromosome inactivation,” says lead researcher Michael Green, professor of molecular medicine at the University of Massachusetts Medical School.

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Last year RSRT awarded a $750,000 grant to Michael Green,  PhD of University of Massachusetts to pursue an unconventional approach to reversing Rett: reactivating the silent X chromosome.  UMASS just released the piece and video below highlighting Dr. Green’s work.  We are struck by the following quote from Dr. Green:  “With NIH funding, you pretty much have to be doing mainstream research. The NIH doesn’t fund bold and innovative projects often. By contrast, organizations like RSRT are willing to take on high-risk projects that have controversial hypotheses and rationales, because these are the ones that really may have a great impact on disease.”

We thank all of our supporters who make it possible for us to fund innovative, out-of-the-box projects that we believe will move us towards a cure for Rett by leaps rather than small incremental steps.

From the UMASS Med NOW website:

UMMS scientist aiding a mother’s quest for rare disease cure
With a $750,000 grant from the Rett Syndrome Research Trust, Michael Green is working to reverse a debilitating neurological disease

By Lisa M. Larson and Bryan Goodchild (UMass Medical School Communications)

Monica Coenraads is discussing work with two business associates in the living room of her Trumbull, Conn., home on a recent spring morning, when the conversation turns to the benefits of face-to-face communication over reliance on electronic devices.

Suddenly, a squeal of laughter erupts from the other side of the room, where her 17-year-old daughter, Chelsea, has been relaxing on the couch, quietly listening to her mother’s every word.

“Chelsea thinks it’s funny, because she believes her mom spends too much time on her phone,” explains Coenraads, who works from her house.

In homes across America, parents and kids are debating texting, cell phones and screen time.

But for the Coenraads family—Monica, husband Pieter, and sons Alex, 15, and Tyler, 14,—the focus is on discovering any method by which Chelsea can communicate. The slender, brilliant-blue-eyed girl, who bears a striking resemblance to her mother, has Rett syndrome, a rare, genetic, neurological disease that locks her thoughts inside her head, as she is unable to speak or to use her hands. With great determination and without speech or hand gestures, Chelsea expresses herself by focusing her gaze on pictures in a three-ring binder of the words she’d like to say.

“A child with classic Rett syndrome is in a wheelchair, unable to talk, fed through a feeding tube, with seizures, anxiety, orthopedic issues, scoliosis, contractures and no hand function,” said Coenraads, co-founder and executive director of Rett Syndrome Research Trust (RSRT) and its director of research. The former restaurateur is credited with helping to raise more than $37 million for research into Rett syndrome since her daughter’s diagnosis 15 years ago.

“They’re really trapped,” continued Coenraads, explaining the disease, which affects approximately 16,000 girls across the country. “They can understand what is going on; cognitively they are quite on track.”

UMass Medical School scientist Michael R. Green, MD, PhD, globally known for his work in gene regulation, keeps the image of Chelsea and that of other girls who suffer from Rett in mind as he works toward finding a drug that would reverse the disease. Dr. Green, a Howard Hughes Medical Institute Investigator, the Lambi and Sarah Adams Chair in Genetic Research and professor of molecular medicine and biochemistry & molecular pharmacology, received a $750,000 grant from RSRT for research aimed at reversing the underlying cause of the disorder. He is one of several dozen researchers around the world, recruited by Coenraads, who have met children with Rett and their parents, and are working on therapies, a cure or a reversal of the disease.

Rett syndrome is caused by a mutation of the gene on the X chromosome called MECP2 that causes numerous devastating symptoms that worsen over time. The symptoms begin in early childhood and leave Rett sufferers completely dependent on 24-hour-a-day care for the rest of their lives. While the function of MECP2 remains elusive, scientists know that it acts globally and impacts numerous systems in the body.

Female cells have two X chromosomes and therefore two copies of the MECP2 gene, and mutations occur in only one of the two copies of the gene. In females, however, one of the two X chromosomes is randomly turned off (or silenced), a phenomenon called X chromosome inactivation (XCI). As a result, in patients with Rett syndrome, half of the cells express a normal copy of MECP2 and the other half express the mutant copy. Importantly, in those cells that express the mutant MECP2, the normal copy is still present—just silent. Green is testing drugs that modulate XCI to reactivate the silent normal MECP2 gene in these cells as a strategy to reverse the disease.

“He is taking a somewhat unconventional approach, as he is attempting to reactivate the entire X chromosome and not just MECP2,” saidCoenraads. “His work first came to RSRT’s attention in 2009. We learned that he was conducting a screen to identify genes that control XCI. As his work matured over the next few years he did indeed identify factors that control XCI, some of which belong to molecular pathways for which there are drugs. These drugs can now be tested in culture and in vivo in Rett syndrome mouse models.”

Green praised the support he has received from RSRT and said the work that Coenraads and her colleagues do is inspirational.

“With NIH funding, you pretty much have to be doing mainstream research,” said Green, who was recently elected to the National Academy of Sciences. “The NIH doesn’t fund bold and innovative projects often. By contrast, organizations like RSRT are willing to take on high-risk projects that have controversial hypotheses and rationales, because these are the ones that really may have a great impact on disease.”

Read in its entirety

In contrast to the leadership of most organizations we yearn for the day when RSRT is no longer in business – that will mean an end to Rett. Until that day comes we will continue to invest in high quality science. In the first half of 2013 RSRT has committed $1.7 million to new projects that range from basic science to clinical trials. We invite you to learn about our investments, which our donors have made possible. As always we welcome your questions and feedback.

Copaxone Clinical Trials

There is a multitude of data suggesting that mice models of Rett have low levels of a neurotrophic factor called BDNF (brain derived neurotrophic factor). BDNF is a very important and complex protein that is implicated in a variety of disorders. Increasing BDNF in the Rett mice models, either genetically or pharmacologically is beneficial. An FDA approved drug for multiple sclerosis called copaxone (or Glatiramer Acetate) is known for increasing BDNF and therefore of interest in treating Rett.

RSRT has committed to funding an open label study of copaxone in two centers, the Tri-State Rett Syndrome Center at Children’s Hospital at Montefiore in the Bronx, under the supervision of Dr. Sasha Djukic, and at Sheba Medical Center in Ramat Gan in Israel under the supervision of Dr. Bruria Ben Zeev. Each center will give copaxone to ten individuals for 6 months. Below is a comparison of the two studies. 

Sasha Djukic, M.D., Ph.D.

Sasha Djukic, M.D., Ph.D.

Bruria Ben Zeev, M.D.

Bruria Ben Zeev, M.D.

USA Israel
Title Pharmacological treatment of Rett Syndrome with Glatiramer Acetate (Copaxone) An open-label exploratory study to investigate the treatment effect of glatiramer acetate (Copaxone) on girls with Rett Syndrome
Principal Investigator Aleksandra Djukic, MD, PhD Bruria Ben Zeev, MD
Location Children’s Hospital at Montefiore, Bronx Sheba Medical Center, Ramat Gan, Israel
Objectives Primary: gaitSecondary: cognition, autonomic function, EEG, quality of life Primary: EEG improvementSecondary: autonomic function, general behavior, communication, hand stereotyping, feeding, gastrointestinal
Study Size 10 girls – 10 yrs old and up 10 girls – 6 to 15 yrs old
Dose (injections) Ramp up to 20 mg per day Ramp up to 20 mg per day
Length of study 6 months 6 months

While copaxone is not going to cure Rett Syndrome we hope that by increasing BDNF we will see improvements in symptoms. The trials are currently recruiting.

The X Factor

If you’ve been following RSRT’s activities then you know that one of the strategies we are pursuing is reactivation of the silent MECP2. We are adding Michael Green of UMass to our existing portfolio of labs who are working in this space.

Michael Green, M.D., Ph.D.

Michael Green, M.D., Ph.D.

Dr. Green is taking a somewhat unconventional approach as he is attempting to reactivate the entire X chromosome and not just MECP2. His work first came to RSRT’s attention in 2009. We learned that he was conducting a screen to identify genes that control X chromosome inactivation (XCI). As his work matured over the next few years he did indeed identify factors that control XCI, some of which belong to molecular pathways for which there are drugs. These drugs can now be tested in culture and in vivo in the Rett mice models.

Recently a paper from a colleague of Michael Green’s, Jeanne Lawrence, received enormous attention for doing the opposite of what Dr. Green proposes – inactivating the extra copy of chromosome 21 that causes Downs Syndrome (DS). While this work is not ready for prime time it is an exciting new avenue that could eventually make treatment for DS a reality.

Continuing our X Factor focus we awarded an additional grant to Jeannie Lee of Harvard University. She is currently funded for a drug screen to reactivate MECP2. While the goal of the new award is the same – activate MECP2 – how she proposes to accomplish it is completely novel.

Jeannie Lee, Ph.D. at an RSRT meeting in November

Jeannie Lee, Ph.D. at an
RSRT meeting in November

The hypothesis of Dr. Lee’s approach rests on an observation that a group of proteins called Polycomb complexes working in concert with a certain type of RNA, called noncoding RNA (lncRNA) are relevant for keeping genes silent on the inactive X.

Dr. Lee’s therapeutic strategy is to awaken the MECP2 gene by disrupting the binding that occurs between the lncRNA and the Polycomb complexes.

While the work is early stage, if Dr. Lee’s hypothesis proves correct this approach would be attractive.

Ketamine – the follow up

Last October David Katz of Case Western Reserve University published a paper showing that certain physiological symptoms in the Rett mice normalized after treatment with an aesthetic called ketamine. With RSRT funding Dr. Katz will continue to pursue this line of exploration with additional drugs that work in the same pathway but have less side effects. He will also attempt combination therapies with various drugs.

Below is a video interview with Dr. Katz that was posted earlier this year.

Gene Therapy for the MECP2 Duplication Syndrome
Kevin Foust (left) and Brian Kaspar at a recent RSRT meeting.

Kevin Foust (left) and Brian Kaspar
at a recent RSRT meeting.

The final award was granted to Kevin Foust of Ohio State University. Dr. Foust has been working with Brian Kaspar and Gail Mandel on gene therapy approaches to treat Rett Syndrome. This award builds on that work by extending a gene therapy approach to the MECP2 Duplication Syndrome. Dr. Foust will deliver RNA interference (RNAi), a biological process in which RNA inhibits protein production) via a vector in duplication syndrome mice.

If the data is encouraging this work would form the basis for a therapeutic approach to treating patients.

This work is being funded via the MECP2 Duplication Syndrome Fund at RSRT and directly supported through the efforts of the duplication families.

We look forward to bringing you updates on these and all of our projects.  Once again we thank all of our supporters – this is your money at work for our girls.