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People suffering from neurological disorders often have gastrointestinal issues. Rett Syndrome is no exception.  Our kids are often tortured by constipation, reflux, gas pains and more.  It should come as no surprise that the brain and the gut are connected, after all, the gut is lined with over 100 million neurons. Furthermore, the gut relies on and makes over 30 neurotransmitters, the same ones that are made in the brain.  No wonder the gut is often coined “the second brain”. 

During the past handful of years the scientific community has begun to appreciate the importance of a person’s microbiome (the population of more than 100 trillion microorganisms that live in our gut, mouth, skin and elsewhere in our bodies) and its influence on our health, including our mental health. Researchers are now exploring whether the microbiome of people with neurological disorders, including neurodevelopmental disorders, is unique. More importantly they are exploring whether manipulating the microbiome can improve neurological disease. 

Last year RSRT awarded funding to Ali Khoshnan and Sarkis Mazmanian (whose cutting-edge research on microbiomes in autism is mentioned in the article below) at Caltech to characterize the gut microbiome of Rett mice and to see whether manipulating it with powerful probiotics could improve the symptoms. This work is currently ongoing. 

The basis for Dr. Khoshnan’s  line of exploration is beautifully explained in a New York Times article published recently. Click the image below to read the article:

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Dear Friends,

I had a remarkable experience recently at an all-day meeting in Boston with Monica and the scientists of RSRT’s Gene Therapy Consortium that I wanted to share.

The Consortium is a collaboration of four labs that are developing a way to use gene therapy to treat or maybe even reverse Rett symptoms. I certainly wasn’t expecting to add anything to the conversation at this meeting, and truth be told I was a little nervous about being there. I’m a parent, not a scientist, and here I was going to a meeting with some of the world’s leading gene therapy experts. This was going to be a far cry from tenth-grade biology class, which was a long time ago. I went to the meeting to be a fly on the wall, learn what I could, and try to get a big-picture sense of progress. It turned out I got all this, but I also got much more.

It was amazing and even moving to see these scientists talking so enthusiastically about gene therapy as a potential way to treat or cure our daughters. It’s one thing to read about these projects; it’s quite another to be there and see ten scientists (the four principal scientists brought lab members with them) discussing and sharing their progress. I was struck by how the Consortium is a true collaboration. These scientists were sharing ideas and resources freely, and I know they returned to their labs with critical new information. Something else that surprised me was their compassion. Maybe I was expecting a sort of detached scientific approach from them. But that’s not at all what I saw. The Consortium members care deeply about their work and the impact it will have on those with Rett. They are constantly thinking about the details of gene therapy of course—the over-and under-expression of genes, DNA packaging, and vector optimization (a vector is the vehicle or “Trojan Horse” that carries a healthy gene to a mutated cell)—but it’s all driven by a desire to change lives. This was wonderful to see. We have Monica to thank for propelling these and other scientists to care about outcomes for our daughters as much as she and all of us parents do.

It was also clear at this meeting that meaningful progress was being made. I’ve learned enough about gene therapy to understand that the vectors that Consortium members are developing are critical. An effective vector will need to deliver just the right amount and parts of a gene, which is much easier said than done. At the meeting one of the Consortium scientists presented data on a vector tested in mouse models that looks promising. While this is very good progress, a lot more research lies ahead. Using gene therapy to treat Rett remains theoretical until the Gene Therapy Consortium members prove otherwise.

Science is complex and I know sometimes it’s hard to envision exactly how funding for it is used. At this meeting I had an acute sense of how every dollar contributed to RSRT matters—what I watched unfold that day simply would not have happened without the generosity of many people. It was another reminder of how grateful I am to everyone who supports RSRT. I feel lucky to have been there and to have had the chance to literally watch progress being made. The meeting renewed my excitement about the future for my daughter and all the other girls and women I’ve met with Rett Syndrome.

Tim Freeman

Neurolixis

RSRT recently awarded $530,000 to Neurolixis, a small biotech firm in southern California that is developing the drug, NLX-101, to treat breathing abnormalities in people affected by Rett Syndrome. The drug targets a specific serotonin receptor (5-HT1A) located in regions of the brain that affect respiration, mood and cognition.  It’s possible that, beyond breathing, the drug may also improve other core symptoms such as anxiety and movement disorders.

Neurolixis has already obtained Orphan Drug status for NLX-101 in both the US and in Europe. This designation provides the company with certain financial incentives as part of the Orphan Drug Act.  

Previous RSRT funding to Neurolixis focused on studies to determine dosage levels for human studies. The next step is for Neurolixis to file an Investigational New Drug (IND) application with the FDA before clinical testing of the drug can begin.

The current award will be used to manufacture and characterize clinical supplies of NLX-101, and to prepare regulatory documents for submission to the FDA. The goal is to have the IND submitted to the FDA within a year.  Once the IND is open, Neurolixis will test the safety, tolerability and pharmacokinetics (the time course of the drug’s absorption, bioavailability, distribution, metabolism and excretion) in healthy volunteers and in people with Rett.

By supporting this program, RSRT will help Neurolixis “de-risk” the project and make it more attractive to investors, who can support the next stage of development and expedite the process. 

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Dear Friends,

I am sitting in a plane on the tarmac at Chicago O’Hare, returning home from an amazing event that was spearheaded by a Rett family.  The captain just announced that we are last in line for takeoff—could be an hour wait.  Bummer!  It’s a beautiful Friday afternoon and I was hoping to get home to my wife and daughter early to start the weekend.

But the delay gives me a chance to reflect a little on the last few months, which have been a whirlwind.  Since the beginning of April, three new events have been held to raise funds for RSRT’s research—one outside of Boston, one in central Massachusetts, and one in Chicago.  Two established events also were held near Baltimore and Phoenix.  There were other successful efforts too—a friend of a Rett family did an online campaign for a 10K race she ran in Philadelphia; a Connecticut fourth-grader, inspired when she met a young girl with Rett Syndrome last year, raised over $1,500 for research.

It always feels like such an understatement to say how grateful I am to people who hold events or raise funds in other ways for RSRT.  They are making possible research that will change so many lives, including my own daughter’s.  No words can adequately express how I feel about that.

Each of these events was different.  Some were hosted by parents of daughters with Rett, others were spearheaded by their friends.  One was organized by Rett grandparents, another was led by a young man whose sister has Rett.  They were in cities, suburbs and rural areas.  They were cocktail galas or sit-down dinners.  I wore a suit to one, jeans and a sports jacket to another, and shorts and a t-shirt to the race.  No two events were the same.  This, I’ve learned, is the beauty of events—they take on the personalities of the people who run them.  They are whatever their hosts want them to be.

But there were similarities too in these events.  At each one, people came together enthusiastically for the cause.  Committees made up of family and friends had key roles in planning and running them.  There was a shared ethos behind all of them of hope and optimism, and with good reason given the progress in research.  The remarks made by parents and others were poignant, filled with the love they feel for their daughter, granddaughter, sister, or friend’s daughter; filled with a sense of empowerment and accomplishment that they are making a difference.  They were tinged with sadness too of course—for what our girls have missed out on; for what their lives and our own might be like if it weren’t for a random and rare mutation on one gene.

I’ll admit something else—I’ve had fun at these events, and I think everyone involved with them has too.  It has certainly been hectic and stressful sometimes, but mostly it has been fun.  It feels slightly out of place to say that; after all we are raising funds to cure a disease that causes such severe disability and physical and mental pain.  But it’s the truth.  I’ve had a good time over the last two months.  We families that have Rett in our lives need some silver lining, and this may be it.  Events give us a chance to be together with family and friends, to meet other families that have the same challenges that we do.  Rett Syndrome has given us a common enemy that together we can fight and ultimately beat.

This has been a rather long-winded way of trying to say one thing—Thank You.  Thank you to everyone who puts so much energy into events and raising funds for RSRT and for your commitment to our daughters’ futures.  Because of you, that future that we all want so badly is getting closer.  We are very fortunate to count you as friends.  And I am now being told to put away my laptop for the flight home.

Tim Freeman

 

 

 

We’re delighted to share this monumental honor with the Rett community. Our very own Monica Coenraads was awarded an honorary doctoral degree from UMass Medical School at their 2015 commencement ceremonies. It goes without saying that Monica’s knowledge, passion and courage provide not only the backbone but the spirit of our organization. We could think of nobody more deserving than Monica. 

The chancellor put it best “A diagnosis that would have been an emotional setback for others, instead set the stage for your emergence as a central figure in one of the most successful advocacy stories in modern medicine.” She is truly a pioneer and our fiercest warrior leading the charge in the war on Rett.

This is a great honor not only for Monica but also for RSRT.  It’s a testament to the respect she and the organization have in the scientific and medical community.  It’s also further testament to why all of us Rett parents are fortunate that Monica does what she does.

 -Tony Schoener, Chair, RSRT Board of Trustees

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by Carol Morton

Three years ago, a study showed that a bone marrow transplant performed in pre-symptomatic male mice models of Rett Syndrome substantially extended their lives and reduced symptoms of disease. The unexpected findings caught the attention of Rett researchers, physicians, and parents.

Seeking to validate the results and therefore strengthen the case for clinical studies, four other research groups launched their own mouse studies. In independent experiments, each lab was unable to replicate the original findings.

The researchers combined their results into a single paper, published May 20 in Nature, the same journal that published the original positive results. The new study is posted online only as a “brief communication arising,” a category for new scientific data that challenge the findings of an original research paper in the journal, according to Veronique Kiemer, executive editor of the Nature Publishing Group.

The new paper means that bone marrow transplants may not be a viable therapeutic option, but the pair of papers could point the way to new insights into Rett and ways to fix it, said Monica Carson, a neuroimmunologist at the University of California, Riverside, who was not involved in any of the studies.

“The key is that both answers are possible,” Carson said. “ It’s important to figure out the differences between the papers.”

The original paper came from the lab of Jonathan Kipnis, a neuroimmunologist at University of Virginia in Charlottesville. Kipnis and his colleagues explore the role of the immune system in healthy and diseased brains. No stranger to controversial findings, he has shown that T cells closely surrounding the brain are somehow crucial to normal cognitive function.

In fact, the team first conducted the transplants to test the idea that inadequate T cells in Rett mice might explain their cognitive impairment. “We proved our original hypothesis wrong,” Kipnis said. But with new immune cells, the mice lived much longer. Most cases of Rett can be traced to a malfunctioning gene on the X chromosome called methyl-CpG-binding protein 2 (MeCP2). A transplant fixed the faulty gene in the mice’s immune cells.

How was a new immune system exerting a protective effect? A clue came from stem cell transplant studies for Alzheimer’s disease, where another kind of circulating immune cell, called monocytes or macrophages, lodge in the brain and clear away debris that may cause neurodegeneration. After further experiments, Kipnis and his co-authors proposed that monocytes with good MeCP2 genes also migrated to the brain in the Rett models and helped their brain-dwelling microglia cousins in some unknown way.

Last month, the Kipnis team reported the first molecular and cellular evidence that MeCP2 controls gene expression in macrophages and that some types of macrophages in the brain and throughout the body may be especially vulnerable early in disease. “This work is a beautiful example of how the immune and nervous systems are intimately associated, sharing common molecular pathways and potentially affecting the function of one another in many dynamic ways,”  according to a commentary published with the paper.

The original paper was funded by RSRT. Given the serious nature and risk of a bone marrow transplant, RSRT felt it was crucial to reproduce the findings before supporting any clinical trials. RSRT awarded funding to Andrew Pieper, now at the University of Iowa, who had provided the original mice for the Kipnis study, and Antonio Bedalov, at the Fred Hutchinson Cancer Research Center, a scientist and oncologist, who works with bone marrow transplant patients.

Independently, Peter Huppke, at University Medical Center Gottingen in Germany, and Jeffrey Neul, now at University of California, San Diego, also attempted replications. None of the four labs saw the significant effects seen by Kipnis.

For his part, Kipnis interprets the new paper differently. “Most importantly, it confirms our initial findings, although not as dramatically,” he said, pointing to a small increased lifespan effect that could be seen if two figures were combined. He and two lead co-authors of the original paper have written a detailed response in the comment section for the paper. It outlines suspected issues with the new paper, including mice that may have inadvertently acquired a mixed genetic background and may therefore have a version of graft versus host disease (GVHD) which would have confounded the results. This would be analogous to a person receiving bone marrow that was not a tissue match. Bedalov denied that possibility, saying GVHD would be obvious because the mice would have additional symptoms.

The first mouse study had prompted clinical investigators to add boys with Rett to a hematopoietic stem cell transplant protocol last year. Boys with classic Rett mutations have more severe disease and usually die by age 2. Based on the new findings, the trial has withdrawn Rett as a disease eligibility, wrote principal investigator Weston Miller at the University of Minnesota in an email. No boys with Rett had enrolled in the trial.

Other researchers contacted by RSRT applaud the attempt to replicate the bone marrow transplant findings before considering clinical trials, but they see a more important unfolding story is the role of the immune system in Rett disease biology.

Looking ahead, “discrepancies between labs do occur,” Kipnis and his co-authors wrote, “and understanding the cause of varying results can ultimately lead to an even better understanding of the scientific or disease-related process in question.”

 

Every cell in our body contains the same genes. Yet a brain cell is distinctly different from a heart cell or a liver cell. What differentiates these cells are the genes that are either silenced or active and the degree of activation of the genes, also known as expression.

Scientists have known for many years that the “Rett protein”, MeCP2, regulates the expression of other genes. The big question has been, which genes?

Michael Greenberg of Harvard University, and his lab members Harrison Gabel and Benyam Kinde, may have an answer: long genes. The journal, Nature, is publishing this finding today.

Genes are made up of nucleotides (think back to high school biology: A,T,C,G) The average gene has about 20,000 nucleotides, but some have as many as a million. The scientists in the Greenberg lab found that the MeCP2 protein acts as a dimmer switch, dampening the expression of long genes. When the MeCP2 protein is absent, as in the case of Rett, with no dimmer switch to regulate it, long gene expression goes up. Any deviation from the normal expression pattern causes problems.

From this finding, the scientists suggest that Rett Syndrome may be caused by a widespread overexpression of long genes.

You may be asking yourself, why does this matter? It matters because there is a drug that can rebalance the expression levels of long genes. The Greenberg lab has already tested this drug in cells missing the MeCP2 protein with encouraging results. Experiments are now underway to test the drug in Rett mice.

This is a promising development. We are providing the following resources to help you understand the progress being reported today.

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Animation of Findings

 

Interview with Greenberg Lab Members

For a variety of reasons the pharmaceutical industry over the last few years has become more and more interested in rare disease. This is great news for Rett Syndrome.  As terms like orphan drug designation, breakthrough therapy, efficacy, drug approval, market exclusivity become part of our everyday lingo it is important that our understanding of them is based in facts. As we start the process of learning and sharing information we bring you this interview with regulatory consultant and Former Director of the FDA Office of Orphan Product Development, Timothy Coté.

Disneyland-Nov 2014[1] Brenna and Mike Johnson of Tustin CA were devastated when their daughter Gisele was diagnosed with Rett last fall. But the Johnsons quickly got to work to make a difference to the research that they know will change Gisele’s life.  In early December they started an online campaign for RSRT using FirstGiving.com. They called it A Cure for Christmas, and their friends, colleagues, and family came out in full force to contribute to RSRT’s research program.   photo1 So far they have raised almost $60,000, a record for an online campaign for RSRT. Mike added further interest by swearing off shaving during the campaign, although their friends and family were so quick to support the cause that his beard didn’t even get very long. As Brenna says, “we were overwhelmed by everyone’s generosity and eagerness to be a part of this; and we’re proud to be helping RSRT move the science forward.” Hearty congratulations and thank you from RSRT to Brenna and Mike and all their network of supporters. Starting a fundraising campaign on FirstGiving.com is easy and effective. Contact Tim Freeman at RSRT if you have questions or need help,  tim@rsrt.org or 609.309.5676.  

This week RSRT announced research investments of $5.8 million bringing total commitment to research to $25 million since its launch in 2008.

Highlights of RSRT’s 2014 awards:

  • Funding of $1.3 million was awarded to Case Western Reserve University and the Cleveland Clinic for a Phase 2 clinical trial of low-dose ketamine for the treatment of Rett Syndrome. Ketamine, a drug that has historically been used for sedation and anesthesia, has recently generated much enthusiasm for its ability to rapidly reverse major depression at low, sub-anesthetic, doses. Studies undertaken by David Katz, Ph.D., showed that low-dose ketamine can reverse deficits in brain activity in mouse models of Rett Syndrome in conjunction with significant improvements in neurological function, including breathing. This trial will determine the effect of single doses of ketamine on breathing abnormalities and other Rett Syndrome symptoms.The study is being led by David Katz, Ph.D., Professor of Neurosciences and Psychiatry at Case Western Reserve University School of Medicine and Daniel I. Sessler, M.D., Michael Cudahy Professor and Chair, Department of Outcomes Research at the Cleveland Clinic.

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“This trial evolved as a dynamic collaboration among basic scientists, clinicians, and clinical trialists including expert advisers recruited by RSRT. We are grateful to RSRT for fostering this collaborative spirit and providing the support necessary to make this trial a reality.”

  • Aleksandra Djukic, M.D., Ph.D., medical director of the Tri-State Rett Syndrome Center at the Children’s Hospital at Montefiore was awarded $403,000 to conduct a Phase 2 clinical trial of lovastatin, a cholesterol lowering medication. The scientific basis for this trial stems from experiments conducted in the lab of mouse geneticist, Monica Justice, Ph.D., who identified the cholesterol pathway as a potential avenue to improve Rett symptoms.  The trial will determine the effect of lovastatin on gait, respiratory function, cognition and other Rett symptoms including the severity of the disease.In addition, Dr. Djukic recently concluded a Phase 2 trial testing safety and effectiveness of a multiple sclerosis drug, copaxone, in treating Rett Syndrome. The data is currently being analyzed.

“Cc93a3f47-7c0d-4bf5-b190-0c2a90073f81holesterol is vitally important for brain function. In fact, although the brain is only 2-3% of total body weight, it contains and makes 25% of the body’s cholesterol. Dr. Justice’s work suggests that elevated cholesterol levels in the brain may play a role in Rett symptoms. Our trial will test the hypothesis that reducing cholesterol in the brain will lead to symptom improvement.”

 

 

 

 

The ketamine and lovastatin trials will begin recruitment shortly. We will send you notification as soon as they are ready to proceed and will provide detailed information on the RSRT website.

  • Individuals with Rett display a broad spectrum of symptom severity. Some girls can run, have a degree of hand use and can speak in short sentences while others cannot even sit or hold their head up. One reason for this variation is the child’s own unique genetic makeup. In other words, we’ve learned that variations in other genes have an impact on the severity of the Rett mutation. Monica Justice, Head and Senior Scientist in the Genetics & Genome Biology program at The Hospital for Sick Children in Toronto, has undertaken a screen to identify these other, modifying genes that potentially impact the severity of Rett symptoms. The first suppressor gene she identified, squalene epoxidase, led to the lovastatin trial described above. The screen is currently at the halfway point, with 12 modifiers identified. RSRT has awarded Dr. Justice $716,000 in additional funding to complete the screen. This brings RSRT’s total commitment to the project to $2.3 million.

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“Monica Coenraads approached me a number of years ago asking how I would identify modifiers.  I thought that an unbiased suppressor screen using a mouse supermutagen would be the most effective approach, and was timely with the advent of new genome sequencing technologies.  Such an approach was considered very risky, requiring funding through a forward-looking organization such as the RSRT.  It has been extremely rewarding to move from the development of a concept…to isolating modifiers that were unexpected…to a clinical trial.  Our ongoing screen is much easier and quicker now as technologies advance. My hope is that many more trials will come from the continuing screen.”

 

  • Two additional projects are aimed at awakening a healthy but silenced back-up copy of the mutated Rett gene. If the flawed gene could be replaced by reawakening its silenced counterpart we could conceivably reverse Rett symptoms.Currently pursuing this approach with RSRT funding are labs at the University of North Carolina at Chapel Hill, the University of Massachusetts, Harvard University, and Fred Hutchinson Cancer Research Center. These labs are now in regular communication because of RSRT’s strong belief in and facilitation of collaborative research models that encourage the sharing of data, cell lines and compounds.RSRT has awarded additional funding totaling $755,000 to two projects ongoing in the labs of Jeannie Lee, Ph.D., of Harvard and Antonio Bedalov, M.D., Ph.D., of Fred Hutchinson to aggressively pursue this work.
  • RSRT funding will allow David Katz to purse research on the drug, LM22A-4, towards an application to the FDA for an IND (Investigational New Drug).
  • Successful fundraising on the part of the MECP2 Duplication Syndrome community facilitated two awards totaling $644,065 to Huda Zoghbi, M.D., Professor in the Departments of Pediatrics, Molecular and Human Genetics, Neurology and Neuroscience at Baylor College of Medicine and director of the Jan and Dan Duncan Neurological Research Institute. The funds will support two strategic approaches to treating the disorder.

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“We are very excited to receive support for exploring two different strategies to reduce MeCP2 levels. The two strategies are complementary, one involving genetic screens in human cells to find potential targets that can be druggable with a pharmaceutical agent, while the other employs antisense oligonucleotides developed by Isis pharmaceuticals and designed to reduce MeCP2  levels directly.”

 

 

 

See Complete List of 2014 Awards  

Our partners in supporting this work are parents’ organizations worldwide including Reverse Rett (UK)Rett Syndrome Research & Treatment Foundation (Israel)Skye Wellesley Foundation (UK)Rett Syndrome & CDKL5 IrelandRett Syndrom DeutschlandStichting Rett Syndrome (Holland); and American organizations, Girl Power 2 Cure, Eva Fini Fund at RSRT, Kate Foundation for Rett Syndrome ResearchRocky Mountain Rett AssociationAnastasi FundClaire’s CrusadeNew Jersey Rett Syndrome AssociationRett Syndrome Association of Massachusetts, and the MECP2 Duplication Syndrome Fund at RSRT.

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