Bird_Print_Finals-15

Sir Adrian Bird has been a trustee of RSRT since our launch in 2008.

If you care about Rett Syndrome then you undoubtedly know about Adrian Bird. He discovered the Rett gene, MECP2, and he made the first animal model of the disease. And if that wasn’t enough his reversal experiments suggested to the world that Rett may be curable.

birdquote3

Listen to the podcast from The Naked Scientist as Prof. Bird discusses his research and his hopes for a cure.

podbtn

 

 

 

 

image

By Delthia Ricks
delthia.ricks@newsday.com

Long Island scientists have moved a tantalizing step forward in efforts to better understand — and alleviate — some of the devastating symptoms of Rett Syndrome, a rare, incurable, neurodevelopmental condition that primarily strikes girls.
The syndrome shares key symptoms associated with autism spectrum disorders but has many symptoms that are unique, including an underlying genetic mutation, said biochemist Nicholas Tonks of Cold Spring Harbor Laboratory.

Writing in the current issue of the Journal of Clinical Investigation, Tonks and colleagues report on a possible — but still distant — drug intervention.

“When you do classical academic research that has the opportunity to help real patients, it’s a reason to get out of bed in the morning,” Tonks said. “It is a very exciting time.”

Tonks and research associate Navasona Krishnan have found that their so-called small-molecule — an experimental drug candidate — extends life expectancy in mouse models bred to develop Rett Syndrome. Tonks hopes eventually to move forward with human clinical trials of the approach. Currently, there are no drugs available to address symptoms associated with the neurodevelopmental disorder.

Tonks’ strategy involves inhibiting the activity of an enzyme called PTP1B, which he discovered a 25 years ago. The enzyme goes awry in Rett Syndrome, as it does in certain cancers and some metabolic disorders. Controlling it, he and his team found, relieved syndrome-related symptoms in the humanized mice.

Tonks and colleagues found, for example, that PTP1B levels are extremely high in the afflicted mice. But when the enzyme was inhibited, cell communication processes flowed normally.

Now, he wants to know whether inhibition with his candidate molecule will do the same in people and is collaborating with scientists at Case Western Reserve University in Cleveland.

Rett Syndrome usually appears in toddlers after a normal period of development during infancy. Scientists have found that mutations in the MECP2 gene, which resides on the X chromosome, cause the condition.
Because males with Rett Syndrome have only one X chromosome, they usually die as infants. Females with the syndrome, however, can survive into middle age, experts say.

But afflicted girls and women have a constellation of problems: breathing difficulties, Parkinson’s-like tremors, small head size, mental retardation, poor muscle development and an inability to speak. People with Rett Syndrome require lifelong, round-the-clock care.

Advocates for children and adults with the syndrome call it the most physically disabling of disorders linked to the autism spectrum.

“Historically it was considered an autism spectrum disorder,” said Monica Coenraads, executive director the Rett Syndrome Research Trust in Connecticut and the mother of an 18-year-old daughter with the syndrome.

“Now that there is a gene associated with it, it’s no longer included in the DSM-V,” Coenraads said of the Diagnostic and Statistical Manual, Fifth Edition. The volume is considered the bible of psychiatry.

Nevertheless, she added, many people still refer to Rett Syndrome as an autism spectrum disorder. An estimated 16,000 people are affected in this country, with 350,000 worldwide.

Dr. David Katz, professor of neurosciences and psychiatry in the School of Medicine at Case Western, said the work at Cold Spring Harbor Laboratory is on an intriguing track. “These are promising results, encouraging results,” said Katz, who has studied Rett Syndrome for years. “This is what we call early stage findings where there are encouraging results in a mouse model.”

What has yet to be discovered, Katz said, is whether the experimental drug candidate can be given over a long period of time. It also is important to know whether there are side effects or other safety concerns.

Katz added that other laboratories in this country and abroad are investigating additional possible strategies.
Coenraads welcomes Tonks’ work as well as that by other scientists.

“It’s a very exciting time,” she said of the collective Rett syndrome research. “We are very optimistic.”

*Sourced from Newsday.com

report

We are delighted to share our 2014 Annual Report. A year of progress made possible by our donors and supporters.  

Key figures:

$5.8 Million Raised

$5.8 Million Awarded to Research

4 Star Charity Navigator Rating 

SuperHeader

Do superhumans actually exist? Apparently they do, and their DNA could hold the key to solving some of the world’s health problems.

Freakishly strong bones and an alarmingly high pain threshold aren’t the result of falling in a vat of toxic waste, they are caused by genetic mutations. Pharmaceutical companies have not only taken notice, but are investing heavily to produce treatments for a variety of disease indications that could have annual revenue in the billions.

If someone with brittle bones or severe pain can get relief in a pill or an injection, could there be a cure for Rett and other MECP2 disorder unknowingly hidden in someone’s DNA? Twenty years ago, when sequencing DNA took decades and billions of dollars, getting to the answer would have been technologically impossible. But today it’s more than feasible. RSRT is funding several projects in the lab of Monica Justice and Jeffrey Neul aimed at identifying mutations in other genes that make an MECP2 mutation less severe.

Bloomberg Business covered this amazing topic with some great illustrations from Stephanie Davidson.

ZylkaHeader

In March of this year, the lab of Michael Greenberg at Harvard Medical School published data showing that the MECP2 gene lowers the expression of genes that are physically long.The scientists 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. This work suggests that drugs that can rebalance the expression of long genes might have therapeutic benefit in Rett.

Mark Zylka from the University of North Carolina at Chapel Hill, working independently on a non-Rett project, discovered that a class of drugs called topoisomerase inhibitors reduces the expression of long genes. Almost by accident, this raised the possibility that this class of drugs could be clinically relevant for Rett. One such drug is topotecan which is FDA approved for cancer. The Greenberg lab is now testing Topotecan in Rett mice models.

However, Topotecan may not be the ideal drug since it doesn’t get into the brain easily and would be toxic for long term use. As a result, RSRT has awarded Mark Zylka $400,000 to screen for other compounds that can rebalance expression of long genes safely.

post

It’s an exciting time for gene therapy with a myriad of disease indications being explored ranging from blindness to potential cures for HIV and successful clinical trials being conducted for infants with Spinal Muscular Atrophy (SMA). These awesome advances have not been ignored by RSRT which is why we recently launched a Gene Therapy Consortium (GTC) that is undertaking key experiments to determine if this approach is a feasible strategy for Rett. Program Director, Tim Freeman had a chance to sit in on a GTC meeting in Boston recently and shared his perspective in this post.

Gene therapy in the traditional sense delivers healthy genes into the body by way of a vector (Trojan horse) to compensate for mutated genes. But what if you could repair a gene by splicing out the mutation with “molecular scissors” and replacing it with the correct bits of DNA? Genome editing, as it’s called, is sounding less like futuristic science fiction and more like a tangible treatment.

A revolutionary new technology, Crispr-Cas9, which capitalizes on a naturally occurring molecular phenomenon allows for the mutated bits of DNA to be snipped out and the correct bits to be inserted. While this technology is not yet ready for prime-time there is lots of research taking place and progress is quick-paced.

What if you could go right to the root cause of that disease and repair the broken gene? That’s what people are excited about,”

– Katrine Bosley, Editas Medicine

We encourage you to read this Wall Street Journal article to learn more about Crispr-Cas9.

NYT-article_V1

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:

NYT-articlelink2

post

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. 

Bissonnette-F15599-3

press

 

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

 

 

Follow

Get every new post delivered to your Inbox.

Join 113 other followers