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by Monica Coenraads
For almost 15 years now, I’ve been immersed in the science behind Rett Syndrome. As Executive Director of RSRT I understand that the work is methodical, that good research takes time, that breakthroughs often come after many tiny, incremental steps. And yet, as a mother witnessing my 16-year-old daughter deteriorate a little more each year, I feel a great urgency to push the research harder and faster. All families with intimate, daily experiences of Rett Syndrome’s harsh rule know the longing for their children to be free and well. RSRT is one-hundred-per-cent focused on that ultimate goal – and that’s what guides our choices about where to invest not just our hard-won funds but our hopes and dreams.
2012 gave us reason to be hopeful. We are grateful for the active engagement of our trustees, the unwavering commitment of the families who fundraise for us and the generous contribution of a wide range of people who give their time and talents freely to help us achieve our goal. We wouldn’t be where we are without the unique global partnerships that we enjoy with Rett Syndrome Research Trust UK and the Rett Syndrome Research & Treatment Foundation (Israel), and with national organizations such as GP2C, Kate Foundation, RMRA. Together you have produced an investment in science that will create a better future for our children.
But that future won’t just happen. Before Rett entered my life, I had never given much thought to the drug development process. Like most people, I assumed that academic scientists, industry and government worked together seamlessly to discover effective therapies for the horrible ailments that afflict us. Nothing could be further from the truth.
There is no “Department of Cures.” Laboratory breakthroughs don’t naturally bubble up and become drugs. The reality is that progress must be relentlessly driven, managed, nurtured and prodded, not to mention funded. It’s a messy, difficult and expensive process that can be slowed and derailed by a multitude of hurdles.
Disease-specific organizations such as RSRT cannot afford to be spectators, passively reviewing proposals and granting money. It is incumbent on us to set the research agenda and to facilitate its execution while staying nimble and vigilant to new opportunities.
Two such opportunities would not currently exist without RSRT: reactivating the silent MECP2 on the inactive X chromosome, and gene modifiers. Following the 2007 reversal, RSRT carefully evaluated the state of Rett research and made the decision to champion these explorations before others had even realized they were, in fact, promising approaches.
Will they lead to a cure? Ongoing research and clinical trials will tell. But in the meantime, RSRT will continue to encourage and support the research that holds the greatest promise to truly change our daughter’s lives. For we have the most to win if we succeed, and the most to lose if we fail.
There is no mystery about why a girl suffers from Rett Syndrome. The cause is that mutated copy of the MECP2 gene inhabiting her every cell. But since MECP2 is on the X chromosome and all females have two X’s, beside each mutated gene rests a healthy but silenced twin. What if we could replace the flawed gene with its perfect counterpart?
That’s the question Ben Philpot of the University of North Carolina at Chapel Hill has asked. RSRT has awarded Philpot, Bryan Roth and Terry Magnuson $2.2 million to answer it.
Philpot’s recent paper in Nature describes successful reactivation of the silenced gene in Angelman Syndrome, demonstrating that replacement is possible.
Joining Philpot and Roth in this effort is Terry Magnusson, a world-renowned leader in X-inactivation. The award will fund a team of three full-time post-docs and two technicians.
The goals of the 3-year project include:
- Screening of 24,000 compounds
- Performing whole genome analyses to test for drug specificity to help predict potential side effects (e.g. what other genes might be affected by the drug)
- Identifying the mechanism of MECP2 unsilencing, which will allow the prediction and design of additional therapeutic targets
- Optimizing drug efficacy through medicinal chemistry (e.g. by designing drugs to maximize transit through the blood-brain-barrier while minimizing off-target effects)
- Advancing lead candidates into preclinical trials. The project will be milestone-driven, with a set of pre-established deliverables. This will allow us to monitor progress utilizing a team of advisors with relevant expertise.
Along with activating the silent MECP2, RSRT has championed a second exciting approach.
In her Baylor College of Medicine laboratory, Monica Justice set out to identify modifier genes – altered genes able to dampen the ill effects of an MECP2 mutation.
The common belief has been that these genes would be hard to find. The reality? With the screen just 15% complete, Justice has already found five. What she is seeing in mice implies that Rett-like symptoms are unstable, and consequently easier to revert to a normal state than anyone had suspected.
None of the modifier genes can suppress the disease entirely, but each reduces a subset of Rett-like symptoms. While we had originally thought that the modifiers were specific to the central nervous system, it turns out they may operate elsewhere in the body. At least one of the modifiers suggests an alternative therapeutic target, using drugs already FDA-approved. With RSRT funding Justice is now testing the drugs in mice and has a manuscript currently under review. A clinical trial is being explored.
At RSRT we’re excited about will happen once the screen is completed. Justice is likely to find many more modifiers, some of which may point to tractable pathways. In support of this goal, RSRT has committed an additional $800K to the Justice lab, bringing its total commitment to the modifier screen to $1.5 million. This funding should provide sufficient resources to allow Dr. Justice to reach the 50 percent mark in the screen within two years – at which point she will propose a plan to us for completing the project. Many more modifiers await discovery. Further surprises are likely in store.
We have also awarded funding of $720K to the lab of Jonathan Kipnis at the University of Virginia. Kipnis and colleagues hope to gain better understanding of the immune system’s involvement in Rett by analyzing patient blood. The hope is that immune-based therapies can be developed.
Previous work from the Kipnis lab suggested that bone marrow transplants could be beneficial. Before proceeding to clinical trials with a procedure that is extremely serious and risky, RSRT committed funding in 2012 for independent corroboration of these findings.
We are also supporting Huda Zoghbi’s work to explore whether symptoms of the MECP2 Duplication Syndrome can be reversed once the protein level is normalized. $236K was awarded to this project via the MECP2 Duplication Syndrome Fund through the fundraising efforts of the duplication/triplication families.
RSRT is supporting work at John Bissonnette’s lab at OHSU (Oregon Health & Science University) to explore serotonin 1a agonists for their ability to reduce apneas, and Andrew Pieper’s lab at UTSW (University of Texas – Southwestern) for ongoing drug screening.
Please join me in wishing all of our scientists Godspeed. I look forward to keeping you apprised of their progress. One last heartfelt thank you to everyone who raises research funds for RSRT. These projects are your money and your effort at work.
Photo credit: Kevin Coloton
The recent publication of the Kipnis paper in Nature has generated understandable excitement and questions in the Rett community. Email and Facebook are difficult vehicles for providing proper answers. Rett Syndrome is complex, and so is the research; this work doesn’t lend itself to sound bites. I know Rett mothers and fathers are often tired and overworked, but I encourage you to find fifteen minutes to sit down together with a cup of coffee, listen carefully to what these researchers are discussing in the video interview, and come away more deeply informed.
The paper has already been euphemistically coined the bone marrow transplant paper. I’ve occasionally called it that myself, sometimes in the presence of Dr. Kipnis, who promptly says, “Please don’t call it that. There is so much more information in that paper than just the bone marrow experiments.” He’s right. In fact, there is enough material to have generated multiple publications.
The paper is attracting an unusual amount of attention in the scientific community, and this is bound to stimulate more interest in Rett Syndrome and the role of the immune system in neurological disorders. The bone marrow transplant result is understandably what families gravitate to because of the potential for clinical application, but it’s important not to ignore the other findings, because they too could point to eventual treatments. In fact, it is my fervent hope that in time, new discoveries will make it possible to manipulate the immune system through a safer route.
Bone marrow transplants (BMT) have been used since 1968 to treat an increasingly wide range of disease, including cancers, metabolic diseases, inherited red cell disorders and immune disorders. The treatment can be lifesaving. It can also be fatal. Accompanied by chemotherapy and/or radiation treatment, BMT is a serious and grueling procedure with significant side effects. The combined expertise of specialists in pediatric BMT, as well as in Rett Syndrome, together with basic scientists is crucial to minimizing risk as much as possible.
As part of a fact-gathering process, RSRT has been facilitating talks between top pediatric transplant centers and Sasha Djukic, Director of the Rett Syndrome Center at the Children’s Hospital at Montefiore, Jonathan Kipnis and his lab members and, most recently, NIH. Discussion includes defining the data needed to consider clinical trials. This must be completed and thoroughly evaluated in order to design the best possible treatment protocol. Independent confirmation of the results achieved by Dr. Kipnis and his team is a standard requirement; this work is already underway. Further experiments in the Kipnis lab itself are ongoing, and we can expect more new information to emerge.
It is perhaps timely for me to reiterate that RSRT is very aggressive about research, and conservative about clinical application. I want to be crystal clear on one thing – parents should not take it upon themselves to pursue BMT for their child. As the mother of a severely afflicted daughter, I understand all too well the desperation for treatment. As Executive Director of RSRT, I understand equally well the importance of applying meticulous due diligence. RSRT does this in all the work we undertake, the projects we review, our financial decisions, and certainly in our approach to clinical trials.
I share your excitement, your urgency and your trepidation, and RSRT will continue to inform you of new developments as they unfold.
– Monica Coenraads
Executive Director, RSRT
A video presentation by Monica Coenraads
On September 9, 2009 the Rett Syndrome Center at The Children’s Hospital at Montefiore in the Bronx hosted its second Parent Gathering. The Director of the Center, Dr. Aleksandra Djukic, gave a presentation entitled Rett Syndrome: What Went Right in the Brain? Dr. Chhavi Agarwal, the pediatric endocrinologist of the Rett Center, gave a talk entitled Osteopenia in Rett Syndrome.
In this presentation, I address some basic questions regarding Rett research. The focus of the presentation is not the actual scientific data but rather the logistics. What are the fields of expertise who are involved in the current research? How does the data get communicated? Where do scientists find funding? How do NIH, pharma and biotech fit into the picture?
As always, I welcome your questions and comments. My email is email@example.com.
A video presentation by Monica Coenraads
On June 28, 2009 the Rett Syndrome Center at The Children’s Hospital at Montefiore in the Bronx hosted a Parent Gathering. The Director of the Center, Dr. Aleksandra Djukic, warmly welcomed the audience and introduced the first of what will be quarterly Gatherings. Dr. Djukic introduced R.E.T.T. (Rethink Education, Therapy & Technology) an engaged group of parents who have designed a survey to gather information to better assess what programs, techniques and settings are most effective for educating individuals with Rett Syndrome. Darcy Minsky followed with some IEP tips to get next year’s educational year off to a good start. The next Gathering will take place on September 27th.
I spoke about an issue that is dear to the heart of anyone who loves a child with Rett Syndrome: How do we get to a cure? The presentation, which is about an hour in length, highlights the key research discoveries of the last decade and lays out the current thinking on treatment/cure approaches in easy to understand language. The presentation is divided into four sections:
• Genetics of Rett Syndrome
• Functions of MECP2
• Treatments and Cures
If you are the parent, relative or friend of a child with Rett Syndrome, I hope this video will give you a glimpse of the excitement that the scientific community feels about the possibilities that lie ahead for our children.
I welcome your thoughts and questions. I can be reached at firstname.lastname@example.org.