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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 recently opened Jan and Dan Duncan Neurological Research Institute (NRI) in Houston, Texas is dedicated to scientific exploration of childhood neurological disorders. Director Huda Zoghbi, whose laboratory established that mutations in MECP2 cause Rett Syndrome, envisioned a center where researchers with diverse interests could work within an environment of ongoing, cross-disciplinary dialogue. The soaring new structure is located in the heart of the Texas Medical Center, close to the basic science campus of Baylor College of Medicine and Texas Children’s Hospital. At full capacity the NRI will provide laboratory facilities for 50 to 60 investigators. All NRI investigators are Baylor College of Medicine faculty.
Below are excerpts from a recent conversation between Dr. Zoghbi and Monica Coenraads, RSRT Executive Director.
MC: Dr. Zoghbi, it was wonderful to witness the recent opening of the NRI, the culmination of a lead fifty million dollar gift by the Duncans, an outpouring of support from the local community and years of work. The unique architecture reflects a specific functional goal: the creation of a powerful center for collaborative research on children’s neurological disorders. In shepherding this concept from an idea to a most impressive reality, I know you were involved in every aspect of its development. Congratulations are in order! And now that this beautiful facility is open for business, tell us how the next steps are progressing.
HZ: I think there are really two phases now that are moving in parallel. One is the recruitment of talented faculty to occupy the laboratories of the first five floors that have been completed. The second will be to continue our expansion, which is being built by stimulus money and will hopefully be ready for additional recruits in 2012.
MC: I know the physical layout of the building goes beyond its striking appearance. You had a particular vision in mind. In fact, you coined a new descriptive term: collaboratory.
HZ: Yes. The design is specifically intended to promote and enhance interaction between investigators within the building, and communication with adjoining faculties. We have tried to structure this within individual labs as well as the institution as a whole. In an age where most people will text or send an e-mail message rather than walk across the hallway to talk to someone, we have arranged work areas that are conducive to actual conversation, and social spaces that invite and encourage movement and exchange. Investigators with different areas of expertise will be able to access shared resources. The collaboratory is a beautiful, very open glass tower, modeled after the DNA double helix; the stairwell is very spacious and pleasant. People will be drawn here, moving from floor to floor to lunch, have a cappuccino, take a break, use the exercise machines, and in doing so will naturally be interacting with fellow scientists from labs on different stories.
So this collaboratory, this getting together people of different disciplines is still rather new, a kind of paradigm-changing shift from traditional science boundaries. As you recruit faculty, I imagine personality will have to play an equal role with intellectual excellence in considering a candidate.
HZ: Yes, it is really important that the scientists we recruit be generous and receptive. Generous means they are willing to help and to share their ideas and contribute to others’ projects if their skills would be useful in a particular area. Receptive scientists are open to hearing input about their work. These are very important qualities and are key for an interactive research environment; we dream of a generation of scientists who really cherish such a philosophy. We are also establishing programs to help scientists transition to independence as soon as they are ready. Toward this end we will be creating NRI fellowship positions, to give brilliant young PhD graduates (two per year) the opportunity to work within an unusually supportive and nurturing environment. If their projects are successful, they will then be well positioned for highly competitive faculty appointments.
MC: And this philosophy of the collaboratory is expanded even beyond the architecture of the new building, by the way the site was chosen. I know the location was very critical to you.
HZ: The NRI is a Texas Children’s Hospital building, but I wanted it in a location where scientists from very different disciplines would have access to it. I also wanted our own scientists to be only steps away from institutions where the focus and expertise are on scientific problems that are quite different from problems seen in childhood neurodevelopmental disorders. For example, a researcher at Mitchell research building at MD Anderson (attached to NRI) who studies cancer and the epigenetics of cancer might make a discovery that has relevance to epigenetics in the nervous system. You really don’t know where the breakthroughs will come from, and so this cross-cultivation of work and ideas from different institutions has great potential value.
MC: Tell us about the potential of this approach to accelerate and validate new work.
HZ: If you know one technique very well, or even have multiple skills in one discipline, this is still not enough when you are trying to understand something as intricate as brain development and brain function. Somebody might come here with expertise in basic synaptic biology and neurophysiology, but is very willing to engage and think about how they could maximize the impact of their work by collaborating with someone who might be studying a model of Rett Syndrome or Fragile X. You truly need a great variety of specializations, including those from the physical sciences, to begin to tackle complex problems. Even with all of the expertise you can begin to put together, these problems are still challenging.
MC: The readers of this blog are of course interested in Rett Syndrome. Can you speak about the kinds of resources that you envision being allocated for Rett research?
HZ: We’ve recruited eight faculty members so far, and one of our first recruits was somebody who works in Rett Syndrome, Jeff Neul. In addition, we’ve really strengthened the physiology core. Our colleagues in neuroscience are doing some work using two-photon imaging of cortical neurons in animal models of Rett, so the NRI has purchased equipment for these experiments. (Editor’s note: Two-photon imaging is a type of microscopy that allows researchers to look in depth at living tissue.) Our behavioral core is designed to address the needs of large scale preclinical trials in Rett mouse models so we can expand the number of trials we do and expand our behavioral assays. Some of our new recruits will be investigators who bring in a skill set to look at Rett from different angles. Since Rett encompasses so many symptoms, the more we learn about it, the more we’ll gain knowledge that may be applicable to a very large range of neurological and neuropsychiatric disorders.
MC: Along those lines, many children with neurological disorders suffer from seizures, chronic GI problems, and orthopedic issues. The approach thus far has been to try to ameliorate symptoms, but often standard treatments don’t work well and they really don’t address the underlying causes. Will existing faculty members or new recruits be focusing on looking more deeply into the mechanisms of these problems across different diagnoses?
HZ: Yes, absolutely. One of the ways information will be exchanged at the NRI will be through series of regularly scheduled seminars, and some of these will focus on a specific symptom. We bring together clinicians with basic scientists, presenting problems from both points of view. We will invite GI experts, bone experts. The very serious problem of uncontrolled epilepsy may be the first topic we explore in this way. A symposium on this topic is currently in the planning stage.
MC: And this leads into the situation of children who have symptoms but no diagnosis. There are girls who have a clinical diagnosis of Rett but no MECP2 mutations have been found for them. Will the NRI be a resource for these families?
HZ: Sequencing costs are coming down, so it’s feasible to look not only at the children but the parents as well. We are beginning an initiative between our NRI investigators and the genome center to do large-scale medical sequencing for these patients.
MC: On all fronts, then, the NRI is gearing up: Creative collaborative strategies, fresh angles of approach, in-depth examination of the symptoms that children suffer from in Rett and many other neurological disorders, and genomic investigation. You are really launching a powerful new interdisciplinary model for 21st century medical research. Thank you so much for your dedication to Rett research all these years, and for this interview. We hope to check in with you periodically for updates and anticipate great work from the Institute.
The trustees, staff and volunteers of RSRT congratulate Dr. Huda Zoghbi on receiving the 2009 Vilcek Prize in Biomedical Science. The Vilcek Foundation was established in 2000 by Czechoslovakian immigrants Jan and Marica Vilcek to raise public awareness of the contributions of immigrants to the sciences, arts and culture in the United States. Dr. Zoghbi, a world renowned physician-scientist, was selected for this honor for her seminal contributions to neuroscience and genetics, including her discovery, a decade ago, that mutations in MECP2 cause Rett Syndrome.
The Vilcek Foundation celebrates the spirit of immigrants and their will to succeed in a new country, sometimes against all odds. Dr. Zoghbi arrived in the US in 1975, escaping war-torn Beirut where she had been attending medical school. She had intended to stay for only a few months, but her parents convinced her to finish medical school in the US after her brother was injured by shrapnel.
Dr. Zoghbi found her way to Baylor College of Medicine where, as a neurology fellow, she saw her first patient with Rett Syndrome. She put aside her clinical practice to focus on research. After 16 years of perseverance, the Zoghbi lab succeeded in identifying the mutated gene responsible for Rett Syndrome. During the past 10 years I have witnessed Rett Syndrome go from unknown entity to high-profile disorder. This transformation is due, in large part, to the efforts of Dr. Zoghbi, who has consistently brought awareness of this disorder to the scientific community.
As the mother of a child with Rett Syndrome I am deeply grateful for Dr. Zoghbi’s patience and tenacity as well as her skill. It has been my pleasure and privilege over the last decade to have worked closely with and learned so much from Dr. Zoghbi. RSRT is honored to support her research and to count her as a key advisor. As I watched her video interview on the Vilcek Foundation website Dr. Zoghbi was asked “What does your future hold?” I was not surprised by her answer: “There is one more thing I’d like to do…make a patient better.”