UC Davis receives more than $21 million to find treatments that reverse common cause of dementia
Largest ever national award for fragile X-related research will improve understanding of age-related
The same research team who discovered an age-related neurological disorder will now receive nearly $21.8 million from the National Institutes of Health (NIH) to develop new treatments for it. The funding establishes the NeuroTherapeutics Research Institute at the University of California, Davis, which is dedicated to finding effective interventions that reduce or eliminate the debilitating balance problems, tremors and dementia associated with older adults who have FXTAS, or fragile X-associated tremor/ataxia syndrome. The five-year grant is the largest funding award in history to focus on this or any other fragile X-related disorder.
Led by molecular geneticist Paul Hagerman, the institute is one of nine interdisciplinary research consortia announced recently by the NIH Roadmap for Medical Research. The roadmap's goal is to integrate different disciplines to address health challenges that have been resistant to traditional research approaches. Funding the consortia represents a fundamental change in both the culture within which biomedical and behavioral research is conducted and the culture within the NIH, where research projects are normally managed by an individual institute or center.
“Dr. Hagerman and his colleagues have put together an impressive team of scientists with expertise in genetics, neurophysiology, neuroimaging and therapeutics development to identify new treatment options for neurogenetic disorders such as FXTAS,” said Larry Tabak, director of the National Institute of Dental and Craniofacial Research and co-chair of the working group that identified the science to be funded. “The environment for interdisciplinary research at UC Davis is viewed as highly conducive for novel research of this type.”
“Today, hope has found a home here at UC Davis — for FXTAS patients and for many more, including the growing millions of Americans who suffer from Alzheimer's, Parkinson's and other neurodegenerative disorders,” said Claire Pomeroy, vice chancellor of Human Health Sciences and dean of the School of Medicine at UC Davis. “This new institute is a perfect fit for the collaborative culture we have fostered throughout UC Davis Health System. Through it, we will continue to break down silos among disciplines, specialties and departments in order to speed the progress of scientific discoveries.”
Discovered in 2001 by Paul Hagerman and Randi Hagerman, FXTAS (pronounced “FAX-tass”) affects carriers of a small mutation — also called a premutation — in the same gene that causes fragile X syndrome. The genetic mutation is the most common cause of inherited mental impairment and the leading single-gene cause of autism in children. Prior to its discovery, FXTAS was often misdiagnosed as Alzheimer's disease, Parkinson's disease or the more rare Charcot-Marie-Tooth syndrome. In addition to finding treatments that specifically target FXTAS, institute researchers will improve understanding of all age-related neurodegenerative processes.
“FXTAS has some similarities to Parkinson's, Alzheimer's and other late-onset dementias,” said Paul Hagerman, the lab scientist of the husband-wife research team. “But while we do not know what causes most cases of Parkinson's or Alzheimer's, we do know the specific trigger for all cases of FXTAS, since it is linked to the fragile X gene. Because of this, FXTAS provides an excellent model for studying more general neurodegenerative processes, since they all involve cellular stress. We can in this next phase of our research target this gene and see how much of the damage it causes can be reversed.”
Randi Hagerman, a developmental-behavioral pediatrician who specializes in diagnosing and treating children with fragile X syndrome, has expanded her practice in recent years to include her young patients' grandfathers and, at times, grandmothers with FXTAS. The outcomes can be heartbreaking.
“It's been difficult to watch the progression of the disease in my patients, especially the cognitive decline and death,” she said. “The first patient I diagnosed with the disorder passed away the year after we announced its discovery in 2004. This new funding allows us to move forward quickly with all of our best ideas about treatment options that can significantly alter the course of the disease, improve quality-of-life and perhaps completely eliminate symptoms and save lives.”
Moving toward future treatment trials
While less is known about the causes of Alzheimer's and Parkinson's, there have been more treatment trials for these disorders than there have been for FXTAS, given that it was identified just six years ago. The Hagermans are anxious to launch treatment trials of promising neuroprotective agents that could slow the progression of dementia for FXTAS patients. However, a central objective of the new institute is not only to test therapies but also to track the molecular and neural changes that can underlie clinical improvements. This approach will provide a defined, quantitative basis for recommended treatment protocols.
To accomplish this goal, the Hagermans will be joined in their research efforts by neuroscientist Robert Berman, cognitive neuroscientist Tony Simon and cognitive neuroscientist Cameron Carter. Each will lead distinct research teams who collaborate to identify, test and measure the outcomes of therapeutic interventions for FXTAS:
- Paul Hagerman's team will further define the molecular processes that lead to the onset of FXTAS, then identify and develop therapeutic agents that target those processes for animal model testing and possible clinical trials. Since discovering the disease, he has found several proteins that may be related to its onset and will now refine those findings to determine which proteins are relevant to triggering FXTAS and how.
- Berman's team will use transgenic mouse models to study progression of FXTAS and whether or not candidate medications alter the course of the disorder. Promising medications will be recommended for human treatment trials.
- Randi Hagerman will lead clinical treatment trials along with neuroimaging and other electrophysiological tests of the brain changes associated with FXTAS to assess treatment effectiveness.
- Simon's team will define the full spectrum of clinical symptoms associated with the fragile X gene, from the intellectual and behavioral problems of children with fragile X syndrome to the neurological issues of fragile X carriers with FXTAS, providing the basis for measuring study outcomes. A significant component of this project will also be to identify the earliest clinical markers of FXTAS.
- Carter will direct the training program for postdoctoral scholars in neurotherapeutics research techniques and outcomes, creating a new generation of fragile X researchers.
“The dramatic back-and-forth transfer of knowledge across the teams that this structure provides greatly accelerates our ability to launch clinical trials and get rapid feedback on their effectiveness,” said Randi Hagerman.
While the hub of the FXTAS research is based at UC Davis, the institute research team includes more than 30 investigators, some of whom are located at Erasmus Medical Center in the Netherlands, the University of Washington in Seattle, the University of Colorado Health Sciences Center in Denver and Scripps Research Institute in Florida. The institute will also maintain important connections to the fragile X and FXTAS community through an advisory board of families who live every day with the challenges of fragile X-related conditions.
“The families touched by fragile X syndrome and FXTAS are the motivating force behind the UC Davis NeuroTherapeutics Research Institute and all of our work leading up to its creation,” said Paul Hagerman. “The advisory board is an integral part of our research that gives patients and their families a voice in our efforts and a means of gaining news about our progress.”
Randi Hagerman was first clued in to FXTAS after hearing similar stories from her fragile X patient's parents about their dads and moms having issues with balance and memory and an array of diagnoses for age-related decline. She encouraged Paul Hagerman to search for answers in his lab to these symptoms in the fragile X gene, which is how he and biochemist Flora Tassone found that being a carrier of a smaller mutation in the fragile X syndrome gene has health consequences as well. Prior to that, carrier status was only considered a concern in terms of passing on the genetic trait that could result in fragile X syndrome in later generations. While FXTAS primarily affects men, Randi Hagerman has diagnosed women with the disorder as well, who can also experience FXTAS-related autoimmune disorders.
Fragile X syndrome results from a large trinucleotide repeat expansion in a stretch of DNA, or the repeat of the same three nucleotides — cytidine and two guanidines (CGG). Typically, people have about five to 45 of these CGG repeats. Fragile X syndrome results when the three nucleotides repeat more than 200 times. The fragile X premutation, which is the risk factor for FXTAS, occurs when the repeat is somewhere in the middle — 55 to 200 times. Roughly 1 in 3,000 men in the general population may develop FXTAS later in life.
More information about FXTAS, including key symptoms, can be found on the UC Davis NeuroTherapeutics Research Institute Web site at www.ucdmc.ucdavis.edu/ntri and on the National Fragile X Foundation Web site at www.fragilex.org. For more information about the institute, including upcoming treatment trials, call 916-703-9827 (916-70FXTAS) or e-mail firstname.lastname@example.org