The same research team who discovered a neurological disorder that primarily affects older men has received $21.8 million from the National Institutes of Health to develop new treatments for the disorder. The grant establishes the NeuroTherapeutics Research Institute at UC Davis to find effective interventions that reduce or eliminate the balance problems, tremors and progressive dementia associated with FXTAS, or fragile Xassociated tremor/ataxia syndrome.
The institute is one of nine interdisciplinary research consortia – and the only one focused on neurological disorders – announced by the NIH Roadmap for Medical Research with the goal of integrating 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.
Discovered in 2001 by UC Davis M.I.N.D. Institute physicians Paul Hagerman and Randi Hagerman, FXTAS affects carriers of a small mutation – also called a premutation – in the same gene that causes fragile X syndrome, the most common cause of inherited mental impairment and the leading single-gene cause of autism.
Prior to its discovery, FXTAS was often misdiagnosed as Alzheimer's disease, Parkinson's disease or the more rare Charcoot-Marie-Tooth syndrome. In addition to finding treatments that specifically target FXTAS, institute researchers will improve understanding of all agerelated neurodegenerative processes.
"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," says Paul Hagerman, the molecular bioscientist of the husband-wife research team and principal investigator for the new grant.
"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 that process is reversible."
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, she says. "It's been difficult to watch the progression of the disease in my patients, especially the cognitive decline and death," she says.
"The first patient I diagnosed with the disorder passed away shortly after we announced its discovery. This new funding allows us to move forward quickly with all of our best ideas about treatment options that can significantly alter the trajectory of the disease, improve quality-of-life and perhaps completely eliminate symptoms."
The Hagermans are joined in their research efforts by neurosurgeon Robert Berman, cognitive neuroscientist Tony Simon and psychiatrist Cameron Carter. Each leads distinct research teams connected by continuous collaboration and the common objective of developing and measuring outcomes for therapeutic interventions for FXTAS:
- Paul Hagerman's team will further define the molecular processes that lead to the onset of FXTAS and suggest 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, including intellectual and behavioral problems of children with fragile X syndrome and 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 help 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 and FXTAS researchers.
While the hub of the FXTAS research is based at UC Davis, the institute research team includes more than 30 investigators, 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 also will maintain connections to the fragile X and FXTAS community through an advisory board of families facing fragile X-related conditions.