The NeuroTherapeutics Research Institute (NTRI) is one of nine funded consortia of the NIH Roadmap for Medical Research. The NIH initiative represents a $21.8 million dollar funding commitment over five years to UC Davis and the participating institutions comprising our Interdisciplinary Research Consortium. For the complete information about the consortia, visit http://www.ncrr.nih.gov/.

Our primary motivation is the desire to develop targeted treatments for neurogenetic disorders. The first question asked by families who have a child or family member with a neurogenetic/neurodevelopmental disorder is, "when will there be a cure?" However, virtually none of the therapies for neurodevelopmental or neurodegenerative disorders is specifically targeted to the pathogenic mechanism. Some treatments, such as L-dopa therapy for late-onset Parkinson's disease (PD), are based on an understanding of selective neuronal loss, but the pathogenic trigger for late-onset PD, or for Alzheimer's disease, are still not known, and existing treatments do not ultimately stop or reverse the neurodegenerative process. Therefore, at least one example of the successful application of a targeted (gene-specific) therapy for a neurogenetic disorder, one that at the same time demonstrates the efficacy of the targeting agents and with the methods for their delivery, is desperately needed.

We will use as our Consortium paradigm the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS) and its neurodevelopmental counterpart, fragile X syndrome; both disorders are linked to the fragile X mental retardation 1 (FMR1) gene. The power of the Consortium approach can be fully realized through the study of these FMR1-allelic neurogenetic syndromes, since the distinct pathogenic triggers are known for both disorders - RNA toxicity for FXTAS and gene silencing for fragile X syndrome (More on FXTAS and Fragile X Syndrome ), the disorders affect different groups of individuals at different ends of the lifespan, and yet both disorders are caused by allelic mutations of the same gene.

The fundamental challenge addressed by the Consortium is how to achieve, and measure, a targeted therapeutic response to a CNS disorder. To meet this challenge, we have developed in the form of four research components (Components 2-5) an integrated approach for studying FXTAS and associated disorders; note that Component 1 is administrative (UL1), and Component 6 is the Interdisciplinary (Postdoctoral) Training Program.

This component represents the molecular/cellular foundation of the Consortium research effort; it will provide candidate targeted neurotherapeutic agents for further analysis in mouse models as well as developing, with Component 3, expectations for the timing and degree of reversibility of the neurodegenerative phenotype of FXTAS. It will also elucidate, with Components 4 and 5, the pathogenic mechanism underlying the developmental problems in children who carry the premutation FMR1 allele. Research under this component will involve the further study of the neural cell model of FXTAS to better understand its pathogenic mechanisms and, in particular, the possible involvement of glutamate toxicity in the neurodegenerative phenotype. The principal objective of this project will be the identification and assessment of various candidate therapeutic agents that might attenuate the effects of the expanded CGG-repeat RNA.

We are developing valid mouse models of FXTAS that will allow us, in concert with the other three research components, to explore systematically the underlying disease mechanisms of FXTAS and to identify molecular targets for new therapies. Specifically, we are developing transgenic mice to model the gene mutation that causes FXTAS (i.e., expanded CGG trinucleotide repeat). We will then use these mice to define critical periods in development for disease onset, identify therapeutic windows for treatment, establish the potential for halting or reversing FXTAS by targeted gene therapies, and test novel therapeutics in mice for their potential to prevent or reverse the development of FXTAS. This project, in concert with the other projects within this Consortium, will generate the essential knowledge about the causes of and potential treatments for FXTAS that will provide the foundation for the development of treatments that can halt or reverse the disease.

This project will target the quantitative changes that occur during mid-life and with aging in the brain of patients who carry a premutation allele of the FMR1 gene. The focus of the proposed studies will be FXTAS and sub-clinical changes that occur before the onset of tremor or ataxia. A variety of clinical problems occur in mid-adult life in premutation carriers, and may precede the onset of tremor and ataxia; such presentations include peripheral neuropathy, various psychiatric problems (including dementia), endocrine dysfunction, neuropsychological problems including memory and executive function deficits, and white matter disease detectable by MRI. Our studies will directly parallel the mouse studies of Component 3, and correlates of the findings in mice can subsequently be assessed in our human studies. One of the main objectives of this project is to develop quantitative measures of CNS dysfunction in premutation carriers, followed by their utilization as outcome measures for target treatment studies. Quantitative measures of CNS dysfunction include event-related potentials (ERPs), psychophysiological and neuropsychological measures, motor dysfunction measures, nerve conduction studies (NCS), and volumetric MRI measures, all to be used as outcome measures for proposed clinical trials.

The principal objective of this project is to understand and quantify how variations in the mutation of a single gene (FMR1) produce a spectrum of cognitive dysfunction in both childhood and adulthood. To this end, we will generate the first detailed neurocognitive profile of an integrated set of cognitive domains that preliminary data suggest are highly vulnerable to changes in the expression of the FMR1 gene. The profile will consist of data derived from hypothesis-driven experimental cognitive processing tasks and magnetic resonance imaging (MRI) methods that will produce structural, functional, and connectivity measures. We will characterize spatiotemporal, memory, numerical, and executive cognitive functions in individuals with the full range of FMR1 protein (FMRP) expression; including those with the full mutation (> 200 CGG repeats), with little or no FMRP production, those with premutation alleles (55 to 200 CGG repeats), with normal to low FMRP levels in the face of elevated FMR1 mRNA levels (in this project mRNA refers exclusively to FMR1 mRNA), and typical controls. Key findings will be utilized as improved outcome measures for the clinical trials in Component 4 and in the development of expectations for clinical outcomes, in conjunction with Components 2 and 3, for future targeted treatments.

UC Davis School of Medicine

UC Davis Health System

University of Colorado Health Sciences Center, Denver, Colorado

Erasmus Medical Center, Rotterdam, The Netherlands

Scripps Research Institute, Jupiter, Florida

University of Washington, Seattle, Washington