Grant reports

FXRFC Awards Three Research Grants for 2012

The Fragile X Research Foundation of Canada continues its drive to increase the number of scientists working towards finding a treatment for fragile X.  The FXRFC is currently funding  five research projects across Canada, and has recently awarded four new additional grants to start in 2012, committing a total of $192,500.00 over the next year,  for research aimed at finding a treatment or cure for fragile X. These projects are being conducted across Canada at the University of Victoria in British Columbia, McMaster University in Hamilton Ontario, the University of Toronto, and McGill University in Montreal.  They will yield valuable information on the pathology of Fragile X, and should stimulate further research in this area.
 
The FXRFC has always  maintained a flexible approach to research funding in order to maximize our ability to identify new “therapeutic targets” that can guide the development of future treatments.  In previous editions of our Newsletter, we reported on the development of a new class of drug as one possible treatment for fragile X.  The development of this drug is based on the “mGluR Theory” of fragile X, a well validated therapeutic target. 
As clinical drug trials using mGluR5 blockers are underway at the Fragile X Clinic at Surrey Place Centre in Toronto, the FXRFC will  focus on identifying new and different therapeutic targets for the treatment of Fragile X.

2012

Adeno-associated Virus Gene Replacement Therapy in Fragile X Syndrome

Fragile X is caused by the inactivation of the FMR 1 gene by a specific inherited mutation. This results in the subsequent absence of its corresponding gene product (FMRP) in the neurons throughout the entire brain. The multifaceted nature of FMRP, namely that it controls the expression of several hundred other genes in the brain, suggests that pharmacological treatments targeted to specific receptors and other proteins may be only partially effective in restoring the natural regulatory role of FMRP.
 
Replacing the missing FMRP could theoretically restore or reverse the fundamental deficit in FXS. Dr. Hampson hypothesizes that the introduction of FMRP directly into the brains of immature fragile X mice (Fmr1 knockout mice) using gene therapy will result in functional FMRP production and reversal of some of the behavioral deficits in this animal model. Dr. Hampson’s lab will inject an adeno-associated viral vector (AAV) carrying the Fmr1 gene directly into the brains of immature Fmr1 mice. The treated mice will then be examined by measuring FMRP levels and distribution in the brain, and assessed using multiple behavioural analyses 2-10 weeks after AAV administration in order to determine if the treatment “rescued” the affected mice.

FMRP expression in DG mediates NMDAr function

In Fragile X syndrome, the loss of production of the FMRP protein disrupts the expression of a number of synaptic proteins thought to be important in intellectual disability. To date, clear links between synaptic dysfunction and behavioural abnormalities have remained elusive. There has been much effort to link Fragile X syndrome with type 1 mGluR5 receptor function in nerve cells of the brain and how this in turn affects the function of AMPA receptors(AMPAr). AMPA receptors are also involved in synaptic plasticity and the absence of FMRP is associated with excessive AMPA receptor internalization. This means that the AMPA receptors are moved from the surface of the neuron and “sequestered” inside the nerve cell in response to mGluR activation. This makes them unavailable to the cell to perform their normal function. The Christie lab is proposing that in the Fragile X mouse model, FMRP plays a different role in a particular region of the brain, and affects the function of another group of receptors involved in synaptic plasticity, known as NMDA receptors (NMDAr). A main goal of the proposal is to determine if there are deficits in the physiology and morphology of this portion of the brain as well as alterations in behaviours that are known to be governed by this region. Positive findings may lead relatively quickly to trials of drugs that improve the symptoms of Fragile X by affecting NMDAr function.

Impaired cortical late-phase LTP and its role in FMRP-related learning and memory deficits

In the Fragile X mouse model, there is evidence that long term potentiation (LTP, the ability of neurons to strengthen synapses) is impaired, and that long-term depression (LTD, the ability of neurons to weaken synapses) is enhanced. Considerable progress has been made in the understanding of the processes involved in excessive LTD in the Fragile X mouse. Although multiple studies have reported a complete absence of LTP in a particular portion of the FX mouse brain, the molecular mechanisms underlying this phenomena are not clear. This project will lead to a better understanding of  FMRP in normal brain function, how the  loss of FMRP leads to cognitive impairment, and the development of better therapies for  Fragile X syndrome.

The rescue of FMRP-related long term learning and memory deficit

This lab has shown that a specific part of the Fragile X mouse brain, known as the ACC (Anterior Cingulate Cortex), has an impaired  ability to increase synaptic strength.  This process is referred to as”long term potentiation” or “LTP” of synaptic strength. This defect is correlated with behavioral relevant memory functions, and the drugs MPEP and Rolipram reduce the deficit of L-LTP in the ACC of these mice. These two drugs will be tested in the Fragile X mice and could lead to potential future treatment of learning and memory deficits in Fragile X syndrome.