FRAXA - Fragile X Research Foundation

News

FRAXA funds research leading to treatments and a cure for Fragile X. We anticipate funding $500,000 to $1 million in new grants and fellowships every six months; the next application deadlines are December 1, 2004 and May 1, 2005.

Click here to view a list of Principal Investigators with FRAXA funding; click on a name to view an abstract. Or, read here about our research strategy, with links to abstracts, to learn how we approach the search for effective treatments and a cure. FRAXA has also embarked on a $7 million dollar joint funding program with the National Institutes of Health.

Towards Treatments and a Cure: Our Strategy
by Katie Clapp

Our primary mission is to speed up progress towards effective treatments and a cure for Fragile X. Here we describe the research approaches that FRAXA supports.

The basic problem in Fragile X Syndrome is that brain cells have a defect in a gene (FMR1) such that this gene cannot produce its normal product, the fragile X protein (FMRP). Without FMRP, probably at least in part due to its roles in development, brain cells cannot communicate cleanly with each other. This underlies the learning and behavioral challenges seen in fragile X syndrome. Potential therapeutic approaches are:

Currently, treating symptoms is the only option available, and the available interventions -- drugs, special education, psychological counseling -- are of limited help. FRAXA's goal is to do more. We fund scientists who are pursuing each of these four approaches. Much of the work is collaborative, as no single research team has the full range of technical skills to address all of the issues involved in developing treatments.

Therapeutic Approach #1: Fix the Gene
Turn on, or replace, the gene in the appropriate cells.

In people with Fragile X, the FMR1 gene is present but switched off (methylated) by a mutation in the DNA which controls activation of the gene. The gene itself is functional and could, theoretically, be switched on. One challenge is to target the FMR1 gene selectively, without turning on other genes which are supposed to remain off. It is also possible that too much Fragile X protein or expressing FMRP in the wrong cells may be toxic. So, we are funding research to evaluate these approaches in animal models, including mice and fruit flies, and in tissue culture. Recent grants in this area have been awarded to Andre Hoogeveen, Giovanni Neri, and Paul Hagerman.

Gene Therapy

Gene therapy aims to deliver a new, working copy of the fragile X gene to brain cells so that the gene will function normally, producing its normal protein. Since all the symptoms of fragile X arise from the lack of FMRP, this in principle could "cure" the syndrome. Gene therapy has received a lot of attention in the press because although it has great potential, there are no reports of clinical success with this technique in the human brain. FRAXA is funding several investigators who are working out basic details using tissue cultured nerve cells before attempting anything with intact brains, including Mario Rattazzi, David Bloom, and Robert Bauchwitz.

Therapeutic Approach #2:
Make and deliver the protein by some other means

Cells use a signaling pathway (or molecular cascade) to trigger the synthesis of FMRP. If we understood how FMRP is normally made and where it needs to be made, we might find a way to bypass complications in this pathway caused by the fragile X mutation, such as impaired translation into protein. Knowledge of this pathway could also provide alternatives to bring about the expression of other proteins regulated by FMRP. Many teams are currently exploring this area; those with some FRAXA support include Claudia Bagni, Gary Bassell, Carl Dobkin, Justin Fallon, Bill Greenough, Kimberly Huber, Walter Kaufmann, and Robert Malinow.

Therapeutic Approach #3:
Substitute for the function of the protein

If we knew precisely what the fragile X protein does in nerve cells, we might find ways to bypass the need for it. We now know that FMRP aids in the production of certain proteins some of which appear to be necessary for communication at the synapses - the connections between the brain's nerve cells. An exciting current research direction is identifying the mRNAs that are either overexpressed or underexpressed when FMRP is lacking. Since mRNAs code for proteins, this may tell us which proteins depend on FMRP for their normal expression in cells. Robert and Jennifer Darnell, Jean-Louis Mandel, Kendall Broadie have all been funded first by FRAXA and currently by NIH and FRAXA for work in this area.

Therapeutic Approach #4
Treat the symptoms of fragile X

How much can we modify the brain by behavioral therapy? Can the actual shape and size of nerve cell connections be reversed by behavioral intervention? Can behavioral symptoms be reversed by behavioral intervention? Can symptoms be reversed by pharmacological intervention? FRAXA awarded grants to Don Bailey, Elizabeth Dykens, Mina Johnson-Glenberg, John Larson and Kenneth Mack to conduct studies of the human symptoms of fragile X, and to Linda Crnic, Rich Paylor, Frank Kooy, to pinpoint symptoms in the fragile X mouse model. If therapies and educational strategies can be designed with the specific needs of patients in mind, they are more likely to be effective. Likewise, the more we understand specific symptoms and their causes in fragile X syndrome, the more likely it is that drugs can be selected, or discovered, that can target these symptoms. The new class of drugs called Ampakines, is an example: FRAXA has funded a trial of Ampakines in fragile X mice and now will fund a trial of this medication in adults with fragile X, under the direction of Elizabeth Berry-Kravis.

Teamwork and Future Prospects

Naturally, these four areas of research overlap and most teams work in several areas. As more is understood about fragile X, refined approaches to treatment become possible. It is critical to develop models and tools to accelerate progress in all areas. Antibodies allow scientists to detect particular proteins in cells; Alan Tartakoff has engineered a set of fragile X antibodies which he is making available to other researchers. Fruit fly (drosophila) models have emerged as a very fruitful avenue of study for many genetic disorders; FRAXA has funded fly studies by Kendal Broadie, Kevin Moses, David Nelson, Tom Jongens, Lynne Regan, and Jerry Yin. A refined fragile X mouse model is being developed by Eric Kandel, and Edouard Khandjian will study fragile X in frogs.

Since no one research facility has the time, funding, or personnel to do all the things necessary to develop effective treatments for fragile X, FRAXA's role in coordinating, facilitating, and often even arranging collaborative efforts among researchers is especially important. While some of the researchers we support have worked on Fragile X for many years, others are new to this ever-growing field. It is our hope that a constant infusion of new talent and ideas will result in effective treatments to help all people affected with fragile X. In the words of Nobel Laureate and FRAXA Scientific Advisor James D. Watson, "We must entice key young scientists now working on nerve cells to focus on fragile X."