Metformin and Aberrant Insulin Signaling in a Fragile X Mouse Model

Metformin and Aberrant Insulin Signaling in a Fragile X Mouse Model

This 2017-2018 grant of $90,000 is funded jointly by FRAXA and the Fragile X Research Foundation of Canada for the first year. A previous FRAXA grant to the Sonenberg lab has led to great interest in the available drug, metformin, as a potential treatment for Fragile X syndrome. FRAXA is currently organizing clinical trials of metformin.

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In Their Own Words: Reports From the International Fragile X Workshop

In Their Own Words: Reports From the International Fragile X Workshop

The 18th International Fragile X and Related Neurodevelopmental Disorders Workshop in Quebec, Canada, was a great success, featuring Fragile X much more heavily than any previous meeting in this series! We asked our speakers to summarize their work in their own words. These brief updates from researchers investigating Fragile X.

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Metformin, Diabetes Drug, Potential Fragile X Treatment

Metformin, Diabetes Drug, Potential Fragile X Treatment

“We treated mice with metformin and corrected all the core Fragile X deficits. We are optimistic about using metformin in human clinical trials. This is a generic drug with few side effects” says Nahum Sonenberg, PhD, James McGill Professor, Department of Biochemistry, McGill Cancer Center, McGill University.

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Repurposing Available Drugs to Treat Fragile X Syndrome – FRAXA Initiatives

Repurposing Available Drugs to Treat Fragile X Syndrome – FRAXA Initiatives
FRAXA Research Foundation was founded in 1994 to fund biomedical research aimed at finding a cure for Fragile X syndrome and, ultimately, autism. We prioritize translational research with the potential to lead to improved treatments for Fragile X in the near term. Our early efforts involved supporting a great deal of basic neuroscience to understand the cause of Fragile X. By 1996, these efforts had already begun to yield results useful for drug repurposing. To date, FRAXA has funded well over $25 million in research, with over $3 million of that for repurposing existing drugs for Fragile X. Here are some examples of FRAXA-funded work on repurposing available drugs for Fragile X syndrome: Lithium In the mid-1990s, the Greenough lab at the University of Illinois discovered that FMRP, the protein missing in Fragile X, is rapidly translated in dendrites in response to stimulation of glutamate receptors. FRAXA funded preclinical validation of this discovery in theRead more

Fragile X Fruit Fly Research Bears Fruit

Fragile X Fruit Fly Research Bears Fruit
Sean McBride, MD, PhD, and Thomas Jongens, PhD, of the University of Pennsylvania Adapted from press release by University of Pennsylvania A new FRAXA-funded study shows how the hormone insulin – usually associated with diabetes — is involved in the daily activity patterns and learning deficits in the fruit fly model of Fragile X Syndrome (FXS). The study also reveal a metabolic pathway that can be targeted by new and already approved drugs to treat Fragile X patients, notably metformin. The scientists study the common fruitfly, Drosophila, whose genome contains a cousin, or homologue, of the human FMR1 gene called dfmr1. The lab of Thomas Jongens, PhD, an associate professor of Genetics, along with doctoral student Rachel Monyak and Sean McBride, MD, PhD, a psychiatrist at the Adult Developmental Disorders and Monogenic Disorders Clinic with Penn Behavioral Health, have been working with the fly model to find new therapies to treat the behavioralRead more

Targeting AMP-Activated Protein Kinase Pathway in Fragile X Syndrome

Targeting AMP-Activated Protein Kinase Pathway in Fragile X Syndrome

With a $100,000 grant from the FRAXA Research Foundation in 2015, Dr. Peter Vanderklish explored a novel strategy to treat Fragile X syndrome: AMPK activators. The good news is that there are FDA approved (for example, metformin) and naturally occurring AMPK activators (such as resveratrol, found in red wine).

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Fruit Flies to Model and Test Fragile X Treatments

Fruit Flies to Model and Test Fragile X Treatments

Dr. Jongens and his collaborators have found an insulin-like protein in the fly brain that is overexpressed in the Fragile X mutant fly, leading to increased activity of the insulin signaling pathway. Furthermore, they found that certain behavioral patterns in the Fragile X flies can be rescued by expressing the FX gene just in insulin producing neurons in the fly brain. In the mutant, there are other changes in the signaling pathways, including a decrease in cAMP and elevation in PI3K, mTOR, Akt and ERK activity. They now propose to study 2 medicines used for diabetes: pioglitazone (increases cAMP and decreases Akt and ERK) and metformin (inhibits mTOR), in flies and mice to validate the potential efficacy of these novel therapeutics for Fragile X.

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FRAXA Grant to Nahum Sonenberg, PhD — Effects of metformin in Fmr1 knockout mouse model of Fragile X syndrome

FRAXA Grant to Nahum Sonenberg, PhD — Effects of metformin in Fmr1 knockout mouse model of Fragile X syndrome

2015 Program Grant funded for $100,000 Mis-regulation of activity-dependent protein synthesis is one of the major cellular abnormalities found in Fragile X.  Upstream neuronal signaling regulates a large cluster of enzymes called the mTORC1 complex, which in turn regulates protein synthesis.  This complex is also controlled by cellular energy levels via the metabolic sensor AMP-activated Protein Kinase (AMPK).  AMPK is a highly conserved kinase that is activated under conditions of energy stress, when intracellular ATP levels decline and intracellular AMP increases.  AMPK normally mediates mTORC1 suppression, but AMPK appears to be decreased in Fragile X. Metformin, an FDA-approved drug, is widely used as a first-line therapy for type 2, and is a well known activator of AMPK.  It controls gene expression at the level of mRNA translation, comparable to the mTORC1 inhibitor rapamycin. This project will explore the potential of metformin and related compounds to rescue known abnormalities in Fragile

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