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Experimental drug cancels affect of Fragile X gene

Study of the most common genetic intellectual disability, Fragile X, has found an experimental drug can reverse — in mice — damage from the gene mutation causing the defect.

Fragile X affects one boy in 4,000 and one girl in 7,000. It has devastating effects on intellectual abilities. Its cause is a mutation in the protein FMRP. In 2011, Xinyu Zhao PhD, Professor of Neuroscience at the University of Wisconsin, Madison, showed that deleting the FMRP gene located in a brain memory region, caused memory deficits in mice that mimic what is found in humans with fragile X.

The gene deletion specifically affected neural stem cells and new neurons forming in the hippocampus.

Zhao's 2011 study revealed in mice that reactivating production of FMRP in new neurons can restore the formation of new memories. But still unclear was exactly how the missing FMRP blocked neuron formation, or any practical way to avoid memory deficits that result from its irradication.

Now, in a study published on April 27 in Science Translational Medicine, Zhao and her colleagues at the Waisman Center at the University of Wisconsin, Madison (UW-Madison) have detailed the complex chain reaction that begins with the loss of FMRP — and ends with mice that cannot remember what they had recently been doing.

The study revealed a biochemical chain of events which became the basis for identifying Nutlin-3 — an experimental cancer drug which blocks the reaction.

Mice with the FMRP deletion took Nutlin-3 for two weeks. When tested four weeks later, they had regained their ability to remember what they had seen and smelled in their first visit.

Confocal microcope image shows neural stem cells (green) in a mouse hippocampus. The cells are actively proliferating because they are expressing Ki67 protein (red) — only present in proliferating cells.

Image Credit: Yue Li

Statistically, the memory capacity of normal mice and fragile X mice taking Nutlin-3 — were identical.

Fragile X appears after birth. Adds Zhao: "Parents start to notice something is wrong, but even if they get an accurate diagnosis, there is no treatment at present. I'm encouraged because affecting this gene's pathway does seem to reverse the memory impairment."

Mouse memory testing relies on their innate curiosity about their environment.

"We placed two objects in an enclosure and let the mice run around,"
Zhao says. "Mice are naturally curious, so they explore and sniff each item. We take the mouse out after 10 minutes, replace one object with a new one, wait 24 hours and put the mouse back in [the enclosure]. If the mouse has a normal learning ability, it will recognize the new object and spend more time with it. Mice without the FMRP gene don't remember the old object, so they spend a similar amount of time sniffing each item in the enclosure."

Nutlin-3 is in a phase 1 trial for treatment of retinoblastoma eye cancer. Finding a new use for it, and several of its derivatives already entered into the drug approval process, may shorten FDA's lengthy approval, hopes Zhao. So far, the dose used on the mice – 10 percent of that proposed for cancer chemotherapy – has caused no apparent harm to the mice, according to Zhao.

Because more than one-third of fragile X patients are also diagnosed with autism, Zhao's study may shed more light on that condition as well.

Zhao stresses it's too soon to declare victory over fragile X.

"There are many hurdles. One the many questions that needs to be answered is how often and long the treatment would be needed. Still, we've drawn back the curtain on fragile X a bit, and that makes me optimistic."

Xinyu Zhao PhD, Professor of Neuroscience, University of Wisconsin, Madison, Wisconsin, USA

MDM2 inhibitor rescues fragile X deficits
Mutation of the FMRP protein in humans leads to fragile X syndrome, the most common inherited intellectual disability. Li et al. now show that FMRP controls the activities of neural stem cells in the adult mouse brain, which is critical for production of new neurons and learning and cognition. They discovered that FMRP regulates neural stem cells through controlling the expression of the E3 ubiquitin ligase MDM2. They found that treatment with an inhibitor of MDM2 called Nutlin-3 rebalanced neural stem cell activities and rescued cognitive deficits in a mouse model of fragile X syndrome.

Fragile X syndrome, the most common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). However, the mechanism remains unclear, and effective treatment is lacking. We show that loss of FMRP leads to activation of adult mouse neural stem cells (NSCs) and a subsequent reduction in the production of neurons. We identified the ubiquitin ligase mouse double minute 2 homolog (MDM2) as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP resulted in elevated MDM2 mRNA and protein. Further, we found that increased MDM2 expression led to reduced P53 expression in adult mouse NSCs, leading to alterations in NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for treating cancer, specifically inhibited the interaction of MDM2 with P53, and rescued neurogenic and cognitive deficits in FMRP-deficient mice. Our data reveal a potential regulatory role for FMRP in the balance between adult NSC activation and quiescence, and identify a potential new treatment for fragile X syndrome.

This research was supported by grants from the National Institutes of Health (R01MH080434, R01MH078972, and R21NS095632, and a Center grant from NIH to the Waisman Center (P30HD03352).
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April 29, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Fragile X affects one boy in 4,000 and one girl in 7,000.
It has devastating effects on intellectual abilities.

Image Credit: Fragile X Syndrome Foundation





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