Experimental cancer drug to treat intellectual disabilities!

Experimental cancer drug to treat intellectual disabilities!

The condition, called fragile X, has devastating effects on intellectual abilities. Fragile X affects one boy in 4,000 and one girl in 7,000. It is caused by a mutation in a gene that fails to make the protein FMRP.

Previously researchers showed that deleting the gene that makes FMRP in a region of the brain that is essential to memory formation caused memory deficits in mice that mirror human fragile X. The deletions specifically affected neural stem cells and the new neurons that they form in the hippocampus.

They showed that reactivating production of FMRP in new neurons could restore the formation of new memories in the mice. But what remained unclear was exactly how the absence of FMRP was blocking neuron formation, and whether there was any practical way to avert the resulting disability.

Now, in a study published in Science Translational Medicine, same researchers have detailed new steps in the complex chain reaction that starts with the loss of FMRP and ends up with mice that cannot remember what they had recently been sniffing.

They 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, they found that increased MDM2 expression led to reduced P53 expression in adult mouse NSCs, leading to alterations in NSC proliferation and differentiation.

This study's newfound understanding of the biochemical chain of events became the basis for identifying an experimental cancer drug called Nutlin-3 (inhibitor of MDM2 interaction with P53), which blocks the reaction.

In the new study, mice with the FMRP deletion took Nutlin-3 for two weeks. When tested four weeks later, they regained the ability to remember what they had seen -- and smelled -- in their first visit to a test chamber. Statistically, the memory capacities of normal mice and fragile X models that were treated with Nutlin-3 were identical.

The 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.

Still, many hurdles remain before the advance can be tested on human patients, author says. "We are a long way from declaring a cure for fragile X, but these results are promising."