By Jordana Lenon
Fragile X syndrome (FXS) is the most common inherited intellec-tual disability and greatest single genetic contributor to autism.
Through two revealing studies at the Waisman Center,
SCRMC member Xinyu Zhao, Ph.D. (right) and
SCRMC Neural Regeneration Focus Group Chair Anita Bhattacharyya, Ph.D. (
left), pictured with their post-doc Meng Li, Ph.D. (
center), are advancing our understanding of this disorder and exploring new treatments.
FXS affects one in 4,000 males and one in 6,000 females. It is linked to an X chromosome gene mutation and shutdown that disrupts normal production of a critical protein, FMRP.
Children with FXS often have deficits in working memory and low IQs, are more prone to anxiety, attention deficit disorder and autism, and display physical features such as a prominent jaw and forehead, and a long, narrow face.
Left: Mouse models of FXS have impaired performance in learning and memory tasks. Their neurons do not mature properly and are not well connected to other neurons. Image A is a normal neuron; B is abnormal. (Doers et al, 2014)
In the first study, involving mouse genetics and published June 4 in
, Zhao, SMPH
of neuroscience, showed that two proteins might actually be involved. FMRP and another suspect protein, FXR2P, while acting through separate mechanisms in new neurons, may also work together to promote neural development.
The findings suggest that manipulating one or both proteins through drugs that foster new nerve cell development postnatally may help those with fragile X syndrome and other disorders involving malformed neurons.
A second Waisman Center FXS study involves screening drugs on neurons grown from pluripotent stem cells. This project involves three phases of research and has just been awarded additional funding from the John Merck Fund.
First, Bhattacharyya, Waisman Center senior scientist, with help from
SCRMC member Su-Chun Zhang, Ph.D., derived human iPS cells and their neural derivatives from individuals with FXS. Second, with a grant from the FRAXA Research Foundation, she and Zhao attempted to test known drugs that could reactivate the fragile X genes in these cells, but without success. In phase three, with a pilot grant from the John Merck Fund and assistance from
SCRMC member Kris Saha, Ph.D., she and Zhao, together with their post-doc
Meng Li, Ph.D., created highly sensitive "reporter cells" through gene editing, so that the FXS cells can "report" when their shut-down gene gets reactivated.
Now, with additional Merck funding, Zhao and Bhattacharyya are screening thousands of small molecule-based drugs using their reporter cells, to try and identify a drug that might cause gene reactivation. The next step will be preclinical testing in mice, with hopes of developing a breakthrough clinical therapy.