Cornell University researcher looks to restore Fragile X protein in neurons

Cornell University researcher Samie R. Jaffrey, MD, PhD and Postdoctoral Fellow Jiahui Wu, PhD were awarded $90,000 by over 2016-2018 by FRAXA for their project, Which is the right FMRP for Therapeutic Development of Fragile X Syndrome?

Here's the Rub

When researchers develop effective drugs that reactivate FMRP — the protein that is normally silenced in fragile X — what in the world will they do next?

So ponders Cornell University researcher Samie R. Jaffrey, MD, PhD. Jaffrey, professor, Pharmacology, Weill Cornell Medical College, Cornell University, knows reactivating FMRP will lead to many important questions, such as:

  • Which cell type needs FMRP?
  • How much FMRP protein is needed to restore brain function?
  • Where in the brain will FMRP protein be needed?
  • Where in a neuron will the FMRP needs to be expressed?
  • Will FMRP protein be created in the correct quantity and location to work as a therapeutic?

In anticipation of effective treatments, Jaffrey’s FRAXA-funded research is addressing those questions and more to determine how to normalize the function of neurons in mice that model fragile X.

His research is focused on two major areas:

  • Understanding how neurons connect with each other during early development to form functional circuits needed for learning, memory and behavior; and
  • Developing new ways to manipulate and control protein expression in neurons in mice to restore normal brain function and behavior.

“These mice have lived their entire lives without the FMRP protein,” he said. “This is similar to humans who have fragile X. We want to know if restoring FMRP protein in neurons can switch them from not functioning properly to normal function.”

Jaffrey’s research goals are to create the metrics needed to establish whether or not such a treatment is producing FMRP in the correct quantity and location to work as a therapeutic and to develop a new technology to induce FMRP protein synthesis in specific cell types and cellular compartments.

Where and How Much?

“There are numerous types of cells in the brain called glia,” he said. “We want to see if we can restore brain function by inducing FMRP expression in glia alone, neurons alone or if we need to induce it in both types of cells. This will give us important information on how to develop future therapies designed to restore FMRP protein expression.”

Jaffrey’s laboratory has a longstanding interest in fragile X. One major ongoing project is to screen for drugs that reactivate FMRP.

“We are developing new highly sensitive assays to determine if FMRP expression is reactivated,” he said. “These new methods will allow us to screen for new drug therapies to reactivate FMRP expression. In order to do this, we have developed embryonic stem cell lines from human embryos that carry the disease-causing FMR1 repeat expansion. We have developed protocols to differentiate these embryonic stem cells into human neurons to test new drugs and gene therapy approaches that might allow us to reactivate the FMR1 gene.

“Our hope is we can reactivate FMRP expression in fragile X patients. We expect only a small amount of FMRP will be made in neurons using these reactivation strategies. This is one of the reasons we want to know exactly how much FMRP is needed in order to restore brain function.”

The Biggest Challenge

Jaffrey’s biggest challenge is time. Experiments take time to optimize and perfect in animals.

“We have outstanding collaborators who are experts in measuring animal behavior in fragile X mouse models,” he said. Jaffrey and postdoctoral scientist Jiahui Wu, PhD, hope to test a new technology for inducing FMRP expression in genetically engineered mice using light. “We also have collaborators who have expertise in selectively delivering light to specific types of neurons. We hope to be able to quickly and efficiently develop our new technologies to restore FMRP expression in the brain.”

Jaffrey credits FRAXA with making this research possible.

“FRAXA support is critical to provide seed funding for testing new ideas,” he said. “One of our biggest challenges is getting the early proof-of-concept data needed for a NIH grant application. FRAXA is great for this and currently supporting a very energetic and motivated postdoctoral scientist in my lab to develop a new technology to control FMRP expression in the brain. Without this funding, it wouldn’t be possible to hire him.”