FRAXA Funds 2 Projects to Tackle Potential New Fragile X Therapies

The FRAXA Research Foundation has awarded two $90,000 grants to university research projects that aim to identify new targets for fragile X syndrome therapies.

The funded projects will use mini-brains grown in the laboratory to unravel the mechanisms underlying the disease and also understand what is behind the loss of effectiveness of potential therapies — a phenomenon called drug-induced tolerance — for fragile X syndrome.

In one of the projects, researchers at Emory University led by Peng Jin, PhD, and Yuhnee Kang, PhD, will further explore their newly developed model system to study fragile X syndrome: mini-brains grown from stem cells, a strategy known as organoids.

Awarded the 2017 Method of the Year by the journal Nature, organoids are mini, self-organized, three-dimensional cell cultures grown from stem cells.

They represent an incredible tool to model human diseases, since they can be grown from actual human stem cells.

The organoid field has exploded in the last decade, and these tiny structures are now used to model the natural biology of several organs, including the brain.

Researchers used blood or skin cells and reprogrammed them back into a naive, stem-cell state where cells regain the capacity to differentiate into any cell type of the body, including neurons.

Using this method, researchers can mimic human brains with fragile X syndrome.

Among other things, these tiny laboratory-grown brains retain the ability to form synapses — electrical impulses that are transmitted beween nerve cells and allow them to communicate.

Human organoids are probably the closest model system there is to understand the mechanisms behind human diseases, thereby representing a valuable tool that researchers now intend to use in the discovery of new fragile X treatments.

A second project, also funded for $90,000, will be conducted by researchers at Massachusetts Institute of Technology (MIT), led by principal investigator Mark Bear, PhD, and Patrick McCamphill, PhD, a postdoctoral fellow in Bear’s lab, will study why fragile X syndrome patients ultimately develop tolerance to certain therapies.

These therapies, which initially looked promising for fragile X, block the metabotropic glutamate receptor 5 (mGluR5), whose signaling may underlie several of the cognitive features of fragile X.

The use of mGluR5 antagonists has been tested in large-scale clinical trials, but the therapies ultimately failed to show effectiveness in fragile X patients.

Previous work has shown that mouse models of fragile X syndrome treated with an mGluR5 inhibitor were protected from developing seizures. But the mice ended up developing a tolerance to mGluR5 antagonists after just three doses.

Now, McCamphill will investigate the mechanisms underlying this tolerance and try to develop strategies to overcome it.

Their work will expand to other fragile X syndrome therapies, including arbaclofen, a GABA-B receptor agonist, and glycogen synthase kinase-3 (GSK3) inhibitors, such as lithium. GSK3 is hyperactive in several brain regions of fragile X syndrome animal models.

Deficient signaling by the GABA-B receptor is known to contribute to fragile X syndrome, and targeting this receptor has shown very promising results in preclinical studies.

However, two large Phase 3 clinical trials by Seaside Therapeutics — NCT01282268 and NCT01325220 — failed to demonstrate any benefits.

Researchers believe that developing tolerance to a treatment may be the underlying cause of the disappointing clinical results obtained so far with several fragile X syndrome therapies, but this possibility remains largely untested.

Bear’s team will also test a phenomenon known as cross-tolerance, when taking one medication induces tolerance to another, similar therapy.

The outcomes of the MIT research project will hopefully find a combination of therapies which can be used to avoid the development of tolerance and maintain therapeutic effectiveness in the long term.