MIT Scientists Created a Novel Treatment for Fragile X Syndrome

According to MIT News, scientists recently discovered that inhibiting levels of the GSK3 alpha enzyme could reduce, or even reverse, symptoms of fragile X syndrome. Their study, which utilized mouse models of fragile X syndrome, saw great results. But the big question now is: can these results be replicated for human patients? Read the MIT scientists’ full findings in Science Translational Medicine.

Fragile X Syndrome

Fragile X syndrome (FXS) is a chronic, genetic, and developmental disability which leads to problems with cognition and learning. It is caused by a mutated FMR1 gene. Males are more affected than females. Many patients cannot live independently.

Symptoms of fragile X syndrome can be seen in early childhood, when babies begin missing expected developmental milestones. These symptoms include:

  • Stuttering or other speech problems
  • Anxiety and depression
  • Hyperactivity or attention deficit disorder (ADD)
  • Epilepsy
  • Developmental delays
  • Learning disabilities
  • Hand-flapping
  • Hypersensitivity to light and noise
  • Unique facial features such as a long face or protruding ears
  • Flat feet

Learn more about fragile X syndrome here.

Symptom Reversals

GSK3 alpha

Glycogen synthase kinase-3 (GSK3) is an enzyme that regulates glycogen metabolism within the liver. Heightened levels of GSK3 are thought to cause certain cancers, developmental delays, or even neurofibrillary tangles in patients with Alzheimer’s disease. However, an article within Pharmacology & Therapeutics notes that GSK3 is a great therapeutic target for:

cancer, cardiovascular diseases, diabetes, inflammatory conditions, neurodegenerative diseases, and psychiatric diseases, as well as other less prevalent conditions.

MIT & Fragile X Syndrome Research

Mark Bear, from MIT’s Picower Institute for Learning and Memory, has been working to understand fragile X syndrome for around 20 years. Prior research showed that a neurotransmitter receptor called metabotropic glutamate receptor 5 (mGluR5) could enhance protein synthesis at neuronal synapses. Normally, FMRP regulates this synthesis. But as those with fragile X syndrome don’t have enough FMRP, mGluR5 causes excessive protein synthesis. Ultimately, this results in many fragile X-related symptoms.

Animal studies showed that mGluR5-inhibitors could not only reduce symptoms of fragile X syndrome, but reverse them. But none of these therapeutic options performed well in clinical trials. Additionally, in mouse models, inhibiting mGluR5 sometimes led to treatment resistance.

However, some studies prompted the discussion on the role of GSK3 in patients with fragile X syndrome, shifting potential therapies in that direction. In mouse models of fragile X, researchers found overactive GSK3. While this could be regulated with lithium, lithium is not an effective or safe option for young patients.

So, researchers began looking to GSK3-inhibitors that repressed both the alpha and beta forms of the enzyme. But again, this turned out not to be an effective option. When both forms are repressed, a protein called beta-catenin builds up. Beta-catenin plays a role in cell development, which means that it can prompt the rapid growth of cancer cells. However, if only one form of GSK3 is inhibited, there is no beta-catenin accumulation.

Understanding the Newest Study

Researchers wanted to understand how to inhibit one GSK3 form. They began by examining over 400,000 different drug compounds. From these, they chose drugs which inhibited both GSK3 alpha and beta. Next, they changed the underlying structure. So instead of inhibiting alpha and beta, the newer version were designed to target just one.

Then, researchers used mice models of fragile X syndrome. Basically, these were mice genetically engineered to have no FMRP protein. The GSK3 beta inhibitor was somewhat unfruitful and did not have great results. However, the GSK3 alpha inhibitor reduced, prevented, and reversed several signs and symptoms, including:

  • Seizures caused by loud noises,
  • Issues with learning and memory,
  • Protein overproduction,
  • Neuron hyperexcitability, and
  • Problems with synaptic plasticity.

One of the issues with mGluR5 inhibitors was the introduction of a new symptom: hallucinations and paranoia. This could be seen while studying mice models. However, GSK3 alpha inhibitors did not cause the same result.

Jessica Lynn

Jessica Lynn

Jessica Lynn has an educational background in writing and marketing. She firmly believes in the power of writing in amplifying voices, and looks forward to doing so for the rare disease community.

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