Science & Technology

Studies show that Fragile X treatment can suffer resistance and suggest ways to avoid it

Mark BearTwenty years ago, MIT professor of neuroscience realized that severe developmental brain disorders (fragile X syndrome) could be treated with a drug that blocks neurotransmitter receptors called mGluR5. I remember “the moment”. The idea that mGluR5 stimulates excessive protein synthesis in fragile X neurons and disrupts their function has been tested in his laboratory and other laboratories around the world using several animal models of the disease. Well verified by.

“There was great hope that this would be a breakthrough treatment for the disease,” says Bear, a faculty member at the Picower Institute for Learning and Memory and the Faculty of Brain Cognitive Science. “Therefore, it was a serious disappointment when the first human clinical trials using the mGluR5 negative modulator showed no benefit.”

Bear admits that this discovery has cast many questions about the theory and usefulness of animal models.But now New research This promising treatment for Fragile X Syndrome in mice provides substantial evidence that the brain has missed the mark as it builds resistance or “resistance” to it. Importantly, the study also points to several new treatment opportunities that may turn the tide for fragile X, the most common hereditary autism.

Bear and his team, led by postdoc David Stoppel, give only a few doses early in life while the brain is still developing, and then no more doses as the subject grows older. Showed that it can bring lasting benefits to cognitive abilities. This finding suggests that the timing and duration of mGluR5 inhibition is more important than previously recognized.

“The development of acquired resistance to drug therapy is nothing new,” said Bear, senior author of the new treatise. Psychiatry frontier.. “The fact that it happens does not therefore mean that you give up all hope. It means that you have to be aware of it.”

In addition to the strategy of administering an mGluR5 inhibitor at an early age and then discontinuing it, the study also suggests that patients may benefit if the medication consists of breaks to prevent the buildup of resistance. doing. In addition, the study also suggests that fragile X mice resumed symptomatic unknown protein synthesis in the face of treatment resistance. Bear adds that identifying and targeting the protein can also be a fertile new path for drug development.

These new findings will continue in 2020 study of Scientific translation medicine (((STM) Bear’s lab and scientists at MIT and Harvard’s Broad Institute have developed compound BRD0705 that acts downstream of the molecular pathway between mGluR5 and protein synthesis. BRD0705 did not cause treatment resistance in mature fragile X mice.

Hard lesson

Fragile X syndrome is caused by mutations in which the repetition of nucleotide CGG negates the ability of the gene to make the protein FMRP. In the absence of FMRP, neurons exhibit hyperexcitability that leads to symptoms such as excessive protein synthesis, poor circuit connections called synapses, and cognitive impairment. In the early 2000s, Bear’s lab realized that blocking the mGluR5 receptor in brain cells could prevent protein synthesis problems and treat many fragile X symptoms. After successful animal studies, treatment was attempted in clinical trials.

One of the participants in the drug Mabogluland trial was Andy Tranfaglia, Massachusetts. At the time of treatment eight years ago, he was 24 years old, his father, Dr. Michael Tranfalia, FRAXA Research Foundation, an organization working to find cures for disorders.

“Andy responded almost miraculously to the drug, showing dramatic improvements in almost all areas of behavioral and cognitive function, but also significant improvement in motor function and lifelong severity. I have completely eliminated gastroesophageal reflux disease (GERD), “says Tranfalia. “Unfortunately, after 3-4 months, the effect of the treatment began to diminish and continued to diminish over time. His reappearance of GERD was closely parallel to the recurrence of his other symptoms. However, eight months after the trial was completed, he still showed some benefit, which strongly suggested the possibility of resistance to this treatment strategy. “

Indeed, in 2005 study In the journal Neuropharmacology Researchers at Transfalia and Columbia University have shown that general testing of mGluR5 inhibitors has found a treatment-resistant effect in mature fragile X mice whether voice tones lead to seizures. .. But until recently, there wasn’t much evidence that patients had acquired treatment resistance, Bear says.

In a new study, Bear’s lab replicated the results of the 2005 study, showing that two other assays also show resistance to treatment. After initial administration of the mGluR5 inhibitor CTEP improved nerve hyperexcitability in the visual cortex, fragile X mice lost their benefits on chronic administration over the next few days. Fragile X mice also gave up their first progress after chronic dosing in suppressing protein synthesis in a region of the brain called the hippocampus, which is central to memory formation. Therefore, the results test the treatment resistance hypothesis by showing that it affects three different tests, including three different parts of the brain.

Routing around the resistor

“This study suggests answers to key questions from the failed X mGluR5 trial and the preclinical studies that influenced them,” says Stoppel. “We are also focusing on the types of experiments that need to be considered as other treatment strategies are being developed for Fragile X Syndrome and other neurodevelopmental disorders. It’s just the first step. The next goal is to uncover the mechanism and generate a strategy to avoid it altogether. Once this work begins, there are some exciting preliminary hypotheses. “

Given the evidence that treatment resistance may be built up, a more effective approach to maintaining benefits from the drug is during administration to the patient to allow resistance to subside. Researchers say it may give a break.

Experiments showing treatment resistance also yielded another important result. In each case, researchers were able to regain the benefits of the drug by adding a drug called CHX, which significantly suppresses protein synthesis. The findings suggest that fragile X mice resumed production of proteins that ameliorate the symptoms of the disease in resistance. Bear says an important next step in his lab is trying to identify the protein.

Do you want to treat it early and then stop?

Study is another follow-up find of STM In 2019, Peter Kind’s lab at the University of Edinburgh discovered that administration of lovastatin appears to save rat memory formation and extinction without signs of treatment resistance. Looking at those results — Bear was a co-author — the MIT team focused on how the first dose was administered to 5-week-old young rats during the “critical period” of brain development. I matched it. Bear, Stoppel, and their team speculated that the first dose probably produced a lasting effect in adulthood by better altering the trajectory of development.

In a new study, MIT scientists treated some vulnerable X mice with CTEP several times at 28 days of age (equivalent to about 10 years in humans) and left other vulnerable X mice untreated. I did. The team then performed a memory test when the mice were 60 days old, after no further treatment. In this test, rodents first learned that an area was associated with a risk of mild electric shock, and then that risk diminished. Vulnerable X mice left untreated at an early age were difficult to test, but vulnerable X mice treated with CTEP at a young age were much more successful.

Bear states that these findings are particularly important because they reproduce the results of Kind’s studies using different drugs of different species. Therefore, they are likely to generalize to the brains of other mammals, including humans.

In fact, a new clinical trial of an mGluR5 inhibitor created by the pharmaceutical company Novartis is underway in infants. Bear says the results of his new study make him feel more encouraged about the exam.

In addition to Bear and Stoppel, the other authors of this treatise are Patrick McCamphill, Rebecca Senter, and Arnold Heynen.

The research was funded by FRAXA, the National Institutes of Health, and the JPB Foundation.

Studies show that Fragile X treatment can suffer resistance and suggest ways to avoid it Studies show that Fragile X treatment can suffer resistance and suggest ways to avoid it

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