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Mark Bear, a professor of neuroscience at MIT, said 20 years ago that severe developmental brain damage (fragile X syndrome) could be treated with a neurotransmitter receptor-blocking drug called mGluR5. I remember the “moment of Eureka” that I noticed. 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,” said 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 admitted that this discovery cast many questions on the theory and usefulness of animal models.But now, a new study in mice, this is Promising treatment In the case of Fragile X Syndrome, I missed the mark because the brain builds resistance, or “tolerance.” 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, gave only a few doses early in life while the brain was still developing, and then no more doses as they grew older. We have shown 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.
“Acquired development Treatment resistance Taking medicine 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 a young age and then discontinuing it, Bear said the study could benefit patients if the medication consisted of breaks to prevent the buildup of tolerance. It also suggests that there is sex. In addition, the study also suggests that fragile X mice resumed the synthesis of unknown symptomatic proteins in treatment resistance. Bear added that identifying and targeting the protein could also be a fertile new path for drug development.
These new findings follow the 2020 survey. 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, decreased 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, said Dr. Michael Tranfaglia, medical director of his father, the FRAXA Research Foundation, an organization working to find cures for disabilities.
“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), “said Tranfalia. “Unfortunately, after 3-4 months, the effect of the treatment began to diminish and continued to diminish over time, although his reappearance of GERD was closely parallel to the recurrence of other symptoms. After 8 months, it showed some effect. At the end of the study, this strongly suggested the possibility of resistance to this treatment strategy. “
Certainly a journal study in 2005 Neuropharmacology A general test of mGluR5 inhibitors showed that a general test of mGluR5 inhibitors found a treatment-resistant effect in mature fragile X mice, whether voice tones lead to seizures, according to Dr. Tranfalia and researchers at Columbia University. rice field. But until recently, there wasn’t much evidence that patients had acquired treatment resistance, Bear said.
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 the first dose of mGluR5 inhibitor, CTEP caused an improvement in 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,” Stoppel said. “We also focus on the types of experiments that need to be considered when developing other treatment strategies for Fragile X Syndrome and other neurodevelopmental disorders, although the definition of treatment resistance is first. The next goal is to uncover the mechanism and avoid it altogether. Once this work begins, there are some exciting preliminary hypotheses. “
Given the evidence that treatment resistance may increase, a more effective approach to maintaining the benefits of the drug may be to give the patient a break between doses to subside the resistance. The researchers said.
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 said an important next step in his lab was trying to identify the protein.
Do you want to treat it early and then stop?
The study also followed up another finding 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 these 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 did. 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 are supposed to first learn that an area is associated with a risk of mild electric shock, and then learn that risk. It was waning. Fragile X mice that were left untreated at a young age were difficult to test, but fragile X mice that were treated with CTEP at a young age were much more successful.
Bear said these findings were particularly important because they recreated the results of Kind’s work 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 young children. Bear said the results of his new study made him feel more encouraged about the exam.
David C. Stoppel et al, mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence, Psychiatry frontier (2021). DOI: 10.3389 / fpsyt.2021.718953
Patrick K. McCamphill et al, Selective inhibition of glycogen synthase kinase 3α modifies the pathophysiology of a mouse model of fragile X syndrome, Scientific translation medicine (2020). DOI: 10.1126 / scitranslmed.aam8572
QJ Yan et al, suppression of two major fragile X syndrome mouse model phenotypes by mGluR5 antagonist MPEP, Neuropharmacology (2005). DOI: 10.1016 / j.neuropharm.2005.06.004
Antonis Asiminas et al, Continuous correction of associative learning disabilities after short-term early treatment in a rat model of Fragile X syndrome, Scientific translation medicine (2019). DOI: 10.1126 / scitranslmed.aao0498
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Studies show that Fragile X treatment can suffer resistance and suggest ways to avoid it
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