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MIT is assisting in the integration of artificial intelligence into health-care delivery

While the brain develops resistance to continuous treatment with mGluR5 inhibitors, if dosing occurs intermittently and during a developmental-critical period, long-lasting effects may still be observed in some individuals.

MIT neuroscientist Mark Bear recalls the "eureka moment" that occurred 20 years ago when he realized that drugs inhibiting a neurotransmitter receptor known as mGluR5 could be used to treat fragile X syndrome, a severe developmental brain disorder that affects the thalamus and other parts of the body. Studies conducted in his lab and elsewhere, using a variety of animal models of disease, have demonstrated that mGluR5 stimulates excessive protein synthesis in fragile X neurons, resulting in impairment of their function. This hypothesis has been well-validated.

"There was a lot of hope that this would be a game-changing treatment for this disease," says Bear, who is a faculty member at the Picower Institute for Learning and Memory and a member of the Department of Brain and Cognitive Sciences at the University of Pennsylvania. Accordingly, when the first human clinical trials using mGluR5 negative modulators failed to demonstrate any benefit, it was "an enormous disappointment."

Bear acknowledges that this discovery caused many people to question the theory or the utility of animal models as a result of the discovery. But a new mouse study provides compelling evidence that the brain developed resistance to, or "tolerance" to, this potentially life-saving treatment for fragile X syndrome, and that the treatment ultimately failed to achieve its potential. Notable among these findings is the identification of a number of novel therapeutic targets that may yet prove effective in turning the tide against fragile X syndrome, which is the most common inherited form of autism.

A study conducted by Bear and his colleagues, led by postdoc David Stoppel, found that administering a few doses early in life, while the brain is still developing, and then refraining from administering additional doses as the subjects aged, could result in long-lasting improvements in cognitive ability. In light of these findings, it is reasonable to conclude that the timing and duration of mGluR5 inhibition are more important than previously recognized.

In Bear's words, "acquired treatment resistance to a medication is not a novel concept." Bear is a senior author of the new Frontiers in Psychiatry publication. "The fact that it occurs does not imply that you should give up on your hopes completely. This implies that you must be aware of the situation."

A structured dosing regimen with breaks may be beneficial to patients, according to Bear, in addition to the strategy of starting mGluR5 inhibitors at a young age and then stopping them. "This study suggests that patients may benefit from structured dosing regimen with breaks to prevent resistance building," Bear says. The study also suggests that fragile X mice re-started the synthesis of an unknown protein associated with symptoms during treatment resistance, which was previously stopped. Bear goes on to say that identifying and targeting that protein may also open up a new avenue for drug development in the future.

Based on a study published in Science Translational Medicine (STM) in 2020 by Bear's lab and scientists from MIT and Harvard's Broad Institute, the researchers developed a compound called BRD0705 that functions downstream in the molecular pathway between mGluR5 and protein synthesis. BRD0705 did not result in treatment resistance in mature fragile X mice, as previously reported.

When the nucleotide repeats CGG prevent a gene from producing the FMRP protein, this results in Fragile X syndrome, which is a genetic condition. Neurons that lack FMRP produce excessive amounts of protein, have degraded circuit connections known as synapses, and are hyperexcitable, resulting in symptoms such as cognitive disability and learning disabilities. After discovering that inhibiting the mGluR5 receptor in brain cells could prevent protein synthesis problems and treat a variety of fragile X symptoms in the early 2000s, Bear's lab set out to prove it. Treatment was evaluated in clinical trials after it was shown to be effective in animal models of disease and injury.

Andy Tranfaglia of Massachusetts was a participant in a clinical trial for the drug mavoglurant, which was conducted at Massachusetts General Hospital. According to his father, Dr. Michael Tranfaglia, medical director of the FRAXA Research Foundation, an organization dedicated to curing the disorder, he was 24 years old when he started treatment eight years ago.

Andrea Tranfaglia, MD, says that Andy responded "almost miraculously" to the drug, demonstrating dramatic improvement in virtually all areas of functioning (behavioral and cognitive), as well as significant improvements in motor function and a complete resolution of lifelong, severe gastroesophageal reflux (GERD). "In the end, the treatment's benefits began to wane after three to four months, and they continued to wane over the next several months. GERD recurred in tandem with the recurrence of his other symptoms, though he continued to benefit after the trials ended after eight months, when he was no longer taking part. The fact that this treatment strategy appeared to be tolerable was a strong indication to us."

Transient resistance to treatment was observed in mature fragile X mice, as demonstrated by Tranfaglia and Columbia University researchers in a 2005 study published in the journal Neuropharmacology, when audio tones were used to determine whether or not a mGluR5 inhibitor caused seizures in the mice. Until recently, however, Bear points out, there was little evidence that patients were developing resistance to their medications.

Bear's laboratory confirmed the findings of the 2005 study and demonstrated that treatment resistance occurs in two additional assays as well as the original one. Although the mGluR5 inhibitor CTEP initially reduced neural hyperexcitability in the visual cortex in fragile X mice, the benefit was lost after a few days of chronic dosing with the drug. Aside from that, after chronic dosing, fragile X mice showed a regress in terms of suppressing protein synthesis in a brain region known as the hippocampus, which is critical for memory formation. Therefore, the results demonstrate that treatment resistance affects three distinct tests that involve three distinct brain regions, thereby validating the treatment resistance hypothesis.

Getting around the resistance

Dr. Stoppel explains that "this study sheds light on critical issues raised by the failed fragile X mGluR5 trials and the preclinical research that was the inspiration for them." "It also demonstrates the types of experiments that should be considered when developing new therapeutic strategies for Fragile X syndrome or other neurodevelopmental disorders. Treatment resistance, on the other hand, is only the first step in the process. Identifying the mechanism by which it operates and developing strategies to completely avoid it are our next objectives. As this research project gets underway, we have some intriguing preliminary hypotheses."

Given the evidence that treatment resistance can develop, the researchers propose that providing patients with dose breaks to allow resistance to subside may be a more effective strategy for sustaining drug benefits in the long term.

In addition, the experiments that demonstrated treatment resistance yielded another important discovery. A drug called CHX, which inhibits protein synthesis on a broad scale, was found to be effective in restoring the benefits of the medication in each case studied by the researchers. Because of this discovery, it is possible that the fragile X mice were able to restart the production of a protein that restored disease symptoms in the face of resistance. Bear points out that attempting to identify the protein will be a critical next step for his laboratory in the coming months.

The research also built on a finding published in STM in 2019 by Peter Kind's lab at the University of Edinburgh, which discovered that administering the drug lovastatin appeared to rescue memory formation and extinction in rats while demonstrating no signs of drug resistance. As part of its analysis of those findings, for which Bear was a co-author, the MIT team focused on how a single dose of a drug was administered to the rats at the age of five weeks, when they were in the midst of what was called a "critical period" of brain development. Bear, Stoppel, and their colleagues hypothesized that the initial dose may have had a long-lasting effect into adulthood by altering the developmental trajectory of the participants.

One group of fragile X mice received CTEP several times after birth — roughly equivalent to about 10 years of age in humans — while the other group of fragile X mice did not receive any treatment. A memory test was administered to the mice at 60 days of age after they had not received any further treatment. The mice were expected to first learn that a particular area was associated with a risk of being shocked, and then learn that the risk had been eliminated. Performing the test was difficult for fragile X mice that had not been treated with CTEP while they were still young, but fragile X mice that had been treated with CTEP while they were still young performed significantly better.

Specifically, Bear points out that these findings are significant because they replicate the findings from Kind's study, which used a different drug and a different species. It appears that they have a higher likelihood of generalization to other mammalian brains, including human brains, as a result of this.

Indeed, a new clinical trial in young children is currently being conducted with the help of a mGluR5 inhibitor developed by the pharmaceutical company Novartis, which is currently enrolling participants. Bear claims that the findings of his latest study have given him renewed hope for the trial.

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