Drug Tolerance is Likely Culprit Behind the Failure of MGluR5 Clinical Trials

Bear lab (Bear 3rd from left, McCamphill on right)

Dr. Patrick McCamphill, a FRAXA Postdoctoral Fellow in the MIT lab of Dr. Mark Bear, presented his latest findings at the October 2019 Society for Neuroscience annual meeting.

With a $90,000 grant from FRAXA, awarded in 2018 and renewed this year, Dr. McCamphill is investigating drug tolerance to potential Fragile X treatments including mGluR5 antagonists, such as investigational compounds from Novartis and Roche which were unsuccessfully tested in large scale clinical trials years ago.

We have long suspected that the main reason for the failures of the trials was drug tolerance. Repeated doses of a drug may induce tolerance — meaning that the body adjusts to the drug and it loses effectiveness over time. So we asked the Bear team to investigate and to explore ways to overcome the problem.

The team’s major findings, described in this article by Spectrum, “Mouse study hints at why fragile X drugs fail in trials” are:

  1. They have confirmed that significant tolerance to mGluR5 drugs readily observable in multiple brain regions of Fragile X mice. This illustrates one of the biggest problems in science: you can get a misleading impression if you focus too narrowly on one model system. Ironically the very first paper to describe mGlur5 antagonists in the Fragile X mouse model did in fact demonstrate tolerance.
  2. Now Dr. McCamphill and colleagues are working to pinpoint the exact mechanism for this tolerance. Their goal is to find an “antidote” for the tolerance, which would allow the mGluR5 drugs to live up to their full potential. They are zeroing in on another target – GSK3 – which is likely in the same general molecular pathway as mGluR5, but less likely to trigger tolerance. They are now testing drugs which inhibit GSK3 in Fragile X mice. This class of drugs is probably the next best validated treatment target for Fragile X syndrome, after mGluR5. One well-known GSK3 inhibitor is lithium, which was showed positive effects in mouse studies and a pilot clinical trial both funded by FRAXA. This new work opens the possibility that combining lithium and mGluR5 drugs might be very effective.

Pharmacological Tolerance in the Treatment of Fragile X Syndrome

With a $90,000 grant from FRAXA Research Foundation over 2018-2019, Dr. Patrick McCamphill, postdoctoral fellow in Dr. Mark Bear's lab at Massachusetts Institute of Technology (MIT), is investigating drug tolerance to mGluR5 antagonists, arbaclofen, and other potential Fragile X treatments. He is also exploring ways to overcome it.
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Mouse study hints at why fragile X drugs fail in trials

Spectrum | Autism Research News

Mouse study hints at why Fragile X drugs fail in trials

Drug after drug has failed in clinical trials for fragile X syndrome. A new study provides an explanation — a decrease in the drugs’ effectiveness over time — and points to a new strategy that could circumvent this problem.

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