Study shows fragile X treatment can incur resistance, suggests ways
around it

Date:
September 29, 2021
Source:
Picower Institute at MIT
Summary:
While the brain acquires resistance to continuous treatment with
mGluR5 inhibitor drugs, lasting effects may still arise if dosing
occurs intermittently and during a developmental critical period,
a new study finds.



FULL STORY ==========================================================================
Mark Bear, Picower Professor of Neuroscience at MIT, recalls the "eureka moment" 20 years ago when he realized that a severe developmental
brain disorder -- fragile X syndrome -- might be treated with drugs
that inhibit a neurotransmitter receptor called mGluR5. The idea, that
mGluR5 stimulates excessive protein synthesis in fragile X neurons that disrupts their functions, became well validated by experiments in his
lab and others worldwide using several animal models of the disease.


========================================================================== "There was great anticipation that this would be a breakthrough
treatment for this disease," said Bear, a faculty member of The Picower Institute for Learning and Memory and the Department of Brain and
Cognitive Sciences. "Thus, it was a profound disappointment when the
first human clinical trials using mGluR5 negative modulators failed to
show a benefit." This finding led many to question the theory or the usefulness of the animal models, Bear acknowledged. But now a new study
in mice provides substantial evidence that this promising treatment for
fragile X syndrome missed the mark because the brain builds up resistance,
or "tolerance" to it. Importantly, the research also points to several
new therapeutic opportunities that could still turn the tide against
fragile X, the most common inherited form of autism.

Bear and his team led by postdoc David Stoppel showed that giving just a
few doses early in life while the brain is still developing and then not
giving further doses as they got older, could produce lasting benefits
in cognitive ability. That finding suggests that the timing and duration
of mGluR5 inhibition are more important than previously recognized.

"The development of acquired treatment resistance to a medication is
nothing new," said Bear, senior author of the new paper in Frontiers
in Psychiatry.

"The fact that it happens doesn't mean that, therefore, you give up
all hope.

It means that you have to be aware of it." In addition to the strategy
of administering mGluR5 inhibitors at a young age and then stopping, the
study also implies that patients could benefit if dosing were structured
with breaks to prevent a buildup of resistance, Bear said.

Moreover, the study also suggests that amid treatment resistance
fragile X mice resumed synthesis of an unknown protein that leads to
symptoms. Identifying and targeting that protein, Bear added, could also
be a fertile new avenue for drug development.



========================================================================== These new findings follow on a 2020 study in Science Translational
Medicine (STM) by Bear's lab and scientists at The Broad Institute
of MIT and Harvard in which they developed a compound, BRD0705, that
acts downstream in the molecular pathway between mGluR5 and protein
synthesis. BRD0705 did not incur treatment resistance in mature fragile
X mice.

A hard lesson Fragile X syndrome is caused by a mutation in which repeats
of the nucleotides CGG disable a gene's ability to make the protein
FMRP. In the absence of FMRP, neurons exhibit excessive protein synthesis, degraded circuit connections called synapses, and hyperexcitability
leading to symptoms such as cognitive disability. In the early 2000s,
Bear's lab recognized that inhibiting the mGluR5 receptor in brain cells
could prevent the problems with protein synthesis and treat many fragile
X symptoms. After successful animal tests, the treatment was tried in
clinical trials.

One participant in the trial of the drug mavoglurant was Andy Tranfaglia
of Massachusetts. At the time of treatment eight years ago, he was 24,
said his father Dr. Michael Tranfaglia, medical director of FRAXA Research Foundation, an organization working to find a cure for the disorder.

"Andy had an almost miraculous response to the drug and showed
dramatic improvement in virtually all areas of function, behaviorally
and cognitively, but he also had significant improvements in motor
function and a complete resolution of lifelong, severe gastroesophageal
reflux (GERD)," Tranfaglia said. "Unfortunately, after 3-4 months,
the benefits of the treatment began to wane and continued to decrease
over time. The re-emergence of his GERD closely paralleled the return of
his other symptoms, though he still showed some benefit after 8 months,
when the trials ended. This strongly suggested to us the possibility of tolerance to this treatment strategy." Indeed in a 2005 a study in the journalNeuropharmacology by Dr. Tranfaglia and researchers at Columbia University showed that in a common test of an mGluR5 inhibitor, whether
audio tones lead to seizures, found a treatment resistance effect in
mature fragile X mice. Until recently, though, the evidence that patients
were acquiring treatment resistance wasn't abundant, Bear said.



==========================================================================
In the new study, Bear's lab replicated the 2005 findings and showed
that treatment resistance emerges in two other assays as well. After
initial doses of the mGluR5 inhibitor CTEP caused improvements in neural hyperexcitability in the visual cortex fragile X mice lost that benefit
with chronic dosing over the next few days. Fragile X mice also gave up
initial progress after chronic dosing in tamping down protein synthesis
in a brain region called the hippocampus that is central for memory
formation. The results therefore validate the treatment resistance
hypothesis by showing it affecting three different tests that involve
three different parts of the brain.

Routing around resistance "This study suggests answers to important
questions from the failed fragile X mGluR5 trials and about the
preclinical research that inspired them," Stoppel said. "It also
highlights the kinds of experiments that are essential to consider
as other therapeutic strategies are developed for Fragile X or other neurodevelopmental disorders. Defining treatment resistance is just
the first step however. Our next goal is to uncover its mechanism and
then generate strategies to bypass it altogether. We have some exciting preliminary hypotheses as this work begins." Given the evidence that
treatment resistance can build, the researchers said, a more effective
approach to sustaining benefits from the drugs may be to give patients
breaks between doses to allow resistance to subside.

The experiments showing treatment resistance also yielded another
important result. In each case researchers were able to restore the
benefits of the medication by adding a drug called CHX, which broadly suppresses protein synthesis. That finding suggests that amid resistance
the fragile X mice resumed producing a protein that restored disease
symptoms. Bear said a key next step for his lab will be to try to identify
that protein.

Treat early, then stop? The study also followed up on another finding
in STMin 2019 by the lab of Peter Kind at the University of Edinborough,
which found that administering the drug lovastatin appeared to rescue
memory formation and extinction in rats without any 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 the rats
at the young age of five weeks, during a "critical period" of brain development. Bear, Stoppel and their team reasoned that maybe the first
dose produced an enduring effect into adulthood by changing the trajectory
of development for the better.

In the new study the MIT scientists treated some fragile X mice with
CTEP a few times at age 28 days after their birth -- roughly equivalent
to about 10 years old for humans -- and left other Fragile X mice
untreated. Then, after no further treatment, when the mice were 60 days of
age, the team administered a memory test where the rodents were supposed
to first learn that an area was associated with a risk of a mild electric
shock and then to learn that the risk had abated. Fragile X mice left
untreated during their youth showed difficulty with the test, but fragile
X mice who were treated with CTEP while young were much more successful.

Bear said these findings are particularly significant because they
replicate the results in Kind's study using a different drug in a
different species. They therefore seem more likely to generalize to
other mammalian brains, including humans.

In fact, a new clinical trial of an mGluR5 inhibitor made by the drug
company Novartis is underway in young children. Bear said the results
from his new study make him feel more encouraged about that trial.

In addition to Bear and Stoppel the paper's other authors are Patrick McCamphill, Rebecca Senter, and Arnold Heynen.

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

========================================================================== Story Source: Materials provided by Picower_Institute_at_MIT. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. David C. Stoppel, Patrick K. McCamphill, Rebecca K. Senter,
Arnold J.

Heynen, Mark F. Bear. mGluR5 Negative Modulators for Fragile X:
Treatment Resistance and Persistence. Frontiers in Psychiatry,
2021; 12 DOI: 10.3389/fpsyt.2021.718953 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210929101905.htm

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