Use the labels in the right column to find what you want. Or you can go thru them one by one, there are only 33,991 posts. Searching is done in the search box in upper left corner. I blog on anything to do with stroke. DO NOT DO ANYTHING SUGGESTED HERE AS I AM NOT MEDICALLY TRAINED, YOUR DOCTOR IS, LISTEN TO THEM. BUT I BET THEY DON'T KNOW HOW TO GET YOU 100% RECOVERED. I DON'T EITHER BUT HAVE PLENTY OF QUESTIONS FOR YOUR DOCTOR TO ANSWER.
Changing stroke rehab and research worldwide now.Time is Brain!trillions and trillions of neuronsthatDIEeach day because there areNOeffective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.
What this blog is for:
My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.
Showing posts with label multiple sclerosis. Show all posts
Showing posts with label multiple sclerosis. Show all posts
A stroke drug may help preserve and repair myelin damaged by multiple sclerosis, according to a review of animal studies.
Nimodipine was also linked to reduced inflammation, nerve damage and disease severity in several of the studies reviewed.
Myelin is the protective coating around nerve fibres that is damaged in multiple sclerosis, or MS, disrupting communication between the brain and the rest of the body.
Researchers in Iran reviewed five animal studies investigating whether nimodipine, a prescription medicine used to prevent blood vessel spasms after bleeding in the brain, could have potential as an MS treatment.
In MS, the immune system mistakenly attacks the myelin sheath, causing inflammation and nerve damage that can lead to a wide range of neurological symptoms.
Most current MS treatments work by modifying the immune system. While they can reduce relapses and slow disease progression, they generally do not directly repair myelin that has already been lost.
Nimodipine works by relaxing narrowed blood vessels to improve blood flow to injured brain tissue.
Previous research has suggested that the drug may also reduce inflammation and nerve damage while supporting myelin repair.
Four of the five studies involved rodents with experimental autoimmune encephalomyelitis, or EAE, a condition commonly used to model MS.
The fifth used cuprizone, a toxin that causes demyelination, meaning the loss of the protective myelin coating around nerves.
The studies differed substantially in the animals and disease models used, nimodipine doses, treatment methods and outcome measures, so researchers could not combine the results into a single statistical analysis.
Instead, they carried out a narrative review of the results.
Overall, nimodipine was linked to reduced disease severity in the EAE models.
One study found that the drug reduced the severity of relapsing-remitting EAE and lessened disease severity during the early active phase.
Other studies reported reduced relapse rates, fewer sensory and motor problems and effects suggesting protection of nerve cells.
Nimodipine was also linked to less myelin loss and fewer demyelinated nerve fibres.
In one study, treatment increased the number of nerve fibres showing signs of remyelination, the process through which damaged myelin is rebuilt.
The findings were accompanied by increased activity in genes linked to myelin and higher numbers of cells involved in myelin regeneration.
Animals treated with nimodipine also showed fewer signs of inflammation in the brain and spinal cord and lower blood levels of some inflammation-related proteins.
The drug was also linked to improved blood flow and oxygen levels in the spinal cord, while one study found reduced clinical scores and improved motor performance.
In the cuprizone model, nimodipine was linked to fewer reactive immune cells in the brain and faster, more complete myelin repair.
The researchers called for further studies to reproduce the findings and early-stage human trials to determine whether nimodipine can safely provide similar benefits for people with MS.
The researchers wrote: “These findings underscore the potential of drug repositioning to uncover novel clinical mechanisms for nimodipine and expand its therapeutic applications to other diseases, such as MS.
“Preclinical evidence suggests that nimodipine may attenuate disease severity and demyelination and may promote repair-related processes in rodent models relevant to MS.”
Among patients with MS-related fatigue, amantadine, fampridine, and methylphenidate improved fatigue-related functioning, but no medication outperformed placebo for fatigue severity.
Amantadine, fampridine, and methylphenidate are associated with improvements in fatigue-related functional burden among patients with multiple sclerosis (MS), although no medication is superior to placebo for reducing fatigue severity, according to a study published in Neurodegenerative Disease Management.
Researchers conducted a systematic review and network meta-analysis to compare the efficacy of pharmacologic treatments for MS-related fatigue. Eligible studies included randomized clinical trials or crossover trials evaluating medications used to treat MS-related fatigue in adults withMS. Outcomes included the Fatigue Severity Scale (FSS), which measures fatigue severity, and the Modified Fatigue Impact Scale (MFIS), which assesses the effects of fatigue on physical, cognitive, and psychosocial functioning.
A total of 15 studies published between 1995 and 2024 were included in the systematic review. Of these, 4 were crossover studies, and the most frequent countries of origin were the United States and Iran. In total, 940 patients in intervention arms and 662 patients in control arms were evaluated. In 4 studies, control groups were not placebo and instead included aspirin, ondansetron, fampridine, and cognitive behavioral therapy (CBT).
[T]reatment decisions should be individualized and consider patient-specific factors, including disability level, comorbid depression, sleep disorders, and functional priorities.
For fatigue severity, none of the medications was superior to placebo. Based on P score rankings, N-acetylcysteine (P score, 0.94), modafinil (P score, 0.63), and aspirin (P score, 0.55) ranked above placebo for improving fatigue severity, although standardized mean differences did not reach statistical significance.
For fatigue-related daily functioning measured using the MFIS, amantadine (mean difference [MD], −12.11; 95% CI −14.28 to −9.94), fampridine (MD, −14.05; 95% CI −22.59 to −5.52), and methylphenidate (MD, −5.25; 95% CI −8.44 to −2.06) were associated with statistically significant improvements compared with placebo. However, CBT (MD, 1.40; 95% CI −1.99 to 4.80) and modafinil (MD, 0.60; 95% CI −1.26 to 2.46) did not differ significantly from placebo.
The authors noted that previously proposed minimally important differences for the MFIS suggest that the improvements observed with amantadine and fampridine may be clinically meaningful, whereas the magnitude of benefit associated with methylphenidate did not exceed the suggested threshold despite reaching statistical significance.
Study limitations include the limited number of trials per comparison, clinical heterogeneity, methodological heterogeneity, and the overall low-to-moderate certainty of evidence.
“[T]reatment decisions should be individualized and consider patient-specific factors, including disability level, comorbiddepression,sleep disorders, and functional priorities,” the authors concluded.
One line in there is interesting; medical cannabis may be beneficial for spasticity in multiple sclerosis(Ask your doctor if this would work for spasticity in stroke. NO answer, your doctor is FUCKING INCOMPETENT!)
With ANY BRAINS AT ALL your stroke medical 'professionals' would immediately use this to objectively diagnose gait abnormalities. And then objectively monitor the recovery. But nothing will occur, we have blithering idiots in stroke!
A longitudinal study of people with multiple sclerosis (MS) found that declines in daytime physical activity detected through wearable accelerometers were associated with increased risk of disability progression and brain atrophy.
The findings, published in Neurology, suggest continuous activity monitoring may serve as a sensitive, noninvasive biomarker for early disease worsening before clinical symptoms become apparent.
“Timely identification of patients at risk for disease progression is essential to reduce long-term disability, but the current tests for measuring MS disability are not designed to detect small changes,” said Kathryn C. Fitzgerald, Johns Hopkins University, Baltimore, Maryland. “Using a relatively inexpensive and accessible device around the wrist may help us identify early changes in the disease.”
The study enrolled 238 adults aged ≥40 years who underwent annual brain MRI scans and wore wrist-based accelerometers 24 hours per day for 2 straight weeks every 3 months, for up to 3 years. The devices captured several activity metrics, including total activity levels, sedentary time, circadian rhythm parameters, and activity during specific two-hour daytime windows.
Participants had been living with MS for an average of 13 years. At the start of the study, they had an average disability level of 3 on the Expanded Disability Status Scale (EDSS).
Over an average follow-up of 2.9 years, 120 participants experienced confirmed disability progression based on the composite EDSS-plus. Overall physical activity declined by an average of about 2% per year.
Importantly, within-person decreases in daytime activity -- particularly between 8:00 AM and 2:00 PM -- were associated with a significantly higher risk of disability progression. A one-standard deviation decrease in morning or midday activity increased the risk of confirmed progression by roughly 20% to 24%.
MRI analyses also showed that reductions in morning activity were linked to greater brain atrophy, including loss of whole-brain, deep Gray matter, and thalamic volume. While individuals with lower average moderate-to-vigorous activity had smaller brain volumes overall, these between-person differences were not associated with disability progression.
“More research is needed to confirm these findings, but it’s exciting to think that using easily accessible devices could help us predict who is at risk of worsening disease and potentially prevent those changes,” said Ellen M. Mowry, Johns Hopkins University. “Detecting small changes could also help us speed up research on new treatments.”
A limitation of the study is that people who did not have MS were not included, which would help researchers understand how activity levels may change as a part of normal aging. Also, the participants were relatively older and more disabled, so the results may not apply to younger people with MS and those with less disability.
Summary: A new study reveals that neural stem cell
grafts can generate new myelin in the central nervous system, offering
hope for treating progressive multiple sclerosis (MS). Researchers
showed that induced neural stem cells matured into myelin-producing
oligodendrocytes and safely integrated into damaged regions in a mouse
model.
The findings suggest stem cell therapies could address the
underlying neurodegeneration in progressive MS, beyond simply managing
symptoms. This breakthrough supports the RESTORE consortium’s mission to
develop patient-centered clinical trials for stem cell-based MS
therapies.
Key Facts:
New Myelin Formation: Neural stem cell grafts formed myelin-producing cells in damaged regions.
Safe Transplants: Human induced neural stem cell grafts were shown to be safe in animal models.
A
study led by Cambridge researchers has shed light on how neural stem
cell grafts could help restore myelin in the central nervous system.
The
findings suggest that neural stem cell-based therapies hold promise as a
potential treatment for chronic demyelinating disorders, particularly
progressive multiple sclerosis.
Multiple sclerosis (MS) is an
autoimmune disease where the body’s immune system mistakenly attacks the
central nervous system, leading to the destruction of myelin, the
protective sheath surrounding nerve fibres. This damage is a leading
cause of neurological disability in young adults.
The
goal of this research is to see how these therapies may mitigate brain
atrophy and slow the progression of MS.Credit: Neuroscience News
In
the early stages of MS, certain cells possess the capacity to partially
repair this damage by generating new myelin. However, this regenerative
ability reduces significantly in the later, chronic progressive stage
of the disease. This decline in repair contributes to further damage to
neurons and increasing disability in individuals with progressive MS.
Despite
advancements in treatments, current therapies mostly focus on managing
symptoms but do not halt or reverse the damage and neurodegeneration
caused. This shows the critical need for a more profound understanding
of how MS progresses and to explore how stem cell technologies could
help MS treatment.
The study, published in the journal Brain,
was spearheaded by University of Cambridge scientist Dr. Luca
Peruzzotti-Jametti and offers crucial insights into the potential of
neural stem cell transplantation in pwPMS (progressive multiple
sclerosis). While neural stem cell transplants present a promising
avenue for repairing the damaged central nervous system, the limits of
their capacity to repair are being investigated by researchers.
This
study focused on using induced neural stem cells (iNSCs) in a mouse
model to evaluate their ability to promote remyelination. The research
showed, for the first time, that induced neural stem cells grafts can
mature into oligodendrocytes, the cells responsible for producing
myelin.
More importantly, the study provided evidence supporting the safety of human induced neural stem cell transplantation.
“This
research provides critical evidence that induced neural stem cell
grafts can effectively turn into myelin-producing cells within the
damaged central nervous system, suggesting a potential new way to treat
progressive MS,” said Dr. Peruzzotti-Jametti, Department of
Clinical Neurosciences, University of Cambridge, the study’s first
author.
The research team is investigating the underlying
mechanisms of MS in the central nervous system and exploring how neural
stem cell-based treatments can influence neuroprotective and
anti-inflammatory processes. The goal of this research is to see how
these therapies may mitigate brain atrophy and slow the progression of
MS.
“Our findings represent a significant step forward in
understanding how stem cell therapies can be harnessed to combat chronic
demyelinating disorders,” said Stefano Pluchino, Clinical Professor of
Regenerative Neuroimmunology at the Department of Clinical
Neurosciences, the study’s senior author.
“We are particularly
excited about the potential to develop central nervous system directed
therapies that not only manage symptoms but also address the underlying
neurodegenerative processes in progressive MS.
“We’ve shown we can
make new myelin with stem cells, and demonstrated it is possible to
target lesions with grafts. This is a major step forward in the research
towards directed therapies for chronic demyelinating disorders such as
progressive multiple sclerosis.”
Future research and RESTORE
This compelling evidence demonstrating the ability of neural stem cell grafts to generate new myelin in vivo within
laboratory animals exhibiting MS-like lesions carries significant
implications for ongoing research and the development of clinical
trials.
One group dedicated to developing innovative stem cell
therapies for people with progressive MS is RESTORE, a collaborative
European and US consortium which includes a number of leading scientists
from Cambridge University including Prof. Pluchino & Dr.
Peruzzotti-Jametti. Supported by the International Progressive MS
Alliance – Experimental Medicine Development Award Scheme 2025,
RESTORE’s mission is to pioneer a groundbreaking efficacy clinical trial
using neural stem cell-based therapy for progressive MS.
A core
focus of the group’s approach is placing patients at the heart of
research, actively involving and engaging people with MS to ensure that
the work addresses their needs, values, and perspectives.
The
success of this study will help support the RESTORE consortium in their
goal of pursuing therapies for the benefit of patients with progressive
MS, and shows that neural stem cell transplantation can lead to
meaningful remyelination and improved neurological outcomes in patients.
It
is hoped this can potentially pave the way for more effective clinical
trial designs and ultimately, a fully biological disease-modifying
therapy.
“We will be working with our partner researchers
worldwide across the RESTORE research consortium to directly put the
findings of this study into further practice, and to explore the
potential for a neural stem cell graft clinical trial in the future,”
said Professor Pluchino.
Dr Catherine Godbold, Senior Research Communications Manager at the MS Society, said:“More
than 150,000 people live with MS in the UK and it can be debilitating,
exhausting and unpredictable. Neural stem cell therapy for MS is still
in the very early stages of research, but these results with mice are
invaluable.
“They help us understand how neural stem cells might
one day be able to unlock desperately needed myelin-repair
treatments. We’re proud to have supported this study and hope it can
bring us another step closer to stopping progression for everyone with
MS.”
Funding
This
work received funding from the Medical Research Council, the Bascule
Charitable Trust, the National MS Society, FISM – Fondazione Italiana
Sclerosi Multipla, the European Committee for Treatment and Research in
Multiple Sclerosis (ECTRIMS), and the UK MS Society Centre of
Excellence.
About this genetics and multiple sclerosis research news
Author: Lucy Theobald Source: University of Cambridge Contact: Lucy Theobald – University of Cambridge Image: The image is credited to Neuroscience News
Ask your competent? doctor how many miles of myelin need to be fixed post stroke. NO answer, YOU DON'T HAVE A FUNCTIONING STROKE DOCTOR! I expect your stroke doctor to OBJECTIVELY know the damage. Like the number of dead neurons, dead myelinated fibers, dead synapses! Without that knowledge your doctor can never correlate what protocols fix them.
Ahmed
Abdelhak, MD, assistant professor of neurology at the UCSF, discussed
the evolving landscape of biomarkers in multiple sclerosis and their
potential to transform remyelination approaches.
Ahmed Abdelhak, MD
(Credit: UCSF)
Emerging
serum and imaging biomarkers are currently aiming to enhance the
ability to monitor remyelination in multiple sclerosis (MS). For
example, serum neurofilament light chain (NfL) has emerged as a
promising biomarker, reflecting neuroaxonal damage and correlating with
disease activity and progression. Recent research has shown that
elevated serum NfL levels were associated with an increased risk of
disability and brain atrophy. Additionally, other serum proteins are
being investigated for their roles in neuroinflammation and could
contribute to a more complete picture of disease activity in MS.1,2
Advancements
in imaging techniques, particularly MRI, have assisted with the
facilitation of identifying remyelinated lesions in vivo.3
Additionally, quantitative susceptibility mapping and myelin water
fraction (MWF) imaging have shown promise in distinguishing remyelinated
from demyelinated lesions.4 These
imaging biomarkers, when combined with serum markers, may provide a more
comprehensive assessment of remyelination and disease progression for
MS. Thus, ongoing research aims to validate these biomarkers and
ultimately, integrate them into clinical practice to enhance
personalized treatment strategies for patients with MS.
At the 2025 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 28-31, in Phoenix, Arizona, MS expert Ahmed Abdelhak, MD, sat down with NeurologyLive® to
discuss recent advances in biomarkers, such as NFL, that may guide
remyelination in MS, based on his presentation given at the meeting.5
Abdelhak, assistant professor of neurology at the UCSF, also discussed
promising imaging modalities and stressed the need for multimodal
biomarker integration in clinical trials. The conversation underscored
the broader goal of tailoring therapies based on individual serum
proteomic profiles and mechanistic markers to enhance clinical outcomes
in MS care.
NeurologyLive: How might emerging serum and imaging biomarkers change the way clinicians monitor remyelination in patients with MS?
Ahmed Abdelhak, MD:
That’s such an important question. And as you said, it’s a very
exciting topic. You could’ve seen from the other talks in the session
that there is immense progress in this field. We are finally starting to
see new drugs showing efficacy in inducing remyelination in our
patients, which is very important for functional recovery and long-term
neuroprotection.
One of the main challenges we’ve
been having so far is finding better and more specific ways to monitor
outcomes in those trials. One of the things that is very well
established—and the group at UCSF, led by Eric Greene, PhD, did immense
work on to validate—is visual evoked potential. There is amazing work
from Christian Cordano MD, PhD, from our lab, who demonstrated in a very
nice way that remyelination really results in changes in visual evoked
potential.
So far, this has been integrated into all
clinical trials related to remyelination, but we’ve been missing a lot
of other markers. Visual evoked potential shows you remyelination only
in the visual tract and has some noise at the center level. So one of
the main aims, and one of the areas where the field is very interested,
is in finding biomarkers that are accessible for many centers and that
can be used in many of the upcoming remyelination trials.
Some
of those biomarkers originate from serum, and there are also very
interesting imaging markers. What we’ve been working on, for example, is
trying to study the blood we’ve collected from participants in those
remyelination trials in great depth, to find which proteins in the blood
change following remyelination. For example, we found that a protein
all neurologists are now aware of—NFL—is affected by changes in myelin
integrity in this context. In fact, we saw that when you induce
remyelination in people with MS, their NFL levels go down.
We
did extensive validation of that in animal models and in other cohorts
of people with MS. I think we demonstrated in a robust way that if you
cause demyelination, NFL levels will go up, and if you remyelinate the
axons, NFL levels will be lower. However, as I stressed during the talk,
you need the right context to study NFL as a remyelination marker. NFL
is heavily influenced by the levels of inflammation we see in our
patients—any MS relapses or MRI activity are really impactful. So, in
clinical studies looking for remyelination, where you have a very stable
patient population, you can use NFL in that context.
In
another part of the talk, we also showed new discovery approaches that,
by looking at broad proteomic changes in the serum, helped us identify
potentially a whole new set of possible remyelination markers. We are
now trying to validate these at the tissue level in animal models and in
different MS cohorts to define their real clinical context of use.
On
the other hand, we have those very promising imaging markers, which
have some advantages and disadvantages compared with fluid biomarkers.
For example, what we understand from most of the MRI sequences being
used now to monitor remyelination is that they might not necessarily
have ultimate specificity to reflect only changes happening in myelin.
They also reflect changes in axonal integrity and axonal structure,
which is one of the limitations.
But on the other
hand, you can really use MRI to explore remyelination happening in
certain regions in the brain—for example, in the corpus callosum with
MWF, or in MS lesions using sequences like MTR. So, I don’t think
there’s one optimal marker. Putting all of them together is very
important for the next stage of remyelination trials.
What are the most promising biomarkers currently being investigated, and how close are they to routine clinical use?
This
is a very exciting field. We have so many possible new markers. I
didn’t disclose most of them during the talk, but we talked about NFL in
detail. If you look at this panel of markers, you’ll see how extensive
the process is of bringing a biomarker from research into the clinical
setting.
For example, with NfL, where we have most of
data in the field of MS regarding a soluble body fluid marker, we are
very close to getting it into the clinic. What we’ve been waiting on is
an FDA-approved assay and instrument to run those tests. But we already
know a lot about how to use NfL and what an NfL value means in an
patient with MS, with our work especially in the context of
remyelination.
For other biomarkers, they are at
different stages. Some have well-functioning assays but still need
further validation to define their clinical context of use. Others are
at a very early stage of discovery and assay development. So I’d say we
have biomarkers at almost all different stages—some are very close to
clinical use, while others still definitely need more work.
The
same applies to MRI. It’s probably easier since we’re using clinically
available MRI scans, so that part doesn’t need extra validation. But
what we do need to validate is what those sequences are actually showing
at the tissue level—are they really reflecting what we are expecting?
Are they delivering the outcomes we want? If not, there may be a need to
develop even more specific sequences. I know this is a topic many
groups are actively working on, and there’s a lot of excitement around
it as well.
How might these biomarkers help guide treatment decisions or personalize remyelination strategies in practice?
This
is actually the topic I’m most focused on now. The beauty of the wide
panel of biomarkers we have is that we’re not only looking at the
ultimate tissue change—like with NFL, where you see tissue injury—but
also at many mechanistic markers and proteins that reflect every
individual’s disease state and story.
For example,
with the data we showed from the ReBUILD trial (NCT02040298) conducted
by Greene, we saw that patients responded to clemastine fumarate in
different ways. Some improved a lot, and some improved modestly.
Clinically, these patients were quite similar in age and stability. Just
looking at the broader clinical picture, you wouldn’t necessarily find a
reason why they responded differently. But if you look at their serum
proteome, the group that responded very well had a different signature
in their blood compared with the group that didn’t respond optimally.
I
think that’s really where we want to go with biomarkers in the
future—to dissect the disease population and give each group the
treatment that works best for them. It’s a long journey, but the fact
that we finally have tools that make this possible makes this a very
exciting decade for biomarker research.
Any final thoughts you’d like to share on your presentation at CMSC 2025?
I
would definitely recommend, as I mentioned in the talk, not to rely on
only one biomarker as an outcome parameter in remyelination clinical
trials. Let’s leverage the different tools we now have. Let’s find out
whether our remyelinating drug really induces functional
electrophysiological recovery.
Let’s find out whether
it’s really protecting axons. Let’s see where in the brain the changes
are happening. And let’s study each patient’s signature related to their
remyelination process. I think by leveraging all these tools together,
we are getting very close to bringing one of these remyelinating drugs
into the clinical setting.
Does your competent? doctor and hospitals have enough functioning neurons to see this as a possibility for lost myelin during your stroke? Or don't you have a functioning stroke doctor or hospital?
Ask your doctor point blank. 'Does
stroke cause demylination?' If it does then what is your doctor doing to
get it repaired?
Summary: A new drug, PIPE-307, shows promise in
reversing multiple sclerosis (MS) damage by promoting myelin
regeneration around nerve cells, potentially restoring movement and
function.
Developed by researchers, this innovative therapy
targets a specific receptor, M1R, and has already demonstrated success
in animal models. PIPE-307 is currently in Phase II clinical trials,
offering hope for a groundbreaking treatment that could stop and even
heal the damage caused by MS.
This novel approach could transform the future of MS therapy by addressing both symptoms and underlying damage.
Targeted Action: The drug precisely targets the M1R receptor, enhancing its effectiveness in treating MS.
Clinical Trials: PIPE-307 is in Phase II trials, showing potential as a transformative MS treatment.
Source: UCSF
Multiple sclerosis (MS)
degrades the protective insulation around nerve cells, leaving their
axons, which carry electrical impulses, exposed like bare wires. This
can cause devastating problems with movement, balance and vision; and
without treatment, it can lead to paralysis, loss of independence and a
shortened lifespan.
Now, scientists at UC San Francisco
and Contineum Therapeutics have developed a drug that spurs the body to
replace the lost insulation, which is called myelin. If it works in
people, it could be a way to reverse the damage caused by the disease.
The
original breakthrough came when Chan invented a method to screen drugs
for their ability to instigate remyelination. Credit: Neuroscience News
The new therapy, called PIPE-307, targets an elusive receptor on
certain cells in the brain that prompts them to mature into
myelin-producing oligodendrocytes. Once the receptor is blocked, the
oligodendrocytes spring into action, wrapping themselves around the
axons to form a new myelin sheath.
It was crucial to prove that
the receptor, known as M1R, was present on the cells that can repair
damaged fibers. Contineum scientist and first author Michael Poon, PhD,
figured this out using a toxin found in green mamba snake venom.
The work, which appears Aug. 2 in PNAS,
caps a decade of work by UCSF scientists Jonah Chan, PhD, and Ari
Green, MD. Chan led the team to discover in 2014 that an obscure
antihistamine known as clemastine could induce remyelination, which no
one knew was possible.
“Ten years ago, we discovered one way that
the body can regenerate its myelin in response to the right molecular
signal, winding back the consequences of MS,” said Chan, a Debbie and
Andy Rachleff Distinguished Professor of Neurology at UCSF and senior
author of the paper. “By carefully studying the biology of
remyelination, we’ve developed a precise therapy to activate it – the
first of a new class of MS therapies.”
A dirty drug creates a clean opening
The
original breakthrough came when Chan invented a method to screen drugs
for their ability to instigate remyelination. The screen identified a
group drugs, including clemastine, that had one thing in common: they
blocked muscarinic receptors.
Clemastine’s benefits begin with its effect on oligodendrocyte
precursor cells (OPCs). These cells stay dormant in the brain and spinal
cord until they sense injured tissue. Then they move in and give rise
to oligodendrocytes, which produce myelin.
For some reason during
MS, OPCs gather around decaying myelin but fail to rebuild it. Chan
figured out that clemastine activated OPCs by blocking muscarinic
receptors, enabling the OPCs to mature into myelin-producing
oligodendrocytes.
Nerves and their myelin are notoriously hard to
repair, whether due to MS, dementia or other injury. Green and Chan
carried out a trial of clemastine in patients with MS, and it was a
success – the first time that a drug showed the capacity to restore the
myelin lost in MS. Despite being safe to use, however, clemastine was
only modestly effective.
“Clemastine is not a targeted drug,
affecting several different pathways in the body,” said Green, Chief of
the Division of Neuroimmunology and Glial Biology in the UCSF Department
of Neurology and co-author of the paper. “But from the get-go, we saw
that its pharmacology with muscarinic receptors could point us toward
the next generation of restorative therapies in MS.”
A snake venom toxin illuminates the right target
The
researchers continued using clemastine to understand the curative
potential of regenerating myelin in MS. They developed a series of tools
to monitor remyelination, both in animal models of MS and in MS
patients, showing that the benefits seen with clemastine came from
remyelination – and pointing the way for how new drugs should be tested
and evaluated.
They also found that clemastine’s benefits came from blocking just
one of the five muscarinic receptors, M1R, but the effect on M1R was
middling, and the drug also affected the other receptors. The ideal drug
would need to zero in on M1R.
At this point, the UCSF scientists
needed an industry partner to advance the project. Ultimately, Contineum
Therapeutics (then known as Pipeline Therapeutics) was formed to take a
meticulous approach to creating that ideal drug. Chan and Green helped
the company confirm that M1R was the right target for a remyelinating
drug, and then make a drug that blocked it exclusively.
Poon, a
biologist at Contineum, realized that MT7, a toxin found in the venom of
the deadly green mamba snake, could reveal exactly where M1R was in the
brain.
“We needed to prove, beyond doubt, that M1R was present in
OPCs that were near the damage caused by MS,” Poon said. “MT7, which is
exquisitely selective for M1R, fit the bill.”
Poon used MT7 to
engineer a molecular label for M1R that revealed rings of OPCs gathering
around damage in a mouse model of MS and in human MS tissue.
Developing a clinic-ready drug
A team of medicinal chemists at Contineum, led by Austin Chen, PhD,
then got to work on the drug that Chan and Green envisioned, designing
PIPE-307 to potently block M1R and get into the brain.
The
researchers tested the effects of the new drug on OPCs grown in petri
dishes and the animal models of MS using Chan’s and Green’s methods for
tracking remyelination. PIPE-307 blocked the M1R receptor much better
than clemastine; prompted OPCs to mature into oligodendrocytes and begin
myelinating nearby axons; and it crossed the blood-brain barrier.
But most tellingly, it reversed the degradation seen in a mouse model of MS.
“A
drug might seem to work in these abstract scenarios, affecting the
right receptor or cell, but the key finding was actual recovery of
nervous system function,” Chan said.
In 2021, PIPE-307 passed a
Phase I clinical trial, demonstrating its safety. It is currently being
tested in MS patients in Phase II.
If it succeeds, it could transform how MS is treated.
“Every
patient we diagnose with MS comes in with some degree of pre-existing
injury,” Green said. “Now we might have a chance to not just stop their
disease, but to also heal.”
Other authors are
Kym I Lorrain, Karin J Stebbins, Geraldine C Edu, Alexander R
Broadhead, Ariana J Lorenzana, Jeffrey R Roppe, Jill M Baccei,
Christopher S Baccei, and Daniel S Lorrain, all employees of Contineum
Therapeutics.
Funding: The work was partially funded by the
NIH/National Institute of Neurological Disorders and Stroke (grants
R01NS115746 and R01MH125515).
Disclosures: All
Contineum Therapeutics employees hold financial shares of the company.
Chan and Green also hold financial shares in Contineum Therapeutics but
no longer serve in any role. Contineum Therapeutics owns patent rights
to PIPE-307.
About this multiple sclerosis and neuropharmacology research news
Author: Levi Gadye Source: UCSF Contact: Levi Gadye – UCSF Image: The image is credited to Neuroscience News
This activity is supported by an educational grant from AbbVie.
0.75 CME
45MINS
$0FEE
SAVE
ADD TOPIC TO EMAIL ALERTS
Activity Overview
Over 80% of patients with multiple sclerosis (MS) experience related
spasticity. This symptom can be debilitating for both physical and
non-physical daily function. Yet, despite the high prevalence and
impact of spasticity, a substantial portion of affected patients remain
unrecognized and undertreated.
Even when cases are accurately identified, achieving adequate
treatment is challenging. Many of the most common therapies are
accompanied by unpleasant side effects (e.g., insomnia, muscle weakness)
that often lead to their discontinuation. Though botulinum neurotoxin
(BoNT) is among those shown to be effective, optimal timing and patient
selection are needed to maximize its benefits. The current activity
seeks to help clinicians circumvent unpleasant side effects and
undertreatment through personalizing and adjusting therapy based on
individual patient needs. In collaboration with the Multiple Sclerosis
Foundation, 239 patients with MS-related spasticity were surveyed to
give deeper insight into evidence-based strategies to improve patient
outcomes.
Target Audience
The target audience for this initiative includes general
neurologists, physiatrists, nurse practitioners, physician assistants,
and other healthcare professionals involved in the diagnosis and
long-term management of patients with MS-related spasticity.
Learning Objectives
Upon completion of the educational activity, participants should be able to:
Identify concerns and preferences of patients with MS
surrounding the experience and treatment of spasticity, and apply this
information in the development of improved patient-driven management
strategies
Assess diverse presentations of MS-related spasticity to
accurately identify patients early in the disease course and intervene
accordingly
Determine patient-centered strategies to target individual
treatment goals using both non-pharmacological and medication-based
approaches
Analyze key considerations for the effective use of BoNT
injections to maximize their benefits and ensure patient satisfaction
with treatment
Over 80% of patients with multiple sclerosis (MS) experience related
spasticity. This symptom can be debilitating for both physical and
non-physical daily function. Yet, despite the high prevalence and impact
of spasticity, a substantial portion of affected patients remain
unrecognized and undertreated. Even when cases are accurately
identified, achieving adequate treatment is challenging. Many of the
most common therapies are accompanied by unpleasant side effects (e.g.,
insomnia, muscle weakness) that often lead to their discontinuation.
Though botulinum neurotoxin (BoNT) is among those shown to be effective,
optimal timing and patient selection are needed to maximize its
benefits. The current activity seeks to help clinicians circumvent
unpleasant side effects and undertreatment through personalizing and
adjusting therapy based on individual patient needs. In collaboration
with the Multiple Sclerosis Foundation, 239 patients with MS-related
spasticity were surveyed to give deeper insight into evidence-based
strategies to improve patient outcomes.
Presenting Faculty
Scott Newsome, DO, MSCS, FAAN, FANA (Chair)
Director, Neurosciences Consultation and Infusion Center Stiff Person Syndrome Center
Johns Hopkins Neuroimmunology and Neurological Infectious Disease Fellowship
Co-Director, Multiple Sclerosis Experimental Therapeutics Program
Associate Professor of Neurology
Baltimore, MD
Daniel S. Bandari, MD, MS
Director, Multiple Sclerosis Center of California & Research Group
Clinical Assistant Professor of Neurology & Neuro-immunology
University of Southern California, Keck School of Medicine
Laguna Hills, CA
Lisa Fox, PA-C
Senior Physician Assistant, Neurology/Neuroimmunology
Associate Director, Neurology Outpatient Infusion Center
Johns Hopkins University
Baltimore, MD
Does your doctor have enough functioning brain cells to spend 45 minutes with this CME to see if anything here will get your spasticity cured? I see nothing useful here since they are talking 'management' NOT CURE!
This activity is supported by an educational grant from AbbVie.
0.75 CME
45MINS
$0FEE
SAVE
ADD TOPIC TO EMAIL ALERTS
Activity Overview
Over 80% of patients with multiple sclerosis (MS) experience related
spasticity. This symptom can be debilitating for both physical and
non-physical daily function. Yet, despite the high prevalence and
impact of spasticity, a substantial portion of affected patients remain
unrecognized and undertreated.
Even when cases are accurately identified, achieving adequate
treatment is challenging. Many of the most common therapies are
accompanied by unpleasant side effects (e.g., insomnia, muscle weakness)
that often lead to their discontinuation. Though botulinum neurotoxin
(BoNT) is among those shown to be effective, optimal timing and patient
selection are needed to maximize its benefits. The current activity
seeks to help clinicians circumvent unpleasant side effects and
undertreatment through personalizing and adjusting therapy based on
individual patient needs. In collaboration with the Multiple Sclerosis
Foundation, 239 patients with MS-related spasticity were surveyed to
give deeper insight into evidence-based strategies to improve patient
outcomes.
Target Audience
The target audience for this initiative includes general
neurologists, physiatrists, nurse practitioners, physician assistants,
and other healthcare professionals involved in the diagnosis and
long-term management of patients with MS-related spasticity.
Learning Objectives
Upon completion of the educational activity, participants should be able to:
Identify concerns and preferences of patients with MS
surrounding the experience and treatment of spasticity, and apply this
information in the development of improved patient-driven management
strategies
Assess diverse presentations of MS-related spasticity to
accurately identify patients early in the disease course and intervene
accordingly
Determine patient-centered strategies to target individual
treatment goals using both non-pharmacological and medication-based
approaches
Analyze key considerations for the effective use of BoNT
injections to maximize their benefits and ensure patient satisfaction
with treatment
Presenting Faculty
Scott Newsome, DO, MSCS, FAAN, FANA (Chair)
Director, Neurosciences Consultation and Infusion Center Stiff Person Syndrome Center
Johns Hopkins Neuroimmunology and Neurological Infectious Disease Fellowship
Co-Director, Multiple Sclerosis Experimental Therapeutics Program
Associate Professor of Neurology
Baltimore, MD
Daniel S. Bandari, MD, MS
Director, Multiple Sclerosis Center of California & Research Group
Clinical Assistant Professor of Neurology & Neuro-immunology
University of Southern California, Keck School of Medicine
Laguna Hills, CA
Lisa Fox, PA-C
Senior Physician Assistant, Neurology/Neuroimmunology
Associate Director, Neurology Outpatient Infusion Center
Johns Hopkins University
Baltimore, MD
