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Treatment with <a href="https://alsnewstoday.com/tregs/">regulatory T-cells</a> (Tregs), a type of anti-inflammatory immune cell, reduced biomarker levels of inflammation and oxidative stress in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), a study shows.
The experimental approach may help curb these contributions to nerve cell damage in ALS, the findings suggest, and routinely measuring the biomarkers could aid in monitoring responses to Treg treatment.
&#8220;The simultaneously assessed levels of immunological and oxidative factors are candidates to monitor disease progression and to properly target clinical trial endpoints response to [Treg] therapy in ALS,&#8221; the researchers wrote in “<a href="https://ageneudisjournal.com/article/view/6047?utm_source=sendgrid.com&amp;utm_medium=email&amp;utm_campaign=website">Immunological, oxidative, and structural factors and their responses to regulatory t lymphocyte therapy in amyotrophic lateral sclerosis</a>,” which was published in <a href="https://ageneudisjournal.com/">Ageing and Neurodegenerative Diseases</a>.
In ALS, motor neurons, the nerve cells that control voluntary movements, become damaged and die. As a result, the brain progressively loses control of movement, triggering <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a> such as muscle weakness, atrophy (shrinking), and stiffness.
Biological hallmarks associated with motor neuron loss include an overactive inflammatory response and <a href="https://alsnewstoday.com/news/oxidative-stress-may-be-therapy-target-in-als-study-of-skin-cells-suggests/">oxidative stress</a>, a type of cell damage caused by highly reactive oxygen-containing molecules generated from normal metabolism. Oxidative stress is increased in ALS and likely contributes to disease progression.
“Our pre-clinical studies have suggested that oxidative stress results from and promotes neuroinflammation and neuronal injury in ALS,” Stanley Appel, MD, scientific advisory board chairman of <a href="https://coyatherapeutics.com/">Coya Therapeutics</a> said in a <a href="https://www.businesswire.com/news/home/20230831425850/en/Coya-Therapeutics-Announces-Publication-of-Potential-Novel-Blood-Biomarker-Data-in-Amyotrophic-Lateral-Sclerosis-ALS-Patients-That-Accurately-Reflect-Therapeutic-Responses-When-Treated-with-Regulatory-T-Cell-Treg-Enhancing-Therapies">company press release</a>. Coya is developing two investigational anti-inflammatory treatments for ALS that boost Treg function.
[recommended-reading id=83988]
<h3>Treg therapy&#8217;s effect on inflammation, oxidative stress</h3>
In the new study, Appel and his colleagues at Houston Methodist Hospital, Texas examined the levels of various blood-based biomarkers associated with inflammation, oxidative stress, and nerve cell structural integrity in 30 people with sporadic ALS (63.3% male). The samples were compared to those from 10 age-matched healthy people (controls).
Blood tests revealed significantly elevated levels of CCL2, an immune signaling molecule associated with inflammatory responses, compared with healthy people. CCL2 levels were particularly increased in patients with rapid ALS progression over those progressing more slowly, although this group&#8217;s levels were still significantly higher than the controls&#8217;.
Similarly, the pro-inflammatory signaling protein interleukin-18 (IL-18) was significantly elevated in patients versus controls and in patients whose disease was progressing rapidly compared with those progressing slowly.
4-HNE, an oxidative stress marker, was also significantly increased in ALS patients with rapidly progressive disease, but slower progressors had levels similar to controls. MDA, another oxidative stress marker, was elevated in both patient groups versus controls, indicating it didn&#8217;t correlate with disease progression.
Levels of NfL and pNfH, two markers of nerve cell damage were examined too. NfL was elevated in rapidly progressing patients compared with slow progressors, but the patient groups didn&#8217;t differ significantly from healthy people. pNfH was reduced in rapidly progressing patients compared with controls, but no other group differences were observed.
<h3>Biomarkers of treatment response</h3>
To validate the biomarkers as indicators of treatment response, the researchers tested samples from ALS patients who participated in one of two clinical trials.
A <a href="https://clinicaltrials.gov/ct2/show/NCT03241784">Phase 1 pilot trial (NCT03241784)</a> enrolled three people with ALS and treated them with a Treg therapy called COYA 101 (formerly ALS001). Tregs are white blood cells that suppress immune responses and prevent unnecessary inflammation.
The cells were isolated, grown to greater numbers in a laboratory, and then infused back into the same patient. The participants also received interleukin-2, an immune signaling protein that boosts Treg function. Data, published in 2018, showed it <a href="https://alsnewstoday.com/news-posts/2021/02/05/coya-therapeutics-als001-treg-off-shelf-therapy-als-progression-phase-2-trial/">slowed progression rates</a> during the early and later stages of the disease.
The Treg/IL-2 combination therapy also suppressed CCL2, IL-18, and 4-HNE, and stabilized clinical status, as assessed with the Appel ALS (AALS) scoring system. During a “washout” period without Treg therapy, the biomarker levels increased and clinical status deteriorated.
A <a href="https://clinicaltrials.gov/ct2/show/NCT04055623">Phase 2a study (NCT04055623)</a> investigated COYA 101 in ALS patients given monthly infusions for six months. A six-month, open-label extension followed.
In this trial, the combination therapy suppressed CCL2 levels in five of the eight patients and IL-18 levels in six. 4-HNE levels were elevated in two patients, but remained low in six. As <a href="https://alsnewstoday.com/news/coya-treg-therapy-als001-als-reduces-inflammation-early-trial/">previously reported</a>, COYA 101 reduced ox-LDL, another marker of oxidative stress, in both the Phase 1 and Phase 2a study patients.
“It is gratifying that biomarkers of oxidative stress — 4-HNE and ox-LDL — correlated with responsiveness to therapy in 2 ALS clinical trials of Treg-enhancing therapies, and may provide an objective confirmation of clinical benefit in forthcoming trials,” Appel said.
“Immunological and oxidative pathological factors accurately reflected therapeutic responses in these pathways and are candidates to target clinical trial endpoints,” the researchers said.
The biomarkers will help assess the effectiveness of COYA 302, a combination of IL-2 and a fusion protein known as CTLA4-Ig or abatacept, Coya maintains. This therapy is designed to further increase Treg activity, reduce inflammation, and slow disease progression.
So far, in a small proof-of-concept clinical trial, four ALS patients saw a <a href="https://alsnewstoday.com/news/mda-2023-coya-302-therapy-slows-als-progression-early-trial/">marked slowing in disease progression</a> with COYA 302. The company plans to <a href="https://alsnewstoday.com/news/coya-meet-fda-about-phase-2-trial-coya-302-als/">file a request</a> with U.S. regulators to continue testing COYA 302 in a Phase 2 clinical trial.

ALS biomarkers are lowered with Coya’s Treg therapy: Study

MRI scans of the brains of people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) have identified a neurochemical called N-acetyl aspartate (NAA) whose levels correlate with the loss of motor function, a study reports.
A drop in NAA levels was associated with the breakdown in communication between the primary motor cortex — the part of the brain that controls the muscles — and other brain regions. These reductions appeared to occur before structural changes in patients&#8217; brains.
The findings suggest clinical imaging to detect NAA changes may be an effective, more sensitive marker of functional changes in ALS and provide an earlier diagnosis, the researchers noted.
&#8220;At this point brain imaging is not used in that way. It remains very much a research tool,&#8221;Sanjay Kalra, MD, study lead author and a professor at the University of Alberta (UA), Canada, said in a <a href="https://www.ualberta.ca/folio/2023/05/researchers-pinpoint-neurochemical-marker-linked-with-loss-of-motor-function-in-als.html">university news release</a>. &#8220;The earlier we can make the diagnosis, the sooner we can start therapies and start counseling, and the sooner we can provide opportunities for enrollment in clinical trials.&#8221;
The MRI study, &#8220;<a href="https://jnnp.bmj.com/content/94/3/193">Motor cortex functional connectivity is associated with underlying neurochemistry in ALS</a>,&#8221; was published in the <a href="https://jnnp.bmj.com/">Journal of Neurology, Neurosurgery and Psychiatry</a>.
Motor neurons are nerve cells in the brain and spinal cord that facilitate voluntary movement, such as walking, speaking, breathing, and swallowing. Upper motor neurons in the brain send signals via the spinal cord to lower motor neurons, which extend to communicate with the muscles.
In ALS, motor neurons are lost, impairing the ability of the brain, namely a region called the primary motor cortex, to communicate with muscles. This leads to <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a> like muscle weakness and difficulty with swallowing, speaking, and breathing.
Brain imaging studies have detected impaired communication between the primary motor cortex and the rest of the brain. This communication is referred to as functional connectivity, the degree to which different brain regions work together during a specific task or at rest.
[recommended-reading id=78093]
<h3>Impaired communication, motor neuron impairment</h3>
Researchers at UA and other Canadian centers hypothesized that such impaired communication could likely be attributed to issues with the structure or neurochemical properties of the upper motor neurons in the primary motor cortex.
&#8220;These upper motor neurons are thought to be more likely to be affected by the neurodegenerative process,&#8221; said Avyarthana Dey, study lead author and a PhD student at UA. &#8220;Because of their big size, they&#8217;re more vulnerable.&#8221;
The researchers collected imaging data on 52 ALS patients and 52 unaffected people matched in age, sex, and education from five academic hospitals affiliated with universities across Canada. Clinical data featured a foot tapping task to examine upper motor neuron function in the participants.
&#8220;One of the things that impedes research in single-center studies is that we only have a very small sample,&#8221; Dey said. &#8220;Having five different centers can capture a wider population with a more varied disease pattern.&#8221;
[quote align=&#8221;center&#8221;]We postulate that the abnormality in NAA occurs before the occurrence of any apparent structural changes.[/quote]
Foot tapping frequency was significantly reduced in ALS patients compared with controls, clinical assessments found. Patients also had impaired cognition and behavior compared with those without ALS.
Regarding symptoms of upper motor neuron involvement, 48 patients had an overactive reflex response in their lower limbs, 21 had an abnormal increase in muscle tone or stiffness (spasticity), and 15 had a foot reflex wherein the big toe flexes up instead of down.
Imaging results showed the primary motor cortex in patients had reduced functional connectivity compared with controls. NAA was also significantly reduced in the patients&#8217; primary motor cortex.
An MRI imaging technique called diffusion tensor imaging (DTI), which measures the diffusion of water molecules in the brain&#8217;s white matter to examine structural changes, showed all measures were increased in the ALS patients.
One of these measures, fractional anisotropy, can be used to measure brain connectivity. Lower foot tapping frequency significantly correlated with both lower fractional anisotropy and lower NAA levels in the primary motor cortex, the researchers found.
<h3>Reduced NAA levels precede brain changes</h3>
[recommended-reading id=39786]
The association between clinical impairment and fractional anisotropy values was stronger than that with NAA levels. Still, functional connectivity was only correlated with NAA levels, suggesting they drop before white matter degenerates.
&#8220;We postulate that the abnormality in NAA occurs before the occurrence of any apparent structural changes,&#8221; Dey said.
&#8220;Clinical investigations could include assessments of primary motor cortical neurochemistry as an effective surrogate imaging marker of functional alterations in ALS,&#8221; the researchers wrote. &#8220;This might help provide an earlier diagnosis of ALS.&#8221;
An earlier diagnosis &#8220;significantly reduces the anxiety, stress, and panic that patients and their caregivers face when something is happening so quickly to them, when they&#8217;re losing function, yet no one can come up with a diagnosis,&#8221; Kalra said.
Future research could explore changes in the primary motor cortex during riluzole therapy (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a> among other formulations), the researchers said.
Riluzole-based oral treatments can slow the progression of ALS and extend survival, and have been shown to increase NAA levels. Whether clinical outcomes and NAA levels are linked remains to be understood, however.
The researchers asked whether higher NAA levels with riluzole correlate with improved survival. &#8220;And if it does, by how much? Because right now riluzole has been shown to increase survival of patients, but we don&#8217;t know exactly how it does that,&#8221; Dey said.
More studies are needed to understand the correlation between NAA levels and loss of function, and how it&#8217;s impacted by <a href="https://alsnewstoday.com/als-treatment/">ALS treatments</a>, the researchers said.
&#8220;We&#8217;d like to know in future studies if improving neurochemistry with medication will improve functional connectivity,&#8221; Kalra concluded.

Loss of motor function linked to neurochemical biomarker: Study

Daily oral treatment with memantine did not slow disease progression nor did it reduce biomarker changes among people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) enrolled in a Phase 2b trial.
Approved under the brand name <a href="https://alzheimersnewstoday.com/alzheimers-disease-treatment/approved-drugs/namenda-memantine/">Namenda</a> to treat cognitive problems in people with <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer&#8217;s disease</a>, memantine has also been shown to help people with <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson&#8217;s disease</a>, but evidence for the therapy&#8217;s benefits in ALS has been conflicting.
Researchers discussed the data in a poster presentation at the American Academy of Neurology (AAN) 2023 Annual Meeting, held April 22-27 in Boston and virtually.
The poster was titled “<a href="https://www.aan.com/MSA/Public/Events/AbstractDetails/54463">A 40-week Phase 2B Randomized, Multicenter, Double-blind, Placebo-controlled Study Evaluating the Safety and Efficacy of Memantine in Amyotrophic Lateral Sclerosis</a>.”
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<h3>Memantine designed to prevent toxic effects of excitotoxicity</h3>
Excitotoxicity, a type of cell death driven by the excessive activity of glutamate — a chemical signaling molecule — in the brain has been implicated in ALS and other neurodegenerative diseases. Glutamate exerts its effects in several ways, one of which involves binding to N-methyl-D-aspartate (NMDA) receptors.
Memantine is a small molecule that blocks NMDA receptors, thereby working to prevent the toxic effects of excessive glutamate signaling.
Consequently, the drug has been associated with reductions in inflammation, prevention of protein misfolding, and reduced production of toxic oxidative molecules, all of which are implicated in ALS.
Preclinical studies have indicated that memantine may prolong survival in a mouse model of ALS. A few small clinical studies testing memantine in ALS patients have been conducted, but yielded conflicting results, according to the scientists.
For example, a <a href="https://clinicaltrials.gov/ct2/show/NCT01020331">pilot open-label study (NCT01020331)</a> involving 19 ALS patients found the treatment reduced the rate of clinical decline by 38% compared with a historical untreated control group. However, another <a href="https://clinicaltrials.gov/ct2/show/NCT00353665">placebo-controlled study (NCT00353665)</a> involving 60 patients did not see any slowing of disease progression.
[quote=&#8221;center&#8221;]Memantine did not slow the progression of ALS nor did it ameliorate the neurocognitive or behavioral effects of ALS.[/quote]
<h3>Phase 2b trial tested memantine&#8217;s safety and efficacy in 89 adults with ALS</h3>
To learn more, the researchers conducted a larger <a href="https://clinicaltrials.gov/ct2/show/NCT02118727">Phase 2b trial (NCT02118727)</a>, called TAME, evaluating memantine&#8217;s safety and efficacy among 89 adults with ALS, ages 18-85, who had started experiencing <a href="https://alsnewstoday.com/als-symptoms/">symptoms</a> of the neurodegenerative disease in the last three years.
In the trial, which took place from December 2018 to September 2020, participants were randomly assigned to receive oral memantine (58 people) or a placebo (31 people) for 40 weeks, or about nine months. The dose of memantine was increased to a maximum of 20 mg twice daily (40 mg total) or to the highest dose tolerated by each patient.
Patients were allowed to continue treatment with approved ALS therapies <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> (edaravone) and riluzole (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a> among others) if they had been stable on treatment for more than a month.
The trial’s main goal was to assess changes in disease progression, as assessed by the Revised ALS Functional Rating Scale (ALSFRS-R), over 36 weeks. Secondary outcomes included changes in disease biomarkers and behavioral measures.
Results showed that monthly rates of functional decline were similar in the two groups, with those given memantine seeing a 1.26-point monthly drop in ALSFRS-R scores, compared with a 1.23-point monthly decline among those in the placebo group.
Likewise, scores on the ALS Cognitive Behavioral Screen and the Neuropsychiatric Inventory Questionnaire, two measures of cognitive and neuropsychiatric function, did not differ between the two groups.
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<h3>No differences found in blood levels of ALS-associated biomarkers</h3>
There also were no differences in blood levels of neurofilament light chain, a biomarker of nerve damage, or other disease-associated biomarkers.
&#8220;Memantine did not slow the progression of ALS nor did it ameliorate the neurocognitive or behavioral effects of ALS,&#8221; the researchers wrote.
The most frequently reported side effects among those treated with memantine included falls (26%), dizziness (26%), confusion (17%), and constipation (14%). Three deaths occurred in each group and were attributed to disease progression.
While the findings overall do not support the use of memantine in ALS, the researchers noted that the study, which allowed remote enrollment because of the COVID-19 pandemic, &#8220;demonstrated the feasibility of an almost entirely remote clinical trial that can be used for future trials.&#8221;
Memantine, taken as an oral solution, is also being examined in the ongoing multi-arm Phase 2/3 <a href="https://clinicaltrials.gov/ct2/show/NCT04302870">MND-SMART clinical trial (NCT04302870)</a>, which is recruiting adults with ALS at sites in the U.K. Its main goals are to assess changes in ALSFRS-R scores and survival with daily memantine compared with a placebo over 18 months, or about 1.5 years.

Tag: ALS biomarkers

ALS biomarkers are lowered with Coya’s Treg therapy: Study

Loss of motor function linked to neurochemical biomarker: Study

AAN 2023: Memantine fails to slow disease progression in Phase 2b trial