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Transcranial stimulation — a noninvasive technique that delivers low electrical currents to the brain to fine-tune nerve cell activity — improved muscle strength and quality of life in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in a small clinical trial.
Researchers also found that a two-week course of transcranial direct current stimulation (tDCS) restored electrical activity through certain neuronal circuits, and that each additional treatment course significantly lowered the risk of death by 71%.
“Our study provides compelling evidence for the potential benefits of cortico-spinal tDCS as a therapeutic and rehabilitative approach for patients with ALS,” the scientists wrote. Still, “larger and more comprehensive clinical trials are necessary to confirm these results and further investigate the mechanisms underlying these effects.”
The study, “<a href="https://www.sciencedirect.com/science/article/pii/S1935861X23019514">Cortico-spinal tDCS in amyotrophic lateral sclerosis: A randomized, double-blind, sham-controlled trial followed by an open-label phase</a>,” was published in <a href="https://www.sciencedirect.com/journal/brain-stimulation">Brain Stimulation</a>.
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<h3>Transcranial stimulation allows neurons to fine-tune responses to stimuli</h3>
ALS is a progressive disease that damages motor neurons, the nerve cells that control voluntary muscles in the body. Without motor neurons, the brain is no longer able to control movement, causing muscle weakness and a range of other <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptoms</a>.
<a href="https://alsnewstoday.com/what-is-als/#Life_expectancy">Life expectancy with ALS</a> varies depending on which symptoms appear first and how rapidly the disease progresses. While medications can slow disease progression and extend survival, not every patient responds well to current <a href="https://alsnewstoday.com/als-treatment/">disease treatment options</a>.
Transcranial direct current stimulation is a noninvasive approach that uses constant, low-intensity electrical currents, passed through small electrodes applied to the scalp, to stimulate certain regions of the brain.
It aims to fine-tune neuronal responses to stimuli, allowing the brain to rewire itself in a way that differs from how it previously functioned. This has been shown to slow progression in neurodegenerative diseases such as <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson’s</a>, and it is thought to hold promise in ALS.
Researchers in Italy conducted a two-part <a href="https://clinicaltrials.gov/study/NCT04293484">clinical trial (NCT04293484)</a> to assess tDCS in 31 adults, all with a <a href="https://alsnewstoday.com/als-diagnosis/">disease diagnosis</a> of early to moderate stage ALS, at a single site in Brescia. Patients in its first part were randomly assigned to either sham (placebo) stimulation or tDCS for five days each week over two weeks.
Using a so-called cortico-spinal approach, scientists stimulated both the motor cortex — a brain region involved in controlling voluntary muscle movement — and the spinal cord at the same time.
&#8220;In ALS, cortical hyperexcitability has emerged as a key factor contributing to the degeneration of motor neurons,&#8221; the researchers wrote.
In the study&#8217;s second part, both patient groups received tDCS about six months after the first course. Follow-up evaluations were done up to 48 weeks from baseline (the study’s start).
<h3>Significant gains in muscle strength seen, starting with two weeks of treatment</h3>
The trial&#8217;s main goal was to determine whether tDCS could increase muscle strength, as assessed with the Medical Research Council (MRC) scale, which ranges from 0 (no movement) to 5 (normal contraction). This score is the sum of scores for each muscle group, like shoulder abductors and knee flexors, with total scores ranging from 100 (no impairment) to 0 (most severe impairment).
Compared with trial&#8217;s sham stimulation, tDCS use resulted in significant improvements in muscle strength at week 24 (about six months), with most improvements seen during the two weeks of treatment. While scores rose by an average of 0.9 points on the MRC scale for people on tDCS, these scores dropped by 6.6 points on average in the sham group.
Treatment also resulted in a better quality of life for patients and a lower burden for caregivers over the 24 weeks.
Nineteen patients had data on intracortical connectivity, or how neurons communicate with each other through circuits within the brain’s cortex. tDCS significantly improved connectivity processes known to be disturbed in people with ALS.
The treatment also appeared to lessen neuronal damage in patients, as assessed by changes in the levels of neurofilament light chain (NfL), a nerve damage biomarker.
While NfL levels peaked about eight weeks after the start of tDCS, they markedly dropped after that, reaching the lowest levels at the 48-week assessment. For initial sham group patients who began tDCS treatment at study week 24, reductions in NfL levels started to become evident between 26 and 32 weeks.
By the study&#8217;s end, 15 patients had died. Bulbar-onset disease, which initially affects the muscles around the face and throat, causing <a href="https://alsnewstoday.com/speech-problems/">slurred speech</a> and <a href="https://alsnewstoday.com/als-symptoms/difficulty-swallowing/">difficulty swallowing</a>, linked with a nearly five times higher risk of death.
In turn, for each tDCS course, there was a 71% lower risk of death, “suggesting that the number of completed tDCS treatments significantly reduced the risk of death and increased survival,” the researchers wrote.
“Our study presents several encouraging findings regarding the therapeutic potential of cortico-spinal tDCS for patients with ALS, comprehensively encompassing highly relevant aspects of ALS: global muscle strength, patient-rated quality of life, caregiver burden and survival,” the researchers concluded.
Despite its small number of patients, “the promising results from our study highlight the potential of cortico-spinal tDCS as a therapeutic intervention for ALS patients, and they open up several avenues for future research,” they added.

Transcranial stimulation seen to boost muscle strength, life quality

Scientists at King&#8217;s College London have identified the site in motor neurons that appears to be the starting point of dysfunction in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) — shedding new light on the workings of the neurodegenerative disease at its earliest stages.
&#8220;This provides a better understanding of the complex mechanism of this disease and a new therapeutic target to improve neuronal function,&#8221; Ivo Lieberam, PhD, a study co-author,  said in a <a href="https://www.kcl.ac.uk/news/specialised-motor-neuron-region-affected-in-amyotrophic-lateral-sclerosis">King&#8217;s College news story</a>.
According to the researchers, motor neurons carrying mutations that cause ALS show abnormal activity in a specialized part of the cell called the axon initial segment, which is where electrical signals are started in these nerve cells.
&#8220;We showed that the axonal initial segment has an important site of dysfunction in motor neurons caused by different genetic mutations,&#8221; Lieberam said.
The study, &#8220;<a href="https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01521-8">Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons</a>,&#8221; was published in <a href="https://www.cell.com/cell-reports/home">Cell Reports</a>.
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<h3>Seeking to understand the &#8216;why&#8217; of changes in ALS motor neurons</h3>
ALS is characterized by the death and dysfunction of motor neurons, the nerve cells that control voluntary movement. Normally, motor neurons are activated by signals from the brain, and then send electrical signals down their long, wire-like fibers, known as axons.
When the electrical signal reaches the end of the axon, it prompts the nerve to release signaling molecules to nearby muscle cells, telling the muscle cells to contract.
In ALS, the electrical activity of motor neurons show characteristic abnormalities. In the early stages of the disease, motor neurons are hyperactive, signaling more than usual, which is thought to contribute to <a href="https://alsnewstoday.com/symptoms-of-als/">ALS symptoms</a> such as muscle twitching. Then, in later stages, motor neurons become hypoactive, with less electrical signaling.
In this study, the team of seven researchers aimed to better understand why ALS motor neurons show these changes in electrical activity. For their experiments, the researchers used patient-derived nerve cells carrying mutations in the TDP-43 or C9ORF72 genes, two of the most common ALS-associated genes.
The researchers noted that, although most cases of ALS don&#8217;t have a clear genetic cause, both genetic and non-genetic <a href="https://alsnewstoday.com/forms-of-als/">forms of the disease</a> are typically marked by similar changes in motor neuron activity.
In the early stages of the disease, the scientists found, the ALS motor neurons had abnormally long axon initial segments, or AISs. The AIS is the specific part of the neuron where electrical signals, called action potentials, are started.
&#8220;This study has shown us that the AIS is a key site in the early stages of ALS pathology and requires further investigation,&#8221; said Juan Burrone, PhD, a co-author of the study and professor at King&#8217;s College London.
Normally, the AIS is able to adjust itself, getting longer or shorter to help regulate how often the neuron fires electrical signals. This phenomenon is called plasticity. However, data showed that the AIS had less plasticity in motor neurons carrying ALS-causing mutations — and this lack of plasticity coupled with the abnormally long AIS ultimately caused the neurons to be overactive.
&#8220;Our study shows that increased AIS length and impaired AIS plasticity is an important mechanism driving abnormal regulation of neuronal activity and intrinsic hyperexcitability in early ALS,&#8221; the researchers wrote.
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<h3>Further work needed into other types of ALS-causing mutations</h3>
In cell experiments in which these motor neurons were coupled with muscle cells, the muscles showed twitches similar to what happens in ALS patients, the researchers noted.
Other experiments indicated that the AIS also was dysregulated in later stages of the disease, where it was abnormally short — contributing to reduced activity of the motor neurons. Consistent with these experiments in cell models, analyses of tissue from people who had died from ALS also were indicative of a shortened AIS in the latter stages of the disease.
&#8220;Taken together, our findings point toward an important and dynamic role of the AIS as a site of dysfunction in ALS [motor neurons],&#8221; the scientists concluded.
The team highlighted that this study was limited to cells carrying only two types of ALS-causing mutations, so further work will be needed to determine whether these findings are applicable in all forms of the disease.
[quote=&#8221;center&#8221;]Taken together, our findings point toward an important and dynamic role of the AIS [axonal initial segment] as a site of dysfunction in ALS [motor neurons].[/quote]
Also, further work is needed to understand exactly how AIS abnormalities in motor neurons may alter the activity of other nerve cells and muscle cells that normally interact with motor neurons, the team noted.
&#8220;We now need to expand our investigation across other spinal cord and brain regions and different genetic mutations,&#8221; Burrone said.
&#8220;It will be important to examine whether these structural and molecular changes of the AIS destabilise the neurons somehow, rendering them vulnerable to further pathological insults,&#8221; he said.

Scientists ID site in motor neurons where ALS dysfunction may start

The U.S. Food and Drug Administration (FDA) has given orphan drug designation to CB03, <a href="https://www.core-biopharma.com/" rel="nofollow">Zhimeng Biopharma</a>’s small molecule treatment candidate for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
CB03 is designed to bolster nerve cell health by regulating potassium channels on these cells, reducing the hyperexcitability that is damaging to neurons.
Orphan drug status aims to encourage the development of treatments for rare diseases, those affecting fewer than 200,000 people in the U.S. It provides benefits such as exemption from FDA application fees, assistance in clinical trial design, and seven years of market exclusivity if the therapy is approved.
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<h3>CB03&#8217;s safety and tolerability in Phase 1 trials in US, Australia</h3>
Available <a href="https://alsnewstoday.com/approved-treatments-for-als/">ALS treatments</a> aim to help with managing <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptoms</a> and in slowing progression.
CB03, a potential therapy for ALS and other conditions of the central nervous system (the brain and spinal cord), is being evaluated in Phase 1 clinical trials taking place in the U.S. (<a href="https://classic.clinicaltrials.gov/ct2/show/NCT05499260">NCT05499260</a>) and Australia (<a href="https://classic.clinicaltrials.gov/ct2/show/NCT05502549">NCT05502549</a>).
They are assessing the safety, tolerability, and pharmacological properties of single and multiple doses of CB03 in healthy adults, with all dosing expected to finish before the year’s end.
“The orphan drug designation by U.S. FDA for CB03 is an important milestone in its global clinical development for ALS and other central nervous system diseases,” Huanming Chen, PhD, Zhimeng’s president and CEO, said in a <a href="https://www.prnewswire.com/news-releases/zhimeng-biopharma-cb03-received-orphan-drug-designation-from-the-us-fda---a-potassium-ion-channel-opener-for-amyotrophic-lateral-sclerosis-301962939.html">company press release</a>.
“Since ALS is a very serious disease without adequate treatment options, we hope our dedicated efforts will allow us to bring a safer and more effective medicine to ALS patients worldwide as the first indication for CB03,” Chen added.
ALS is a neurological disease that damages motor neurons, the nerve cells that control voluntary movements, causing the loss of muscle control. While exact <a href="https://alsnewstoday.com/causes-of-als/">disease causes</a> are unknown, several genetic and environmental factors and lifestyle habits are viewed as increasing its risk.
Neuronal hyperexcitability — the increased likelihood that a neuron will be activated by a certain stimulus — also can be damaging to nerve cells, and it is thought to play an important role in neurodegenerative diseases such as ALS. Potassium channel proteins, which regulate the passage of potassium ions, are important modulators of neuronal excitability.
CB03 is a next-generation small molecule that selectively opens potassium channels called KCNQ2/3. It demonstrated better stability and higher biological or pharmacological activity in lab dish and in ALS animal models than earlier molecules with a similar mechanism.
“CB03 is unlikely to present the same safety concerns as other channel openers and warrant further clinical development to demonstrate potential benefits in the ALS patient population,” Zhimeng stated in its release.

FDA names CB03, aiming to protect neurons, an orphan drug for ALS

PrimeC, <a href="https://www.neurosense-tx.com/" rel="nofollow">NeuroSense Therapeutics</a>&#8216; investigational, fixed-dose combination therapy for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), significantly boosted the survival of patient-derived motor neurons to levels similar to healthy controls in a lab study.
The independent study was led by Justin Ichida, PhD, a professor of stem cell biology and regenerative medicine at the University of Southern California (USC).
&#8220;Dr. Ichida has been described as being beyond the cutting edge in his field and we are honored that he and his lab chose to evaluate PrimeC in this non-sponsored study,&#8221; Alon Ben Noon, founder and CEO of NeuroSense, said in a <a href="https://www.prnewswire.com/news-releases/neurosenses-primec-demonstrates-outstanding-effect-on-als-survival-in-innovative-ipsc-model-301946965.html">company press release</a>.
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<h3>PrimeC combines the antibiotic ciprofloxacin with anti-inflammatory celecoxib</h3>
Findings were presented by Shiran Zimri, PhD, NeuroSense&#8217;s vice-president of research and development, at the recent Northeast Amyotrophic Lateral Sclerosis (NEALS) annual meeting in Florida.
&#8220;These results further bolster our confidence that PrimeC may offer a much-needed therapy for this debilitating disease,&#8221; Noon said.
<a href="https://www.neurosense-tx.com/primec/" rel="nofollow">PrimeC</a> is an oral, fixed-dose combination of two approved compounds with well-established safety profiles: the antibiotic ciprofloxacin and the anti-inflammatory celecoxib.
Together, the medications are expected to prevent ALS progression by targeting inflammation and other mechanisms that damage motor neurons, the nerve cells in the brain and spinal cord that coordinate movement by sending commands to muscle cells.
Ichida and his team at USC&#8217;s Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research examined the efficacy of PrimeC in patient-derived motor neurons.
These cells were generated from blood cells using a kind of cellular programming. First, the scientists collected blood cells from ALS patients and healthy people. Then, through a series of biochemical manipulations, the blood cells were reprogrammed into induced pluripotent stem cells, or iPSCs, which are lab-made stem cells able to grow into other types of cells.
Because the iPSCs retain the genetic code of the person that the blood cells were collected from, they enable the creation of nerve cells that recapitulate the same features of diseased motor neurons. iPCS also provide an almost unlimited source of patient-derived motor neurons, which can be used for large screenings of potential therapies.
&#8220;At our lab, we screen thousands of compounds in search of one that may be effective in ALS, and we were very impressed by the data resulting from our iPCS in vitro study of PrimeC,&#8221; Ichida said. “We chose to evaluate PrimeC based on the growing body of clinical, pre-clinical, and biomarker data on its efficacy in ALS.&#8221;
<h3>PrimeC protected motor neurons more effectively than its components alone</h3>
In a previous study, Ichida found PrimeC to be among the best at improving motor neuron survival in a list that included multiple approved and <a href="https://alsnewstoday.com/experimental-treatments-for-als/">experimental ALS therapies</a>, NeuroSense reported, adding that PrimeC outperformed <a class="waffle-rich-text-link" href="https://alsnewstoday.com/amx0035/">Relyvrio</a> (sodium phenylbutyrate and taurursodiol) and <a class="waffle-rich-text-link" href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> (edaravone) in that study&#8217;s model.
In the current study, researchers compared survival rates of ALS motor neurons with PrimeC versus each of its components. They also tested each of those treatments against motor neurons derived from healthy individuals.
Data showed that, while both ciprofloxacin and celecoxib led to significantly better survival rates than no treatment, the combination therapy was better than either drug alone at improving cell survival.
Notably, ALS motor neurons treated with PrimeC had survival rates similar to those seen in healthy motor neurons, NeuroSense reported.
&#8220;These findings present a new opportunity to potentially screen super responder patients using iPSCs, a non-invasive method which only requires a blood draw from the patient. Using this screening model may result in higher efficacy in people living with ALS who are most likely to benefit from PrimeC,” Zimri said.
In a <a href="https://classic.clinicaltrials.gov/ct2/show/NCT04165850">Phase 2a clinical trial (NCT04165850)</a> that concluded in 2021, an early formulation of PrimeC showed a potential to <a href="https://alsnewstoday.com/news/primec-safe-lowers-als-disease-biomarkers-phase-2-clinical-study/">safely slow overall disease progression</a> and lung function decline compared with an historical group of patients.
A new, extended-release formulation of PrimeC is being investigated in a Phase 2b clinical trial, called <a href="https://classic.clinicaltrials.gov/ct2/show/NCT05357950">PARADIGM (NCT05357950)</a>. There, 69 adults were randomly assigned to the experimental medicine or a placebo, given twice daily for six months alongside standard ALS medications. <a href="https://alsnewstoday.com/news/neurosense-paradigm-trial-primec-als-completes-enrollment-patients/">Top-line trial findings are expected</a> in the coming months.

PrimeC boosts survival of motor neurons derived from ALS patients

Scientists have devised a technique for transplanting healthy motor neurons — the nerve cells that are lost in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) — in a mouse model with &#8220;highly aggressive&#8221; disease.
Transplanted motor neurons, given stimulation, were able to form healthy connections with muscle cells to control the animals&#8217; muscle movement, and they also helped to lessen muscle atrophy or wasting.
&#8220;Our study demonstrates that replacement motor neurons can robustly and reliably reinnervate target muscles in an advanced model of ALS,&#8221; Linda Greensmith, PhD, a study co-author and professor in the department of neuromuscular diseases at University College London (UCL), said in a <a href="https://elifesciences.org/for-the-press/c59727d7/donor-motor-neurons-could-restore-muscle-function-in-als">UCL press release</a>.
The study, &#8220;<a href="https://elifesciences.org/reviewed-preprints/88250v1">An optogenetic cell therapy to restore control of target muscles in an aggressive mouse model of Amyotrophic Lateral Sclerosis</a>,&#8221; was published in <a href="https://elifesciences.org/">eLife</a>.
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<h3>Transplanted motor neurons placed close to target muscles, then stimulated</h3>
Motor neurons are the specialized nerve cells that control muscle movement. <a href="https://alsnewstoday.com/causes-of-als/">ALS, caused</a> by the progressive dysfunction and death of these cells, results in a loss of control over muscle movement.
&#8220;The cellular and molecular changes that underlie neuron degeneration in ALS are extremely complex, and can vary greatly between individual patients. Due to this, there are currently no therapies that can prevent the progression of symptoms in ALS patients,&#8221; said Barney Bryson, the study&#8217;s co-senior author and a senior fellow at UCL&#8217;s neurology institute.
Researchers explored a technique aiming to transplant healthy motor neurons to restore muscle movement in ALS. In this technique, the transplanted neurons are placed very close to target muscles, which helps them to form connections with the muscles. But this placement also means that the motor neurons aren&#8217;t hooked into the brain or spinal cord, so they aren&#8217;t getting any of the signals that normally tell motor neurons when to activate.
Instead, the transplanted motor neurons are activated using a technique called optogenetics, where the cells are engineered to fire when a specific type of light is shone on them. The research team also has been developing implantable devices that use light to control motor neurons in this way.
The scientists previously conducted proof-of-principle experiments in a mouse model of nerve injury, where existing motor neurons were severed and then replaced with transplanted ones. Here, they aimed to translate the approach into a mouse model of severe ALS caused by a mutation in the SOD1 gene.
For these ALS model experiments, the scientists used healthy motor neurons generated from mouse stem cells in a lab. They suggested that similar procedures might be used to provide healthy cells for ALS patients if this technique can be translated to the clinic.
<h3>Activated motor neurons triggered muscle movement in the mice</h3>
In their first experiments, over 95% of the transplanted motor neurons died because the mice&#8217;s immune system mistook the transplanted cells as a threat and attacked them.
Based on this finding, the researchers tested whether the transplant procedure could be improved by treating the mice with an immune-suppressing therapy.
They initially tried a drug called tacrolimus, which is often used to suppress the immune system prior to an organ transplant in people. While tacrolimus&#8217; use allowed more motor neurons to survive, it had toxic effects on the mice&#8217;s bodies, so the transplanted neurons weren&#8217;t able to form healthy connections with muscle cells.
Researchers next tried a more targeted therapy called H57-597, which specifically inhibits the activity of T-cells (a type of immune cell) by blocking the receptor that these cells normally use to detect threats. With H57-597 treatment, all of the transplanted motor neurons survived and formed healthy connections with the mice&#8217;s muscles.
This procedure could be reliably replicated in dozens of individual mice, the researchers showed, and they found that similar results were obtained regardless of what subtype of motor neuron was used in the transplant.
&#8220;If this approach can be successfully translated to ALS patients, the redundancy of the motor neuron subtype used would mean that a single type of motor neuron could be produced to target a large number of different muscles in individual ALS patients. This in turn would lead to a more efficient and wide-scale treatment option,&#8221; Greensmith said.
When the motor neurons were activated via optogenetics, they could trigger movement in the mice&#8217;s muscles, experiments showed. At first the movement was very weak, but the researchers found that if they regularly activated the motor neurons — imposing muscle contractions for one hour each day — connections between the nerve and muscle cells grew stronger, allowing for about 13 times more powerful muscle movements.
<h3>Gains seen in muscle innervation, atrophy prevention, and contractile force</h3>
<h3></h3>
By the end of the experiments, mice that had undergone daily muscle stimulation in this manner had larger muscles than those that did not receive stimulation, implying that this process helps to reduce muscle atrophy in the mouse model.
&#8220;The highly significant improvements in muscle innervation, atrophy prevention and maximum contractile force, as a result of the daily [regimen of activating the motor neurons with optogenetics], confirms that stimulation-induced activity is necessary to maximize connectivity between engrafted motor neurons and their target muscles,&#8221; the researchers wrote.
The scientists stressed that there&#8217;s still more work to be done — these tests all were conducted in mice, so it will be necessary to see if human cells can be engineered for an optogenetics-controlled transplant in the same manner. They also noted that, because people are much larger than mice, it will be necessary to test whether this technique can be effective in bigger animals.
&#8220;Despite these remaining challenges, the findings of this study provide strong support for this novel cell therapy, which, if successful, could finally begin to deliver major health benefits for ALS patients,&#8221; the scientists concluded.

Transplanting motor neurons strengthens muscles in mouse model

Mutations in the gene NEK1, a major genetic cause of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), may work to drive the disease by destabilizing the structure of nerve fibers and disrupting the movement of molecules inside nerve cells, according to a new study.
The findings, which show for the first time how NEK1 gene mutations lead to ALS, illustrate &#8220;two problems in the neuron,&#8221; or nerve cell, researchers from Northwestern University, in Illinois, noted in a <a href="https://news.northwestern.edu/stories/2023/08/als-gene-destabilizes-neurons-structure-and-chokes-off-nucleus/">university press release</a>.
&#8220;By illuminating these two pathways, we’re suggesting these are great therapeutic targets for the disease,&#8221; said Evangelos Kiskinis, PhD, a co-author of the study.
The study, &#8220;<a href="https://www.science.org/doi/10.1126/sciadv.adi5548">Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import</a>,&#8221; was published in <a href="https://www.science.org/journal/sciadv">Science Advances</a>.
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<h3>Understanding the impact of mutations in the NEK1 gene</h3>
Although the causes of ALS remain incompletely understood, <a href="https://alsnewstoday.com/causes-of-als/#Genetics_of_ALS">genetic factors</a> are known to play a role in some cases. Studies in recent years have suggested that mutations in <a href="https://alsnewstoday.com/news/nek1-gene-variants-increase-odds-of-developing-als-study-finds/">the NEK1 gene</a> might account for up to 2% of all ALS cases, making it one of the most common genes linked with the neurodegenerative disease.
The <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms of ALS</a> are driven by the progressive death and dysfunction of motor neurons, the specialized nerve cells responsible for controlling movement. While NEK1 gene mutations have been strongly linked with ALS, exactly how these mutations might cause motor neuron dysfunction has been unknown.
In this study, Northwestern scientists conducted a battery of experiments in cell models — including motor neuron models derived from ALS patients carrying NEK1 mutations — as well as tests in fruit flies to better understand how NEK1 affects motor neurons.
Their results showed that two major cellular processes get disrupted in motor neurons carrying a mutation in NEK1.
[quote=&#8221;center&#8221;] We are linking this new cause of ALS to other genetic causes in which the same process is disrupted.[/quote]
First, NEK1 mutations lead to disruptions in the function of microtubules, which are tube-shaped molecules that form a critical component of the cytoskeleton (literally meaning &#8220;cell skeleton&#8221;). Just like the bones in the skeleton help to support the body, the microtubules in the cytoskeleton help to support the structure of a cell.
In motor neurons, the cytoskeleton is especially critical because it helps to support the long, wire-like axons, or nerve fibers, that these nerve cells use to connect with each other and with the rest of the body. But in motor neurons carrying NEK1 mutations, the microtubule cytoskeleton was not able to properly support the cells.
The second major pathway affected by NEK1 mutations was nuclear import. The nucleus is the central cellular compartment that houses DNA. Normally, proteins and other molecules are constantly being moved in and out of the nucleus as different genes are turned on or off. However, in cells with NEK1 mutations, this movement in and out of the nucleus was disrupted.
&#8220;This discovery is important because a major breakthrough in ALS research in the last few years was discovering that nuclear import is disrupted in other forms of genetic ALS.&#8221; Kiskinis said.
Certain cancer drugs, such as the chemotherapy paclitaxel, work to stabilize microtubules, which can stop cells from dividing. The researchers found that treating NEK1-mutant motor neurons with these drugs led to improvements in nuclear import — suggesting that both processes are connected.
&#8220;Our findings demonstrate that NEK1 can independently modulate [microtubule] dynamics and [nucleus-related] transport, while the effects of the [microtubule]-stabilizing drugs &#8230; highlight an association between these pathways,&#8221; the scientists concluded.
The researchers stressed that these cancer drugs are fairly toxic and can cause a lot of unpleasant side effects, so they might not be suitable for use in ALS. But still, these findings serve as a proof-of-principle for the idea that &#8220;stabilizing microtubules is a rational therapeutic approach in ALS,” Kiskinis said.
The scientists now are working to better understand exactly how NEK1 regulates these processes, with the hope that better understanding the mechanisms may open opportunities to develop new treatments.

NEK1 gene mutations found to drive ALS in new study

A “velcro-like” protein called alpha-5 integrin consistently is found at high levels in immune cells near motor neurons being damaged or killed in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) and those of mice in a disease model, a study reports.
Blocking the protein in the mice slowed disease progression, and it helped in restoring their motor skills and overall health.
&#8220;We demonstrated that targeting α5 [alpha-5] integrin with an anti-α5 integrin antibody extended survival and improved [the animals&#8217;] motor performance,&#8221; the researchers wrote, suggesting that therapies targeting the integrin might treat ALS.
The study, “<a href="https://doi.org/10.1073/pnas.2306731120">Elevated α5 integrin expression on myeloid cells in motor areas in amyotrophic lateral sclerosis is a therapeutic target</a>,” was published in <a href="https://www.pnas.org">PNAS</a>. It was a collaborative effort between <a href="https://www.pasithea.com" rel="nofollow">Pasithea Therapeutics</a> and researchers at Stanford Medical School, the Mayo Clinic, and Oregon Health &amp; Science University.
[recommended-reading id=82116]
<h3>Treatment ideally to &#8216;kill the big eaters before they kill the motor neuron&#8217;</h3>
Last year, Pasithea used an award worth AU$1 million (about $660,000) from <a href="https://fightmnd.org.au">FightMND</a>, an Australian nonprofit supporting disease research, to further its <a href="https://alsnewstoday.com/news/pasithea-therapeutics-receives-au1-million-develop-antibodies-als/">work into anti-integrin antibodies</a> as potential ALS treatments.
ALS occurs when motor neurons, the nerve cells that control voluntary movement, become damaged and progressively die. Without motor neurons, muscles become weak and waste away, leading to such <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptoms</a> as difficulty walking and breathing, slurred speech, and trouble chewing and swallowing.
Although the exact <a href="https://alsnewstoday.com/causes-of-als/">causes of ALS</a> are not known, immune cells like microglia and macrophages are believed to play a role.
Microglia and macrophages work to engulf and destroy dead cells, harmful invaders, and debris. While macrophages can be found in various tissues outside the brain, microglia are the brain&#8217;s resident immune cells.
Microglia are important for maintaining the health of the brain and spinal cord. But in ALS they become overly active, causing excessive inflammation and damage to motor neurons. Peripheral macrophages, those outside the brain, also are <a href="https://www.nature.com/articles/s41593-020-00718-z">involved in disease progression</a>.
“The motor neurons are ‘eaten’ by cells called macrophages and microglia,” Lawrence Steinman, MD, a neurologist and professor at Stanford Medical School, said in an email exchange with ALS News Today. “We have pictures of these ‘big eaters’ ingesting motor neurons.”
But determining exactly how inflammation damages motor neurons is hard, because microglia are very diverse. Examining them one by one is crucial to understanding the disease better.
In a study co-led by Steinman, researchers used a technique called single-cell mass cytometry, which uses tagged antibodies to look at individual cells, allowing them to detail a cell&#8217;s characteristics with high precision.
An initial analysis used a model of ALS where mice carry a mutated version of the SOD1 gene and develop symptoms similar to those of ALS patients. Mutations in this gene are linked to both <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a> and <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic disease forms</a>.
Researchers analyzed 78,293 single cells isolated from these mice, including 21,250 myeloid cells from the brain and spinal cord, a group of immune cells that include microglia. The alpha-5 integrin was present at high levels in myeloid cells of mice with late-stage disease, marked by paralysis, but not in healthy mice, results showed.
An integrin is a type of protein found on the surface of cells, which helps them attach to nearby cells. These proteins also receive and transmit chemical signals that tell the cells how to behave in response to cues from their surroundings.
“We show that a particular [velcro-like] molecule called alpha-5 integrin is present at the site of disease in ALS,” said Steinman, who is also co-founder and chairman of Pasithea.
<h3>Microglial cells positive for integrin seen in damaged motor areas of patients</h3>
In animals with late-stage ALS, considerably more microglia tested positive for alpha-5 integrin in the ventral horn of the spinal cord, which houses the cell bodies of lower motor neurons, than in healthy mice (25.6% vs. 0.06%).
A similar observation was made for macrophages found along the sciatic nerve (49.6% vs. 11.7%), a long nerve that runs from the lower back down through the lower limbs.
Notably, these integrin-positive cells produced significantly higher levels of inflammatory molecules than their integrin-negative counterparts. This included “higher levels of the IL-6 cytokine, which is known to participate in macrophage recruitment toward neurons,” the researchers wrote.
To determine if these findings also held true for people with ALS, the researchers looked at post-mortem samples from 132 patients, and compared them with samples from 10 healthy individuals.
Most of these patient samples (75%) had markedly higher levels of microglia positive for the alpha-5 integrin. These positive cells typically were located close to motor neurons and in empty regions where a motor neuron previously was found.
They &#8220;appear at the scene of where motor neurons are being destroyed,&#8221; Steinman said.
&#8220;Importantly, findings &#8230; show that ALS patients irrespective of sex, age, disease duration, genotype, or treatment consistently had increased α5 integrin-positive microglial cells, specifically in damaged motor areas, suggesting that modulation of α5 integrin-positive immune cells may prove beneficial for ALS across a wide range of ALS etiologies [causative factors],&#8221; the researchers wrote.
<h3>Better health, motor skills evident in mice treated with anti-integrin antibody</h3>
Returning to the ALS mouse model, the scientists tested whether an antibody to block the alpha-5 integrin could ease disease manifestations and improve outcomes. Mice were treated twice a week starting before symptoms were apparent through to a late disease stage.
While mice treated with the antibody developed the disease around the same time as animals given a placebo, their symptoms appeared later and treated mice lived significantly longer, &#8220;consistent with microglia/macrophages playing a major role in ALS disease progression but not in its initiation,&#8221; the scientists wrote.
In a beam walking test, a measure of coordination and balance, treated mice experienced fewer slips and moved across the beam faster than placebo mice, suggesting better motor function. They also showed “better general health and reduced symptoms.”
&#8220;These results provide novel data on the role and spatial distribution of α5 integrin in ALS and provide efficacy data of anti-α5 integrin treatment in the [SOD1] mouse model, the gold standard preclinical ALS model,&#8221; Tiago Reis Marques, MD, PhD, Pasithea Therapeutics&#8217; CEO, said in a <a href="https://www.globenewswire.com/news-release/2023/08/01/2715739/0/en/Pasithea-Therapeutics-publishes-study-in-Proceedings-of-the-National-Academy-of-Sciences-PNAS-that-shows-an-increase-in-%CE%B15-integrin-expression-in-ALS-human-and-mouse-brain-tissue-a.html">company press release</a>.
&#8220;We believe this treatment may be used as a monotherapy or in combination with existing standard of care in both sporadic and genetic&#8221; ALS, he said, adding that company work is ongoing and aims “to select the most optimized antibody as our lead candidate later this year.”
Likewise, the researchers noted that five approved treatments for different diseases target integrins, suggesting that a “clinical trial to test α5 integrin as a drug target in ALS might be worthwhile.&#8221;
“We are dedicated to pursuing this to develop a potential treatment for ALS,” Steinman said. “The basic idea is to &#8216;kill the big eaters&#8217; before they kill the motor neuron.&#8221;

ALS therapy target: Integrin that spurs immune cells to ‘eat’ neurons

The gene expression profiles of motor neurons — the specialized nerve cells that control movement and are lost in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) — vary among men and women, with substantial differences found between the sexes in a new study done using induced pluripotent stem cells, or iPSCs.
&#8220;The data using iPSC-derived motor neurons show a significant separation between males and females&#8221; that reflects &#8220;widespread inherent gene expression differences between male and female neuronal cells and tissues,&#8221; according to the researchers.
&#8220;The striking sex differences in our data suggest that males and females may need to be analyzed separately, requiring twice as many subjects for equivalently powered studies,&#8221; the team wrote.
After taking these sex-based genetic differences into account, the scientists were able to identify a suite of more than 350 genes that are abnormally active in male ALS patients. These findings may help to better understand the differences between the sexes in ALS — and ultimately, to design more targeted therapies for men and women.
“It is known that women are less likely to get ALS than men, and if they do get diagnosed with it, it’s generally a little later in life and affects different sets of motor neurons,&#8221; Clive Svendsen, PhD, the study&#8217;s senior author, said in a <a href="https://www.cedars-sinai.org/newsroom/large-scale-generation-of-muscle-controlling-nerve-cells-from-als-patients/?ppn=Y3Mtb3JnOmNlZGFycy1zaW5haS1lZHU6cmVzZWFyY2g6bmV3cw%3D%3D">press release</a>, adding, &#8220;Now that we have discovered gene expression patterns that can distinguish male and female motor neurons, it may help with designing therapies in the future.&#8221;
[recommended-reading id=24594]
<h3>Study finds genetic differences between the sexes in ALS</h3>
The researchers&#8217; findings were detailed in a study, &#8220;<a href="https://www.cell.com/neuron/fulltext/S0896-6273(23)00034-X#secsectitle0020">Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects</a>,&#8221; published in the journal <a href="https://www.cell.com/neuron/home">Neuron</a>. The work was led by scientists at the Cedars-Sinai Board of Governors Regenerative Medicine Institute, in Los Angeles, California, of which Svendsen is executive director.
ALS is caused by the death and dysfunction of motor neurons, and studying them in humans is essential for understanding the disease. However, it&#8217;s not feasible to collect motor neurons from patients for research — which is where iPSCs come in.
iPSCs are stem cells that are generated from other, easily accessible cells — in this study, the researchers used blood cells collected via a simple blood draw. When given the right biochemical cues, iPSCs can be programmed to grow into other types of cells, such as motor neurons.
As part of a large-scale research effort called <a href="https://alsnewstoday.com/news/answer-als-project-to-better-treat-understand-disease-moves-into-new-phase/">Answer ALS</a>, the researchers developed iPSCs from 341 ALS patients as well as 92 controls without neurological disease.
&#8220;This is the first time that nearly 450 lines of stem cells have been simultaneously differentiated and turned into motor neurons from patients with ALS and healthy controls,&#8221; said Svendsen, who also is the Kerry and Simone Vickar Family Foundation Distinguished Chair in regenerative medicine.
The team used an established 32-day protocol to grow the iPSCs into motor neurons. Then, they conducted analyses of gene expression, or activity, for thousands of genes in each sample. In simplistic terms, gene expression denotes which genes are turned on or off.
Analyses also were conducted to look for differences in gene expression between ALS patients and controls — but the scientists found very few.
&#8220;The disease status of the participant (ALS versus control) only explained an average of 0.22% of the variation in total gene expression and a maximum of approximately 15% of the variation of any single gene,&#8221; the researchers wrote.
Instead, the results showed that motor neuron gene expression profiles divided very clearly into two distinct groups. Closer inspection of the groups revealed that they were sex-specific, for male and female.
[recommended-reading id=82060]
<h3>Data suggest separate analyses for male and female patients</h3>
The fact that these cells were generated in laboratory settings suggests that these differences are probably due to intrinsic genetic differences in the cells, rather than other factors like hormones that can affect gene expression profiles for cells in the body, according to the team.
Indeed, closer inspection of the specific genes that showed differences between the two groups found that many of them were located on the sex-determining X and Y chromosomes. However, there also were a number of genes on other chromosomes that showed differences between the sexes, the scientists noted.
[quote align=&#8221;center&#8221;]The striking sex differences in our data suggest that males and females may need to be analyzed separately, requiring twice as many subjects for equivalently powered studies.[/quote]
Given the difference in genetic activity between sexes, the team then looked for ALS-specific differences in male and female samples separately. In female samples, they did not identify many genes that showed significant differences based on disease state.
Among the male samples, however, more than 300 genes were differentially expressed in ALS patients. Specifically, 220 genes were expressed at unusually high levels in male ALS patients compared with male controls, while 132 genes were expressed at low levels.
&#8220;We hypothesized that we would see differences in gene expression between ALS and healthy control groups, but the changes were subtle,&#8221; said Michael Workman, PhD, of Cedars-Sinai and a study first author.
&#8220;However, when we analyzed males and females separately, some specific changes in gene expression were seen — particularly in male ALS samples,&#8221; Workman said.
The iPSC lines and gene expression datasets have been made available to other scientists in the ALS community in an effort to spur further research.
&#8220;The take-home message is that these big data sets and large numbers of ALS and control stem cell lines are now available to the ALS community to use and look for new causes and treatments,&#8221; Svendsen said. &#8220;This was a collaborative effort with incredibly hard-working teams of scientists across many laboratories to provide a vital resource for the ALS community.&#8221;

Significant differences between sexes seen in ALS gene study results

A new pig model of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) more accurately reflects the gradual motor neuron loss and disease progression seen in patients, and it may speed the development of ALS treatments, included gene and cell-based therapies, researchers report.
The model carries a mutation in the SOD1 gene, an underlying cause of familial ALS, and it has a longer presymptomatic period than ALS mouse models, which are marked by rapid disease progression.
Examined before the onset of motor symptoms, the pig model shared many features with patients and mouse models, such as damage to motor neurons caused the <a href="https://alsnewstoday.com/news/altered-toxic-sod1-protein-als-shared-feature/">toxic buildup of the SOD1 protein</a>.
&#8220;Neurodegeneration progresses even before the patient becomes aware of motor symptoms and seeks medical attention,&#8221; so that &#8220;early intervention is essential,&#8221; the researchers wrote. The pigs &#8220;developed in this study demonstrated that &#8230; [they] are useful for assessing the effectiveness of therapeutic interventions before the onset of neurologic symptoms.&#8221;
[recommended-reading id=81696]
<h3>Rapid progression in mouse models thought to hinder ALS research</h3>
The model was described in the study, “<a href="https://li.uscap.org/article/S0023-6837(22)00013-7/fulltext">A Transgenic Pig Model With Human Mutant SOD1 Exhibits the Early Pathology of Amyotrophic Lateral Sclerosis</a>,” published in the journal <a href="https://li.uscap.org/">Laboratory Investigation</a>.
In some ALS patients, SOD1 gene mutations result in the buildup of a misfolded SOD1 protein in motor neurons, the nerve cells that control voluntary movement. This affects both upper motor neurons, which connect the brain to the spinal cord, and the lower motor neurons that run down the spinal cord and connect to all the muscles in the body.
The dysfunction of these cells leads to a range of <a href="https://alsnewstoday.com/symptoms-of-als-2/">ALS symptoms</a>, such as limb weakness and difficulty breathing, speaking, and swallowing.
Most experimental ALS therapies are developed using rodent models carrying mutant SOD1, but this approach has yielded few effective treatments. Differences in body size and longevity have been cited as reasons for this failure.
ALS in humans typically begins between the ages of 40 and 60. By contrast, the most widely used ALS mouse model, with a SOD1 mutation called G93A, shows symptoms at 3 months of age and dies by 6 months. As a result, this model may not be sufficient for reproducing the gradual loss of motor neurons seen in patients.
To address this problem, researchers in Japan developed a pig model of ALS carrying the same G93A mutation in the SOD1 gene. They noted that pigs are becoming an important disease model because their organs, including their spinal cord, are &#8220;similar in size to those of humans.&#8221;
While other animal models show motor neuron abnormalities before symptom onset, “once a clinical decline in motor function appears, neurologic symptoms progress rapidly,” the researchers wrote. Thus, they specifically examined the ALS animals before the onset of motor symptoms.
<h3>Signs of motor neuron degeneration seen at around age 2 in pig model</h3>
To create the model, dubbed mSOD1-Tg, a copy of the human SOD1 gene carrying the G93A mutation was delivered by in vitro fertilization into oocytes (female eggs), then transferred into 1-year-old female pigs. At birth, the team noted no differences between the ALS model and unaffected (control) piglets.
Researchers also noted that the approach taken in this model&#8217;s development &#8220;can be beneficial for application to preclinical studies such as cell and gene therapy.&#8221;
At about 2 years of age — again, before motor symptom onset — structural abnormalities, including signs of cell degradation, appeared in a portion of the lower motor neurons near the base of the spinal cord (lumbar region) in ALS pigs but not in control pigs.
A lower number of motor neurons also was evident, but not significantly so, in the ALS pigs.
“These results demonstrate that the motor neurons in mSOD1-Tg pigs showed initial pathological [disease-related] abnormality of motor neurons before the manifestation of symptoms,” the team wrote.
Bunina bodies, round-shaped clumps of cellular components normally found in the neurons of ALS patients, were not observed in the motor neurons of mSOD1-Tg pigs. But consistent with ALS patients, misfolded SOD1 protein accumulated in the lower motor neurons of the pigs&#8217; spinal cords.
Researchers also detected misfolded SOD1 protein buildup and damage in the large nerve fibers that extend from motor neurons, called axons. They noted that axonal degeneration is one of the “early abnormalities in ALS” and is similar to that seen in other rodent models.
“In the present study, characteristics of mSOD1-Tg pigs with a long asymptomatic period permitted reproduction by natural mating,” the researchers wrote. “In the future, it is expected that the development of ALS treatment methods will be accelerated by the use of mSOD1-Tg pigs.”

Tag: motor neurons