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A new compound that significantly extended survival in a mouse model of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) by blocking the activity of a group of proteins called MAP4Ks has been identified by researchers.
The molecule was associated with modest benefits, but researchers believe it can be tweaked to improve its ability to reach the brain and boost its effectiveness, potentially acting as a future treatment candidate for ALS.
“This study will significantly advance the ALS field by providing a leading compound and a signaling pathway for future investigations,” Chun-Li Zhang, PhD, co-author of the study at the University of Texas Southwestern Medical Center, Dallas, said in a <a href="https://www.utsouthwestern.edu/newsroom/articles/year-2024/feb-als-mouse-model.html">university press release</a>. The study, &#8220;<a href="https://www.nature.com/articles/s41419-023-06395-7">Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease</a>,&#8221; was published in <a href="https://www.nature.com/cddis">Cell Death and Disease</a>.
ALS is marked by the progressive death and dysfunction of motor neurons, the nerve cells that control voluntary movements. Finding ways to keep motor neurons healthy is a major priority for ALS research.
Because motor neurons can&#8217;t be collected directly from patients for study, scientists commonly rely on indirect cell models. One of the most common models involves using motor neurons derived from induced pluripotent stem cells (iPSCs). This involves taking skin or cells from a patient, reverse engineering them into stem cells and growing them into motor neurons.
One drawback of this method is that in the stem cell step, iPSC-derived motor neurons lose cellular markers of age. Given that ALS usually affects people in middle to late adulthood, this means iPSC-derived motor neurons won&#8217;t have the age-related markers seen in patients&#8217; motor neurons that could be promising targets for new therapeutics.
A research team led by scientists at UT Southwestern previously developed a method whereby skin cells can be directly engineered to grow into motor neurons, an approach that provides a motor neuron cell model that maintains its age-related markers. They previously showed this approach could aid in making motor neurons out of skin cells from people with ALS. As would be expected, neurons derived from ALS patients had disease features and were less functional than those from healthy people.
[recommended-reading id=75832]
<h3 class="p1"> Treating motor neurons with Hit3</h3>
Here, they used the new cell model to screen a library of roughly 2,000 medications and other biologically active compounds to look for substances that could improve the health of ALS motor neurons.
The screen and subsequent follow-up tests identified a compound dubbed Hit3. ALS motor neurons treated with Hit3 more closely resembled normal motor neurons and were better able to form healthy connections with muscle cells.
&#8220;Hit3 could remarkably rescue both the morphological and functional deficits of ALS-hiMNs [motor neurons derived from people with ALS],&#8221; wrote the researchers, who determined in further experiments that Hit3 exerts its protective effects in ALS motor neurons by blocking the activity of a group of proteins called MAP4Ks, short for mitogen-activated protein kinase kinase kinase kinases.
Blocking MAP4K activity sets off a chain of molecular events that appears to promote nerve health and function. These effects were seen both in cells from people with ALS and from healthy people.
The researchers next tested the effect of blocking MAP4Ks in a mouse model of ALS caused by a mutation in SOD1, a genetic <a href="https://alsnewstoday.com/forms-of-als/">form of the disease</a> that&#8217;s typically more aggressive. For these experiments, they used a MAP4K inhibitor (MAP4Ki) called PF6260933, which was chosen instead of Hit3 because it could reach higher concentrations in the blood and nervous systems in mice.
The treatment significantly extended their lifespan. The median survival was 139 days with MAP4Ki compared with 129 days in mice given an inactive vehicle. Treated mice also had less motor neuron damage.
Although MAP4Ki itself isn&#8217;t well suited for people — it degrades quickly and isn&#8217;t able to cross into the brain to target nerve cells — the results support the idea that blocking MAP4K activity may be therapeutically beneficial in ALS.
“Even though MAP4Ki extended survival by just a short time, our results suggest treatments that block the MAP4K pathway could one day be useful therapeutically,” Zhang said.
More research &#8220;to develop more potent blood-brain barrier-penetrating MAP4K inhibitors for ALS and other neurodegenerative diseases&#8221; is needed, the researchers said.

Blocking MAP4Ks proteins extends survival in ALS mouse model

Researchers have developed an algorithm to generate personalized survival predictions for people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) based on clinical and MRI features. The scientists believe the algorithm could help patients and doctors make better treatment and care plans.
&#8220;The disease progression varies greatly for ALS patients, so it is important to consider their condition when planning future treatments. Our learned model considers the personal descriptions of the patient when giving survival curve predictions,&#8221; the researchers wrote in &#8220;<a href="https://www.nature.com/articles/s41598-023-47935-7">Accurate personalized survival prediction for amyotrophic lateral sclerosis patients.</a>&#8221; The study was published in <a href="https://www.nature.com/srep">Scientific Reports</a>.
ALS is a rapidly progressing neurodegenerative disease characterized by <a href="https://alsnewstoday.com/symptoms-of-als/">muscle weakness and wasting</a> that affects the muscles needed for moving, speaking, and breathing. The most common cause of death is respiratory failure.
While <a href="https://alsnewstoday.com/als-treatment/">therapies</a> can help slow the disease&#8217;s progression, most patients survive an average of about 2-5 years after the onset of symptoms. Survival time can range from a few months to more than 10 years for some patients, however, the researchers said.
&#8220;This range makes it impossible for clinicians to effectively counsel patients on advance care planning, or to select patients with specific survival characteristics for drug trials,&#8221; the researchers wrote.
Better ways of predicting survival time in ALS are needed to guide clinical care. While some models have been developed, they come with limitations. Most approaches don&#8217;t estimate exactly how long a person will live, but instead predict the probability of survival after a certain amount of time.
[recommended-reading id=88594]
<h3>Predicting ALS survival time</h3>
The researchers worked to develop a personalized prediction model to estimate the time until a patient will reach respiratory failure, an indicator of survival, based on clinical and MRI features.
They used machine learning, wherein an algorithm learns to predict an outcome — in this case, survival — by examining patterns across a large amount of patient data. Here, the model learned by analyzing data from 172 patients in the Canadian ALS Neuroimaging Consortium, a long-term MRI-based study. The patients, who had an average age of 59.7, had had symptoms for an average of a little more than two years.
The algorithm took into account 114 clinical features, such as disability, cognitive function, disease duration, age, and sex, among others, along with 68 MRI features related to the thickness of the brain’s cortex, a measure of brain tissue wasting.
Data were included from the time of enrollment in the study until the time of death or the patient’s last follow-up. Overall, 72% of patients (95 of 172) had a recorded composite respiratory failure event, defined as death, used noninvasive ventilation for more than 23 hours per day, or needed a breathing tube placed.
From this information, the so-called SuperLearner algorithm selected an individual survival distribution (ISD) for each evaluated patient. The ISD provides the probability of survival at multiple points in time.
“Our learned model gives a personalized prediction specific to this patient rather than only telling the patient the average survival time of all ALS patients,” the researchers said.
The algorithm was found to have an accuracy of 77% for one-year survival, 57% for two years, and 85% for three years. As an example, the researchers presented the predicted survival curve for Patient A, where it was estimated based on the algorithm the patient would survive 40.4 months (a little less than 3.5 years). The patient died after 42.8 months. Similarly, a patient with a predicted survival of 8.3 months died after 1.5 months.
A strength of the machine learning model is that it takes into account and learns from patients who reached respiratory failure (called uncensored data) as well as those where data collection was stopped (censored) at a follow-up time before that outcome was reached.
“The simplifed approach of just testing on the uncensored instances can lead to biased results because patients whose events happen early are less likely to be censored (e.g., a patient who died on day 1 is less likely to be censored than a patient who died on day 1,000),” said the researchers, who noted the study &#8220;provides a way to predict the time until composite respiratory failure, as this will help patients make decisions about future treatment or care.&#8221;

Researchers develop algorithm to predict ALS survival

Up to about 2.5 years of treatment with <a href="https://alsnewstoday.com/cnm-au8/">CNM-Au8</a> in an open-label extension of the HEALEY ALS platform trial significantly reduced the risk of death for individuals with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) relative to a historical placebo group of patients from previous ALS clinical trials, according to new analyses.
These long-term analyses add to previous findings from the platform trial, which found the experimental therapy from <a href="https://clene.com/">Clene Nanomedicine</a> reduced the risk of death for these ALS patients by more than 90% compared with a placebo in the first six months.
Similar results were observed when pooled data from <a href="https://clinicaltrials.gov/ct2/show/NCT04414345">CNMAu8&#8217;s arm in HEALEY (NCT04414345)</a> and the <a href="https://clinicaltrials.gov/ct2/show/NCT04098406">RESCUE-ALS Phase 2 clinical trial (NCT04098406)</a> were compared with the historical placebo-treated patients.
“To show such profound survival improvement using the HEALEY ALS Platform Trial data set alone and a pooled HEALEY and RESCUE data set is remarkable,&#8221; Benjamin Greenberg, MD, head of medical at Clene, said in a <a href="https://www.globenewswire.com/news-release/2023/09/25/2748500/0/en/Clene-Reports-Significant-Long-Term-Survival-Improvement-From-CNM-Au8-Treatment-in-HEALEY-ALS-Platform-Trial-Compared-to-PRO-ACT-Historical-Controls.html">company press release</a>.
&#8220;Clene is extremely gratified to see this consistent long-term survival data from the HEALEY ALS Platform Trial [open-label extension], with a continued clean safety profile, adding to the totality of the survival evidence,” Greenberg added.
[recommended-reading id=83732]
<h3>New analyses also used data from RESCUE-ALS Phase 2 trial</h3>
CNM-Au8 is an oral liquid suspension of gold nanocrystals, which is expected to support the energetic needs of nerve cells and protect them against forms of cellular stress implicated in the neurodegenerative disease.
The ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT04297683?term=HEALEY+ALS&amp;draw=2&amp;rank=1">HEALEY ALS Platform Trial (NCT04297683)</a>, launched in 2020, is designed to simultaneously test multiple <a href="https://alsnewstoday.com/experimental-treatments-for-als/">ALS treatment candidates</a> using a shared placebo group. This strategy helps to cut costs and accelerate therapeutic development.
Adults with ALS, with symptom onset in the prior three years, are screened through the trial&#8217;s master protocol, and if eligible, are randomly assigned to one of the trial arms that is actively enrolling. <a href="https://clinicaltrials.gov/ct2/show/NCT04297683?term=HEALEY+ALS&amp;draw=2&amp;rank=1#contacts">Recruitment</a> is ongoing across 67 study locations in U.S. sites.
A CNM-Au8 arm was among the trial&#8217;s first, and ultimately enrolled 161 patients. Of them, about 75% were randomly assigned to receive CNM-Au8 at doses of 30 mg or 60 mg for six months, while the other 25% were given a placebo. After the main trial, 92% of the participants continued on in an open-label extension (OLE) trial, where all were given CNM-Au8 at the 30 mg dose.
The main trial did not meet its main goal of slowing functional declines, nor did it demonstrate benefit in measures of lung function.
Still, exploratory analyses indicated that the 30 mg dose was associated with a more than 90% <a href="https://alsnewstoday.com/news/cnm-au8-found-lower-risk-death-als-healey-platform-trial/">lower risk of death</a> and combined risk of death or need for permanently assisted ventilation relative to a placebo after six months. It also was associated with a <a href="https://alsnewstoday.com/news/cnm-au8-delayed-clinical-worsening-als-patients-healey-trial/">74% lower risk</a> of overall clinical worsening.
Because the therapy&#8217;s placebo-controlled portion was just six months, it would be difficult to ascertain CNM-Au8&#8217;s potential long-term survival benefits for ALS patients across the OLE portion. A common solution to this issue is to compare the therapy to an external, historical placebo group.
In the new analyses, the researchers compared CMN-Au8 treatment data from the HEALEY trial with placebo-treated patients from PRO-ACT, the largest U.S. clinical database of previous ALS trials.
The database contains data from 29 completed Phase 2 and 3 ALS clinical trials, including records from more than 11,600 ALS patients.
[recommended-reading id=78394]
<h3>Treatment with CNM-Au9 led to 49% lower risk of death for patients</h3>
For the analysis, 59 people who were originally treated with CNM-Au8 30 mg in the placebo-controlled part of HEALEY were compared with matched placebo participants in the PRO-ACT database.
These results showed that CNM-Au8-treated participants demonstrated a statistically significant, 49% lower risk of death compared with PRO-ACT participants with up to 133 weeks, or about 2.5 years, of treatment.
A similar analysis was performed that pooled 82 CNM-Au8-treated patients across the HEALEY and RESCUE trials. Again, the therapy was associated with a statistically significant 59% reduction in mortality risk relative to matched placebo-treated patients from PRO-ACT.
[quote=&#8221;center&#8221;]Improved survival status is an important measure of drug effect. &#8230; We are pleased to see these data from our long-term follow-up as further support of a survival signal in our HEALEY ALS Platform Trial.[/quote]
Previous analyses from RESCUE and its <a href="https://clinicaltrials.gov/ct2/show/NCT05299658">open-label extension trial (NCT05299658)</a> have similarly indicated a <a href="https://alsnewstoday.com/news/cnm-au8-seen-to-extend-survival-by-more-than-1-5-years-in-als-trial/">survival benefit of CNM-Au8</a>.
&#8220;Improved survival status is an important measure of drug effect,&#8221; said Merit Cudkowicz, MD, neurology chair at Massachusetts General Hospital, director of the Sean M. Healey &amp; AMG Center for ALS, and the principal investigator of the HEALEY ALS Platform Trial.
&#8220;We are pleased to see these data from our long-term follow-up as further support of a survival signal in our HEALEY ALS Platform Trial,&#8221; Cudkowicz said.
Over more than 500 years of collective exposure to CNM-Au8 across ALS, <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a>, and <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson&#8217;s disease</a> clinical trials and expanded access programs, no safety signals or serious adverse events from the experimental therapy have been observed.
“I am also happy to see how helpful a shared open-source dataset such as PRO-ACT is to the field to analyze data from the [open-label extension] portions of clinical trials,&#8221; Cudkowicz said.
&#8220;We encourage all companies working in ALS to contribute their data to PRO-ACT once their trial is complete. I want to also thank all the people with ALS who are part of clinical trials and are helping the community find new treatments,” she added.

Long-term ALS survival benefit with CNM-Au8 seen in trial analyses

Elevated blood levels of the Cystatin C protein are significantly associated with faster disease progression and shorter survival in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to a study in China.
The protein may serve as a biomarker to predict disease outcomes in people with ALS and identify those who need more invasive strategies earlier in the disease course, the findings suggest.
Cystatin C “has the potential to be a widely used and reproducible biomarker for monitoring disease progression in ALS,” the researchers wrote in “<a href="https://link.springer.com/article/10.1007/s10072-023-06957-9">Serum Cystatin C is a potential biomarker for predicting amyotrophic lateral sclerosis survival</a>,” which was published in <a href="https://www.springer.com/journal/10072">Neurological Sciences</a>.
ALS is caused by the damage and death of motor neurons, the nerve cells that control voluntary movements. This causes a loss of control of muscle movements, and patients progressively become less able to go about their daily lives without assistance.
About 90% of cases are <a href="https://alsnewstoday.com/sporadic-als/">sporadic</a>, meaning they occur spontaneously. The remaining 10%, which run in families, are called <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a>. Although many studies have focused on the genetic causes of familial ALS, less is known about the mechanisms leading to sporadic ALS.
[recommended-reading id=85520]
<h3>Connecting Cystatin C levels to disease progression, survival</h3>
Cystatin C is a small protein used to monitor kidney problems and has also been associated with disease severity in ALS. Yet, studies examining the link between Cystatin C and ALS survival and progression have yielded conflicting results, leading researchers in China to assess the potential biomarker&#8217;s levels in 356 patients with sporadic ALS at their hospital between 2016-2019 to shed more light on this association.
Most participants (57%) were men, with a mean age at disease onset of 53.3 and a mean interval between symptom onset and <a href="https://alsnewstoday.com/als-diagnosis/">diagnosis</a> of 13.8 months. They were followed by neurologists via phone or in-person interviews every six months until January 2022. During that time, 226 patients (63.5%) died and 26 (7.3%) were lost to follow-up.
On average, the levels of Cystatin C in serum (the liquid portion of blood) at diagnosis were 1 mg/L. Based on that average, patients were divided into two groups: those with levels of 1 mg/L or higher and those with levels below the average.
The high Cystatin C group had a significantly higher proportion of men (71.5% vs. 44.5%) and of patients with limb-onset disease (89.1% vs. 55.5%), a form of the disease in which the first <a href="https://alsnewstoday.com/als-symptoms/">symptoms of muscle weakness</a> appear in the limbs. This group was also significantly older at the onset of the disease (57.7 vs. 49.5%).
The participants in the high and low Cystatin C groups also had differences in clinical measures. In fact, the high group had significantly less disease severity, as measured with the ALS Functional Rating Scale-Revised (ALSFRS-R), but a faster rate of disease progression.
The higher the Cystatin C levels, the less severe the disease was, but the faster it progressed, according to statistical analyses that looked at Cystatin C levels as a continuous variable.
This suggests “serum [Cystatin C] may be a useful indicator for assessing disease severity, [and that] patients with higher [Cystatin C] levels might have faster disease progression,&#8221; the researchers wrote.
The median survival time for all the patients was 42 months (around 3.5 years). However, consistent with the faster rate of disease progression in those with high Cystatin C levels, this group also had a significantly shorter survival compared with the group with low levels (38 vs. 48 months). In a multivariate analysis, which took into account potential confounding factors such as age and sex, low serum Cystatin C remained associated with a longer survival time with ALS.
Other factors significantly associated with longer survival included a lower age at disease onset, limb onset, a longer time between the appearance of the first symptoms and diagnosis, a slower disease progression rate, and being male.
“Our study found that serum [Cystatin C] seems to be associated with ALS survival and serum [Cystatin C] may be an independent predictor of ALS survival,” the researchers said.

Cystatin C may be biomarker to predict survival, disease progression

<a href="https://www.mt-pharma-ca.com/">Mitsubishi Tanabe Pharma Canada</a> (MTP-CA) is teaming up with the <a href="https://cndr.org/">Canadian Neuromuscular Disease Registry</a> (CNDR) in Canada&#8217;s first real-world, evidence-generating study of <a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava</a> (edaravone) in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
Data are expected to provide real-life insights into the survival benefits of Radicava in the progressive neurodegenerative disorder, thought to affect about 3,000 Canadians.
When Radicava was approved in Canada in 2018, it became the first new ALS treatment in that country in nearly two decades. The treatment is infused into the bloodstream and an oral formulation called Radicava Oral Suspension was approved Canada last year. The effect of edaravone — the active ingredient in both formulations — on real-world survival in ALS hasn&#8217;t been established, however.
&#8220;Edaravone has previously been shown to slow disease progression in people with ALS over six months; however, further real-world effectiveness evidence is needed,&#8221; Agessandro Abrahao, MD, CNDR&#8217;s co-principal investigator, said in a <a href="https://www.newswire.ca/news-releases/mitsubishi-tanabe-pharma-canada-announces-collaboration-with-the-cndr-on-first-canadian-real-world-evidence-study-of-radicava-r-iv-edaravone-survival-benefits-in-als-864837565.html">press release</a>.
[recommended-reading id=86038]
<h3>What does the real-world Radicava study seek to accomplish?</h3>
Edaravone is known as a free radical scavenger, meaning it extracts the reactive molecules that contribute to oxidative stress, a type of cellular damage implicated in ALS. Neurons are especially <a href="https://www.hindawi.com/journals/omcl/2019/2105607/">sensitive to oxidative stress</a>. By removing them, the therapy should mitigate nerve damage and slow disease progression.
While Radicava is approved in Canada, the U.S., and some other countries, the evidence showing its effectiveness isn&#8217;t settled and regulators in Europe and other regions have declined to approve it.
&#8220;The objective of this study is to describe real-world survival effectiveness over a longer time frame,&#8221; said Abrahao, a neurologist and associate scientist with the Sunnybrook Health Sciences Centre in Toronto who is co-leading the study.
&#8220;This collaboration with the CNDR is part of our legacy in Canada and ongoing commitment to benefit patients, caregivers, and loved ones touched by rare diseases, including ALS,&#8221; said Andy Zylak, president of Mitsubishi Tanabe Pharma Canada.
The study is enrolling ALS patients across Canada whose symptoms started in the past three years. So far, about 182 patients on Radicava for at least six months between 2017-2022 and 860 controls on other medications have signed on, Abrahao announced in a poster presentation in June at the 2023 Canadian Neurological Sciences Federation Congress.
Its main goal is to see if Radicava can extend the time until a tracheostomy, or a tube in the neck to help with breathing, is needed. This outcome is known as tracheostomy-free survival.
&#8220;Real-world data provides additional insight into treatment for rare diseases like ALS, which can sometimes be challenging to research and evaluate in clinical trials,&#8221; said Dung Pham, medical affairs director, Mitsubishi Tanabe Pharma Canada. &#8220;Through our collaboration with the CNDR, we hope to gain important real-life insights into the role of Radicava in the treatment of ALS — insights that will ultimately benefit people living with this progressive, life-threatening disease and their families.&#8221;
&#8220;Access to innovative therapies is an urgent issue for people living with ALS,&#8221; said Tammy Moore, president of <a href="https://als.ca/">ALS Canada</a>. &#8220;Understanding how innovative treatments perform in a real-world setting can assist stakeholders from across the healthcare system with decision making and potentially lead to faster access for people living with ALS and improved health outcomes.&#8221;
The Canadian Neuromuscular Disease Registry is an independent registry of people — more than 4,500 to date — with a neuromuscular disease. It works to improve understanding of such disorders and accelerate the development  of treatments.

ALS survival benefits with Radicava to be studied as part of collaboration

Increased accumulation of p62, a protein involved in a cellular recycling process called autophagy, in the spinal cord is associated with worse survival outcomes in people with sporadic <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), a study revealed.
Autophagy is the cellular process responsible for breaking down proteins and other complex molecules that are abnormal or no longer needed. The buildup of p62 clumps generally indicates that this process is no longer working as it should, as the toxic protein aggregates contributing to ALS are not cleared properly.
“These findings implicate the autophagy pathway in ALS survival and provide support for further study of p62 as a potential prognostic biomarker in ALS,” researchers wrote.
The study, “<a href="https://academic.oup.com/jnen/advance-article/doi/10.1093/jnen/nlad051/7220740?login=false">Survival in sporadic ALS is associated with lower p62 burden in the spinal cord</a>,” was published in the <a href="https://academic.oup.com/jnen">Journal of Neuropathology &amp; Experimental Neurology</a>. The work was funded by Australia’s <a href="https://fightmnd.org.au/">FightMND</a>.
In ALS, the loss of the specialized nerve cells that control voluntary movement, called motor neurons, results in <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a> such as muscle weakness and wasting, and an inability to control movement.
Both upper motor neurons, which connect the brain to the spinal cord, and lower motor neurons, extending from the spinal cord to muscles, are affected in people with the disease.
[recommended-reading id=85814]
<h3>Formation of toxic clumps of TDP-43 protein occurs in almost all ALS patients</h3>
A hallmark of ALS, occurring in about 97% of patients, is the formation of toxic clumps of the TDP-43 protein, which contribute to motor neuron loss. The p62 protein, a marker for autophagy, is often found within these TDP-43 aggregates.
In this report, researchers at the University of Sydney investigated p62 aggregates in the motor neurons of 31 <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a> patients to assess p62’s association with TDP-43 accumulation, neuron loss, and survival.
All participants had upper and lower motor neuron degeneration accompanied by TDP-43 protein clumps. A group of 15 patients had short disease duration, defined as less than two years (short survival), while 16 patients had a longer disease duration of 4-7 years (longer survival). There were no differences in age at death, site of onset, sex, or ALS stage between the two groups.
Tissue analysis of donated samples found the density of motor neurons in the spinal cord was significantly lower in patients who lived longer compared with those in the short-disease duration group.
No significant differences in neuron density were observed in the motor cortex, a part of the brain that generates signals to direct body movements, and the hypoglossal nucleus, a prominent cluster of large motor neurons that supply the tongue muscles.
Aggregates of p62 were detected in lower motor neurons, which had three types of structures: thread-like, dense and round, and dot-like. By contrast, p62 aggregates were not seen in upper motor neurons.
A significantly greater density of p62 aggregates was found in the spinal cord of the short-disease duration cases compared with longer duration cases, driven by mainly thread-like aggregates.
“Because the accumulation of p62 is considered an indicator of autophagy inhibition, the present findings of significantly more p62 aggregates in the spinal cord of patients with a shorter disease duration implicates deficits in [autophagy] pathways in ALS survival,” the researchers wrote.
Motor neurons with TDP-43 aggregates were significantly more common in the spinal cord and hypoglossal nucleus of the short compared with the extended survival group. Thread-like aggregates also were more prominent in the spinal cord of those with shorter survival. No significant difference was found in upper motor neurons.
Statistical analysis found a significant correlation between p62 and TDP-43 aggregates, and increasing p62 and TDP-43 aggregates were associated with increasing numbers of spinal cord motor neurons.
ALS patients with longer survival had significantly fewer p62 and TDP-43 aggregates and lower motor neuron density in the spinal cord.
“The present study demonstrates significantly more p62 aggregates in the spinal cord of patients with shorter ALS survival,” the team concluded. “Future longitudinal [over time] studies will be able to determine the viability of in vivo [in living organisms] measures of p62 expression in identifying patients with poorer prognosis at presentation.”

Survival in sporadic ALS linked to autophagy protein p62

Researchers have identified new genetic variants that might influence survival among sporadic <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) patients in Japan.
Genetic analyses in more than 1,000 ALS patients uncovered that small changes in the FGF1, THSD7A, and LRP1 genes could affect patients&#8217; prognosis. In patient-derived nerve cells, the identified variants led to low gene activity and reduced cell survival.
&#8220;The identification of genetic factors associated with the survival of patients with ALS and the development of patient-derived cellular models that reflect these factors could contribute to the formulation of targeted therapy for ALS,&#8221; researcher wrote.
The study, &#8220;<a href="https://jnnp.bmj.com/content/early/2023/05/03/jnnp-2022-330851">Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients</a>,&#8221; was published in the <a href="https://jnnp.bmj.com/">Journal of Neurology, Neurosurgery &amp; Psychiatry</a>.
Mutations in <a href="https://www.als.org/research/research-we-fund/scientific-focus-areas/genetics#linked-genes">more than 40 genes</a> have been linked to <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a>, or ALS that runs in families. On the other hand, in most cases of <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a>, or those without a known family history, a disease-causing mutation hasn&#8217;t been identified.
Still, studies indicate that small genetic variations, called single nucleotide polymorphisms (SNPs), can influence disease prognosis and <a href="https://alsnewstoday.com/news/association-locus-camta1-gene-survival-patients-sporadic-amyotrophic-lateral-sclerosis/">survival</a> in these patients.
[recommended-reading id=86121]
<h3>Genetic factors in Asian patients have not been identified, scientists say</h3>
SNPs refer to genetic changes that only affect a single nucleotide, or DNA building block. They are the most common type of genetic variation seen in humans, including in healthy people. While they typically don&#8217;t directly cause disease on their own, they can influence disease risk, disease manifestations, or prognosis.
Most studies evaluating SNPs linked to ALS prognosis have been performed in white populations, so the genetic factors influencing survival among Asian patients have not been identified, according to the scientists.
In the study, the Japanese Consortium for Amyotrophic Lateral Sclerosis Research (JaCALS) study group, which included researchers from multiple Japanese centers, performed a genome-wide association study (GWAS) to look for genetic contributors to survival among 1,076 patients with sporadic ALS in Japan.
GWAS studies examine a large number of genes — in a large number of patients — looking for relationships between SNPs and an outcome of interest, which in this case was survival.
Ultimately, they identified SNPs in three particular genes — FGF1, THSD7A, and LRP1 — that were significantly associated with survival outcomes in ALS patients.
Variants in other genes, such as CAMTA1 or IDE, that had previously been found to influence survival in white patients, were not associated with survival among the Japanese individuals.
&#8220;Genetic factors that affect the prognosis of Japanese patients with ALS may differ from those of Caucasian patients with ALS,&#8221; the researchers wrote.
To learn more about the effects of these SNPs, the researchers generated motor nerve cells from reprogrammed blood cells isolated from patients with the different variants.
<h3>Certain SNPs associated with reduced gene activity</h3>
In these motor neurons, which are the nerve cells that are damaged in ALS, they found that certain SNPs in FGF1 and THSD7A were associated with reduced gene activity, as well as reductions in cell survival.
Genetic manipulations to reduce FGF1 or THSD7A in nerve cells derived from healthy adults similarly led to cell death and reduced survival.
FGF1 is a gene involved in nerve cell growth and development. Mutations in the gene have been previously linked to a range of neurological diseases. Given that the SNP identified in this study seemed to reduce FGF1 activity and negatively affect survival, &#8220;FGF1 may have a beneficial effect on the survival of patients with ALS and may be a therapeutic target to improve prognosis,&#8221; the researchers wrote.
The potential role of THSD7A in ALS is less clear, according to the team, who noted  &#8220;further research is warranted.&#8221;
Ultimately, the scientists believe their findings will contribute to developing better therapies for ALS patients.
&#8220;Given the diversity of patients with sporadic ALS, it is necessary to develop a system of personalised medicine,&#8221; the researchers wrote.
They added that the use of patient-derived nerve cells to more closely study genetic variants identified in GWAS studies &#8220;may serve as a breakthrough model for the development of personalised medicine for patients with ALS.&#8221;

Genetic factors influencing ALS survival identified in Japanese study

ATH-1105, a treatment candidate by <a href="https://www.athira.com/">Athira Pharma</a>, significantly prolonged survival in a mouse model of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to a <a href="https://www.globenewswire.com/news-release/2023/05/11/2667327/0/en/Athira-Pharma-Reports-First-Quarter-2023-Financial-Results-and-Recent-Pipeline-and-Business-Updates.html">company update</a>.
Consistent with previous analyses, the treatment also reduced neurodegeneration, inflammation, and the toxic buildup of the TDP-43 protein in nerve cells, which resulted in significant motor and nerve function improvements.
The findings were presented in a poster at the American Academy of Neurology (AAN) Annual Meeting last month.
Athira is completing preclinical studies so it can submit an investigational new drug application to conduct in-human studies of the therapeutic candidate. The company hopes to initiate clinical studies in 2024.
“We are encouraged by the compelling preclinical evidence with ATH-1105, which demonstrates statistically significant improvements on survival and nerve and motor function in an ALS animal model,&#8221; Kevin Church, PhD, Athira&#8217;s chief scientific officer, said in a <a href="https://investors.athira.com/news-releases/news-release-details/athira-pharma-presents-new-clinical-and-preclinical-data">press release</a> announcing the presentation last month. &#8220;We are advancing IND-enabling studies with ATH-1105 and plan to begin clinical evaluation next year.&#8221;
ALS is marked by progressive neurodegeneration and inflammation. Nearly all patients exhibit abnormal clumps of the TDP-43 protein in nerve cells, which is thought to be a key driver of nerve cell damage in the disease.
ATH-1105 is an oral small molecule that activates the HGF/MET system, a signaling pathway involved in maintaining nerve cell health via its ability to counteract neurotoxicity, inflammation, and oxidative stress, a type of cell damage implicated in ALS.
A growing body of evidence indicates boosting the pathway&#8217;s activity may help treat neurodegenerative diseases like ALS.
[recommended-reading id=84040]
<h3>Prolonged survival with ATH-1105</h3>
Last year, the company presented data indicating nerve cells treated with ATH-1105 in cell cultures showed <a href="https://alsnewstoday.com/news/ath-1105-aid-nerve-health-motor-skills-als-mouse-model/">significantly better survival</a> under toxic conditions than untreated cells.
ATH-1105 was also associated with higher body weight, lower levels of inflammatory markers, preserved nerve cell health, and better motor function in a mouse model of ALS. The model featured mutations in TARDBP,  the gene responsible for producing TDP-43, leading to ALS-like symptoms and TDP-43 buildup.
In the AAN poster &#8220;<a href="https://www.athira.com/wp-content/uploads/2023/04/AAN2023_ALS_04172023.pdf">ATH-1105, a Small-Molecule Positive Modulator of Hepatocyte Growth Factor (HGF)/MET, Is Neuroprotective in a TDP-43 Mouse Model of Amyotrophic Lateral Sclerosis</a>,&#8221; researchers provided additional findings from this TDP-43 mouse model.
TDP-43 mice were treated with 20 mg/kg ATH-1105 or a placebo daily for four months to assess its effects on survival.
ATH-1105 significantly prolonged survival in the ALS model, delaying the time to a first death from 59 days in the placebo group to 101 days, results showed.
Two months of treatment also led to measures of motor function stabilizing, while untreated mice saw significant declines over time, which was consistent with previous analyses.
&#8220;Together, these behavioral data demonstrate that ATH-1105 helps to preserve balance, coordination, and muscle strength, which progressively decline in ALS mice,&#8221; Jewel Johnston, PhD, the director of in vivo pharmacology at Athira, said in the poster presentation.
The therapy was also associated with preserved muscle and nerve function, and it protected mice from nerve cell degeneration and loss of <a href="https://multiplesclerosisnewstoday.com/myelin-sheath/">myelin</a>, the fatty substance that surrounds and protects nerve cells.
Treated mice treated also had significant reductions in key inflammatory markers, as well as neurofilament light chain (NfL), a biomarker of nerve cell degeneration. The accumulation of TDP-43 in nerve cells was significantly reduced in ATH-1105-treated mice over those given the placebo.
Finally, mice given ATH-1105 saw increases in body weight that resembled those seen in healthy animals, indicating good general health, while untreated mice had consistently lower body weight.
&#8220;This study highlights the therapeutic potential of ATH-1105 in a mouse model of ALS and supports further investigation of ATH-1105 in this disease indication,&#8221; the researchers wrote.

ATH-1105 prolongs survival in mouse model of ALS

<a href="https://alsnewstoday.com/radicava-edaravone-for-als/">Radicava </a>(edaravone) significantly prolongs long-term survival for people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to an analysis of nearly 3,000 patients. It didn&#8217;t significantly slow the progression of disease symptoms, as assessed by scores on the ALS Functional Rating Scale-Revised (ALSFRS-R), however.
The results were presented at last week&#8217;s American Academy of Neurology (AAN) 2023 annual meeting in the poster, “<a href="https://www.aan.com/MSA/Public/Events/AbstractDetails/54324">Survival in Amyotrophic Lateral Sclerosis Patients Treated with Edaravone &#8211; a Pooled Analysis of 2845 Patients</a>.”
Radicava is an approved <a href="https://alsnewstoday.com/als-treatment/">treatment for ALS</a> that&#8217;s thought to reduce oxidative stress — a type of cell damage that plays a major role in driving the disease. It&#8217;s available as an intravenous (into the vein) infusion or in a newer oral formulation called Radicava ORS. Both are sold by <a href="https://www.mt-pharma.co.jp/e/">Mitsubishi Tanabe Pharma</a>, which was not involved with this analysis.
Despite Radicava&#8217;s approval in <a href="https://alsnewstoday.com/news/fda-approves-radicava-first-new-als-therapy-in-20-years-and-cause-for-hope/">the U.S.</a>, <a href="https://alsnewstoday.com/news-posts/2018/10/09/radicava-now-approved-to-treat-als-patients-in-canada/">Canada</a>, Switzerland, and a number of other countries, evidence on its effectiveness <a href="https://alsnewstoday.com/news/radicava-suggests-more-real-world-data-needed-to-determine-efficacy-of-edaravone-in-als/">isn&#8217;t settled</a>, leading scientists at Al-Azhar University, Egypt to analyze pooled data from 12 previously published studies to assess its effect on disease progression and survival.
[recommended-reading id=82936]
The analysis included data on 2,845 patients, among whom, 1,141 were treated with Radicava, sometimes in combination with the older ALS therapy riluzole (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek </a>and other formulations). The other 1,704 were given a control treatment, either a placebo or riluzole alone.
After 18 months (1.5 years) of follow-up, the chances of survival were significantly higher, by about 13%, for patients given Radicava. Later analyses also showed a significant survival benefit with Radicava — by 22% at 24 months (two years) and by 17% at 30 months (2.5 years).
At earlier timepoints (six or 12 months), survival tended to be slightly better in the Radicava group, but the difference with the control group was not statistically significant. That means it&#8217;s mathematically plausible the difference could be due to random chance.
Rates of symptom progression, as measured by the change in ALSFRS-R scores, tended to slightly favor Radicava, but weren&#8217;t significantly different from controls. Rates of side effects and other safety issues were comparable in the two groups, leading the scientists to conclude that Radicava “improves long-term survival with no effect on the ALSFRS-R score&#8221; and with a similar rate of adverse events between the groups.

Tag: ALS survival