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Genetic and clinical factors that can influence how <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) progresses were identified in a recent analysis of data from <a href="https://www.precisionals.ie/">PRECISION-ALS</a>, a large European research project.
Consistent with known risk factors for <a href="https://alsnewstoday.com/stages-of-als/">ALS progression</a>, C9ORF72 genetic mutations, <a href="https://alsnewstoday.com/forms-of-als/#Clinical_onset">bulbar-onset disease</a>, and faster functional declines were linked to a shorter survival time, as was older age at disease onset.
However, differences were seen among the project&#8217;s centers in the time it took for interventions like feeding tube placement (gastrostomy) or noninvasive ventilation to be needed, and the reasons require further study, according to the scientists.
Harry McDonough, a clinical researcher at the University of Sheffield in England, and Alejandro Caravaca Puchades, a clinician at the Hospital of Bellvitge in Spain, discussed findings in the oral presentation &#8220;<a href="https://www.tandfonline.com/doi/pdf/10.1080/21678421.2023.2260189" rel="nofollow">Mapping the natural history of ALS in Europe</a>,&#8221; given at the 34th International Symposium on ALS/MND held last week in Basel, Switzerland, and virtually. It was supported by <a href="https://www.biogen.com/" rel="nofollow">Biogen</a>, which also supports the PRECISION-ALS study.
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<h3>Likely ALS progression via factors like speed of diagnosis, disease type at onset</h3>
PRECISION-ALS, launched last year, is a European collaboration with the broad goal of <a href="https://alsnewstoday.com/news/e10m-european-collaborative-project-hopes-use-ai-als-precision-medicine/">better understanding the natural history of ALS</a> and the factors that influence differences in <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptoms</a> and progression among patients.
&#8220;We know that ALS is a condition with lots of variation between individuals,&#8221; McDonough said in the presentation. &#8220;By studying the natural history we hope to be able to understand the factors that impact this variation, and hopefully, in turn, that helps us clinically to improve outcomes for our patients &#8230; [and] hopefully directing them towards trials that are most likely to benefit them.&#8221;
Nine clinical sites across eight countries are involved in the project, which brings together clinical researchers, data scientists, and industry partners.
The recent analysis concerned PRECISION-ALS&#8217; extant data study, meaning it was an analysis of previously collected and existing clinical data. All nine sites contributed information from patients in their individual databases, which were combined for a population-based assessment of ALS progression from symptom onset, to diagnosis, clinical interventions, and death.
Data covered 21,571 ALS patients, mostly male (57.2%). Across the entire group, the median age at symptom onset was 63.9, with a delay of about one year between symptom onset and an <a href="https://alsnewstoday.com/als-diagnosis/">ALS diagnosis</a>.
Disease onset tended to be earlier in men, patients with spinal-onset ALS — where symptoms of limb weakness are the first to emerge — and those with mutations in the ALS-associated genes FUS or SOD1.
Individuals with bulbar-onset ALS — where symptoms initially affect muscles in the head and neck needed for speech, swallowing, and breathing — and those with mutations in the C9ORF72 gene experienced a shorter diagnostic delay.
An earlier symptom onset tended to link with a slower functional decline — indicated by a less than 0.3 point monthly decline in a patient&#8217;s ALS Functional Rating Scale-Revised (ALSFRS-R) scores — compared with patients with intermediate or quickly progressing disease. In turn, a faster functional decline, defined as a monthly change in ALSFRS-R scores of more than 1.06, was associated with a shorter diagnostic delay.
<h3>Earlier need for gastrostomy seen with bulbar onset, C9ORF7 mutations</h3>
Overall median survival among these patients was 2.59 years. Bulbar-onset ALS, fast disease progression, older age at onset (ages 70 and older), and FUS and C9ORF7 mutations all were seen as independent predictors of poorer survival in a final analysis. Better lung function and a slower arrival at a definitive ALS diagnosis linked with longer survival times.
The time to reach certain clinical interventions — namely, gastrostomy and noninvasive ventilation — also were influenced by these factors, with bulbar-onset ALS and C9ORF7 mutations linked to an earlier need for a gastrostomy.
In adjusted statistical analyses, the start of noninvasive ventilation was significantly associated with respiratory-onset ALS and male sex, whereas better lung function and a longer diagnostic delay again were seen to protect against a need for such ventilation.
Notably, significant differences among clinical sites were seen in the time from ALS diagnosis to a gastrostomy or noninvasive ventilation, as well as in patients&#8217; average lung function when ventilation started.
Analyses taking these factors into account indicated that centers with less ready use of noninvasive ventilation had poorer survival outcomes, but these differences were not statistically significant.
&#8220;It&#8217;s important to note that given the significant amount of missing data that we have, it is difficult to draw conclusions on this alone,&#8221; McDonough said.
Currently, it&#8217;s not clear whether differences among clinical sites are &#8220;due to differences in clinical practice, differences in the cohorts between these clinical centers, or data collection or a combination of these factors,&#8221; the scientists noted.
PRECISION-ALS is working on a prospective study, where data will be collected across its nine sites using a specific data platform, to help improve uniformity.

ALS/MND 2023: European study spotting factors that affect progression

Colchicine, an anti-inflammatory medication used to treat gout, was safe, but did not significantly slow the progression of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in a small Phase 2 clinical trial.
While some clinical measures suggested a possible benefit of a low dose of colchicine in slowing disease progression and extending survival, most efficacy and biomarker outcomes failed to reach statistical significance. Researchers believe more clinical trials will be needed to establish the possible efficacy of the medication in ALS and to understand responses to different doses of colchicine.
&#8220;The absence of statistically significant results in most outcome measures &#8230; does not indicate a clinical efficacy of colchicine in this context,&#8221; Jessica Mandrioli, MD, of the University of Modena and Reggio Emilia in Italy, said in an oral presentation at the 34th International Symposium on ALS/MND, being held Dec. 6-8 in Basel, Switzerland, and virtually.
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&#8220;In this moment, we have to deepen the knowledge of this drug before going on,&#8221; Mandrioli added.
The presentation was titled &#8220;<a href="https://www.tandfonline.com/doi/pdf/10.1080/21678421.2023.2260189">Safety profile, biological and clinical effects of colchicine in ALS: results from a phase 2 multicenter, randomized, controlled, double-blind clinical trial.</a>&#8221; (C61 in the symposium abstract book.)
In nearly all cases of ALS, a misfolded version of the TDP-43 protein toxically accumulates in nerve cells, driving cell damage and death. That&#8217;s why therapeutic strategies to target this abnormal protein — including ones that would enable its proper folding or clear it altogether — are of interest for treating ALS.
Colchicine is an approved medication — sold in the U.S. under distinct brand names and generics —used to prevent and treat gout attacks, to treat a rare condition known as familial Mediterranean fever, and to lower the risk of cardiovascular conditions. It works to ease inflammation and reduce the buildup of uric acid in the joints, which causes the painful symptoms of gout.
Among its effects, colchicine induces the activity of certain proteins involved in autophagy, a cellular process by which old, damaged, or faulty proteins are engulfed and recycled. Some evidence suggests that <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694295/#:~:text=Increasing%20evidence%20suggests%20that%20ALS,and%20Alzheimer%27s%20diseases%20%5B85%5D.">a failure of the autophagy process</a> could contribute to the accumulation of misfolded proteins in ALS and related conditions.
Previously, the scientists found that colchicine <a href="https://www.nature.com/articles/srep22827">boosted the activity of HSPB8</a>, an autophagy protein that&#8217;s been shown to promote the removal of misfolded proteins implicated in ALS.
As such, the researchers are exploring it as a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549675/#R13">possible therapeutic option</a> for enhancing autophagy-mediated clearance of TDP-43. The scientists also believe the medication&#8217;s anti-inflammatory effects could be of benefit in ALS.
<h3>Reasons for choosing colchicine</h3>
&#8220;We chose to study colchicine in ALS because colchicine is an inexpensive drug and immediately available and it has two mechanisms of action that can be useful for ALS,&#8221; Mandrioli said.
The <a href="https://clinicaltrials.gov/study/NCT03693781?cond=Amyotrophic%20Lateral%20Sclerosis&amp;term=Colchicine&amp;rank=1">Phase 2 Co-ALS clinical trial (NCT03693781)</a> was designed to evaluate the effects of oral colchicine treatment in ALS patients.
A total of 54 participants, ages 18-80, were enrolled across several sites in Italy and assigned randomly to receive colchicine at a dose of 0.01 or 0.005 mg/kg, or a placebo. Treatment was taken orally once a day for 30 weeks (about seven months), and patients were followed for up to week 54, or about one year. All could continue to receive a stable dose of riluzole (i.e., <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a>, <a href="https://alsnewstoday.com/tiglutik-for-als/">Tiglutek</a>) throughout the trial.
<h3>Evaluating ALS progression was main goal of trial</h3>
The trial&#8217;s main goal was to evaluate changes in disability progression, as assessed by the ALS Functional Rating Scale-Revised (ALSFRS-R), where a lower score indicates greater disability. Specifically, researchers were looking for the proportion of patients who achieved a positive treatment response, or no more than a 4-point decline in ALSFRS-R scores after 30 weeks.
Among patients treated with colchicine at its 0.005 mg/kg dose, about a third (33.3%) achieved this endpoint, compared compared with 13.3% who achieved that in the placebo group. This indicated a slower disability progression with this colchicine dose, but the difference did not reach statistical significance. Among those given colchicine at its higher dose, 7.1% achieved a positive response.
While positive responses were not significantly more frequent with either colchicine dose, monthly ALSFRS-R scores declined significantly slower for those receiving low dose colchicine than those on a placebo, and this significant difference was maintained throughout the post-treatment follow-up.
A trend toward prolonged survival and preserved respiratory function for patients on the lower dose also was observed, although not statistically significant. Secondary outcomes related to biomarkers of neurodegeneration, inflammation, or autophagy, were generally not different between groups.
Blood levels of a toxic version of TDP-43 increased in the placebo group, and generally decreased with colchicine, with a significant difference observed between the placebo and the combined colchicine groups at 30 weeks.
<h3>Interpret results cautiously, researcher says</h3>
&#8220;I would like to underline that the numbers are very, very small, so we have to be very cautious in interpretation,&#8221; Mandrioli noted.
Rates of side effects were similar between groups. Gastrointestinal side effects were more common in patients receiving colchicine, consistent with its known safety profile.
&#8220;Colchicine treatment was safe, but further trials are necessary to evaluate efficacy of this commercial drug in ALS,&#8221; the researchers concluded in the presentation&#8217;s abstract.

ALS/MND 2023: Gout med fails to show efficacy in small trial

Eating foods with a higher glycemic index — those more likely to quickly raise a person&#8217;s blood sugar — is associated with slower functional declines and prolonged survival among people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to a recent analysis.
Foods with high amounts of sugar include white bread and rice, while foods such as oatmeal, lentils, or kidney beans have a low glycemic index, resulting in lower blood sugar peaks but sustained sugar levels for longer periods.
Ikjae Lee, MD, of Columbia University in New York, presented the data in an oral presentation, &#8220;<a href="https://www.tandfonline.com/doi/pdf/10.1080/21678421.2023.2260189">Higher Glycemic Index and Glycemic Load Diet is associated with Slower Disease Progression in Amyotrophic Lateral Sclerosis,</a>&#8221; at the 34th International Symposium on ALS/MND, being held Dec. 6-8 in Basel, Switzerland. The findings also were <a href="https://pubmed.ncbi.nlm.nih.gov/37975189/#:~:text=Results%3A%20Baseline%20higher%20glycemic%20index,%2C%20p%3D0.04)%20respectively.">published recently in a study</a> in the <a href="https://onlinelibrary.wiley.com/journal/15318249?utm_source=google&amp;utm_medium=paidsearch&amp;utm_campaign=R3MR425&amp;utm_content=Medicine&amp;gad_source=1&amp;gclid=CjwKCAiA98WrBhAYEiwA2WvhOuvBbr3b0WyrogdMkACCEF3HzvrQh8t1JWaQRABVahPo0bAMeo3gzxoCKh0QAvD_BwE">Annals of Neurology</a>.
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&#8220;Dietary [glycemic index] is associated with functional decline and survival in ALS,&#8221; Lee said in the presentation, noting a need for more studies to confirm this relationship.
In ALS, degeneration of the nerve cells involved in muscle control causes weakness in the muscles needed to walk and speak, but also those needed to eat and drink. <a href="https://alsnewstoday.com/als-symptoms/difficulty-swallowing/">Difficulty swallowing</a> food can lead to malnutrition and weight loss, which have been <a href="https://www.sciencedirect.com/science/article/pii/S026156142030248X">linked to a worse prognosis</a> among ALS patients.
As such, an <a href="https://alsnewstoday.com/non-drug-therapies/diet-and-supplements/">appropriate diet</a> is thought to be important for helping patients maintain their health for as long as possible.
Studies have suggested that a diet high in calories could help to slow the neurodegenerative disease and help patients live longer, although most studies have been small and the <a href="https://alsnewstoday.com/news/more-evidence-needed-support-use-high-calorie-diet-als/">findings sometimes conflicting</a>.
It hasn&#8217;t been established whether there is a nutritional intervention that might be of benefit for a broad ALS population, Lee noted. Moreover, it is not known which specific dietary components (macronutrients) — such as carbohydrates, fats, and proteins — might be most important for influencing <a href="https://alsnewstoday.com/stages-of-als/">ALS progression</a>, and if their effects on blood sugar play a role.
<h3>The ALS Multicenter Cohort Study of Oxidative Stress</h3>
In the study, researchers examined the possible relationship between dietary components and ALS progression and survival among a group of 304 ALS patients in the U.S. involved in the ALS Multicenter Cohort Study of Oxidative Stress (COSMOS).
Participants — 59% men and 41% women — had a mean age of 61.6 and had experienced their first <a href="https://alsnewstoday.com/als-symptoms/">ALS symptoms</a> less than 1.5 years prior to enrollment.
Dietary intake was assessed with a food frequency questionnaire at the study&#8217;s start (baseline). Disease progression was monitored using the ALS Functional Rating Scale — Revised (ALSFRS-R).
Initial analyses adjusting for age and sex indicated that higher caloric intake and greater fat consumption were linked to slower functional declines. But these findings failed to reach statistical significance in final analyses where the team also accounted for clinical factors such as disease duration, disability levels, respiratory function, and initial symptoms.
However, &#8220;this is an observational study,&#8221; Lee noted. &#8220;We would not conclude that there is no association &#8230; just with our data.&#8221;
<h3>Measuring glycemic index and glycemic load</h3>
Meanwhile, the glycemic index (GI) and glycemic load (GL) of participants&#8217; diets were associated significantly with ALS progression at a three-month follow-up in adjusted analyses.
GI is a measure of how quickly a carbohydrate-containing food will increase a person&#8217;s blood sugar (glucose). Carbohydrates are the nutrients that are broken down into glucose to produce energy. In turn, GL takes into account the glycemic index and the total number of carbohydrates in a serving of that food.
For each one-unit increase in GI, reflecting a faster blood sugar spike, patients saw a 0.13-point slower ALSFRS-R decline. The 25% of participants with the lowest GI also experienced significantly faster ALSFRS-R score progression relative to the other participants.
Likewise, for every unit increase in GL, ALSFRS-R declines were 0.01-points slower, and the 25% of patients with the lowest GL also experienced a significantly faster decline in ALSFRS-R scores than the remaining participants.
Higher GI also was tied significantly to slower ALS progression after six months, a finding the scientists validated in another group of ALS patients.
Finally, survival analyses indicated that the 25% of patients with the lowest GI had the shortest survival relative to the other patients, &#8220;about eight months shorter than the other group,&#8221; Lee said. In final adjusted analyses, a higher GI also was associated with longer survival without the need for a tracheostomy, or breathing tube placement.
<h3>Preventing protein misfolding may slow ALS progression</h3>
Mechanistically, the scientist believes a higher glucose-based diet could help slow disease progression by preventing protein misfolding. Misfolded proteins are known to toxically accumulate in the patients&#8217; brains, where they&#8217;re implicated in ALS progression.
Lee emphasized, however, that the observed relationship between GI and disease progression &#8220;does not confirm causation.&#8221;
&#8220;Now, that being said, I really believe in our data,&#8221; the researcher added, noting that when looking at individual high-carb food items, such as French fries, spaghetti, or macaroni and cheese, greater intake of each of these foods also appeared linked to slower functional declines.
To confirm these relationships, &#8220;ultimately we need an interventional trial focusing on providing a higher GI diet or supplement,&#8221; Lee concluded.

ALS/MND 2023: Blood sugar-boosting diet may slow ALS progression

<a href="https://www.amylyx.com/">Amylyx Pharmaceuticals</a> is developing AMX0114, a new experimental treatment for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) that&#8217;s designed to promote the health of nerve fibers by lowering levels of calpain-2, a protein.
AMX0114 is being tested in preclinical studies with the aim of supporting an investigational new drug application (IND), a formal request to test it in people. If all goes well, AMX0114 could enter clinical trials as early as 2024.
A team led by scientists at Amylyx presented an update on the therapy&#8217;s development at the 34th international symposium on ALS and motor neuron disease (MND), Dec. 6-8, in Basel, Switzerland and online. Their poster was titled, &#8220;<a href="https://www.amylyx.com/document/neals-aso-calpain-poster.pdf">Update on AMX0114: An Antisense Oligonucleotide Targeting Calpain-2, a Critical Effector of Axonal Degeneration</a>.&#8221;
Amylyx is also the maker of <a href="https://www.relyvrio.com/">Relyvrio</a> (sodium phenylbutyrate and taurursodiol), formerly known as AMX0035. The oral therapy is <a href="https://alsnewstoday.com/news/relyvrio-amx0035-approved-us-als-treatment/">approved to treat ALS</a> in the U.S. and <a href="https://alsnewstoday.com/news/amx0035-oral-als-therapy-called-albrioza-approved-canada/">Canada</a>, where it&#8217;s sold as Albrioza.
&#8220;AMX0114 is intended to potentially complement AMX0035. We believe that it is going to take a combination approach, targeting multiple cellular pathways implicated in disease pathogenesis [disease development], to find a cure for ALS,&#8221; Evan Mizerak, lead of preclinical research at Amylyx Pharmaceuticals, said in an email to ALS News Today.
ALS is marked by the progressive death of motor neurons, the specialized nerve cells that control voluntary movement. While the precise <a href="https://alsnewstoday.com/causes-of-als/">causes of ALS</a> are not fully understood, its progression involves the degeneration of the long, wire-like extensions, called axons, that nerve cells use to send electrical signals. Reducing axonal degeneration may slow the <a href="https://alsnewstoday.com/stages-of-als/">disease&#8217;s progression</a>.
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<h3>Reducing calpain-2 levels</h3>
Calpain-2 is a protease, a protein that&#8217;s able to chop up and destroy certain other proteins. It plays an active role in the degeneration of axons, and experiments in animal models and nerve tissue from deceased patients indicate its activity is high in ALS.
&#8220;Calpain-2 activation has been shown in the scientific literature to be a key executioner of axonal degeneration (also known as Wallerian degeneration), a process that has been increasingly recognized as a key early contributor to the pathogenesis and clinical presentation of ALS and other neurodegenerative diseases,&#8221; said Mizerak, an author on the poster presentation.
AMX0114, which belongs to a class of medications called antisense oligonucleotides (ASOs), is designed to reduce calpain-2 levels by interfering with its production in cells. Reducing the protein is expected to check axonal degeneration.
<a href="https://www.amylyx.com/document/development-of-aso-targeting-calpain-2.pdf">Data presented last year</a> were consistent with this idea and showed AMX0114 decreased the degeneration of nerve fibers in cell experiments where nerve cells were exposed to toxic chemicals.
<h3>AMX0114 chosen as best potential ASO treatment</h3>
ASO treatments like AMX0114 bind to and destroy messenger RNA (mRNA), an intermediary molecule that&#8217;s produced as part of the process of making new proteins in cells. AMX0114 targets mRNA from the CAPN2 gene, which provides instructions for making calpain-2.
At the ALS/MND symposium, researchers shared data on how AMX0114 was selected as a therapeutic candidate after dozens of ASO-based therapies designed to reduce calpain-2 production were tested. AMX0114 showed the best potential, reducing CAPN2 mRNA levels by 72%, nearly twice as much as the next best candidate, without any added toxicity to nerve cells.
While the greatest reduction in CAPN2 mRNA levels was observed about two days after treatment with AMX0114 (a 94% reduction), the effects were long-lived, with mRNA levels remaining 77% lower than normal three weeks after the therapy was withdrawn.
The therapy&#8217;s impact on calpain-2 levels took longer to become evident, with the protein reaching its lowest levels (51% lower than normal) two weeks after treatment. Levels then remained stable throughout the study, up to day 21.
&#8220;The extent of knockdown conferred by AMX0114 exhibits little decrease over time, suggesting a durable effect,&#8221; wrote the researchers who noted the data will help determine the therapy&#8217;s dose in living animal studies.
&#8220;AMX0114 is currently in investigational new drug (IND)-enabling studies, potentially allowing for initiation of a first-in-human study during 2024,&#8221; Mizerak said.

Tag: ALS/MND

ALS/MND 2023: European study spotting factors that affect progression

ALS/MND 2023: Gout med fails to show efficacy in small trial

ALS/MND 2023: Blood sugar-boosting diet may slow ALS progression

ALS/MND 2023: AMX0114 may enter clinical testing next year