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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

SOL-257, an experimental one-time gene therapy, was well tolerated and significantly improved disease outcomes in two distinct mouse models of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
Developed by <a href="https://www.sola-bio.com/">Sola Biosciences</a>, SOL-257 is designed to clear the toxic TDP-43 protein that accumulates and forms clumps in ALS nerve cells, contributing to disease progression. The therapy significantly extended survival in one model, and improved muscle strength and motor function in the other.
Data from the preclinical studies were presented this week at Neuroscience 2023 in Washington, D.C.
“Our findings underscore SOL-257 as a highly promising translational therapy for ALS,” Akinori Hishiya, PhD, chief scientific officer at Sola, said in a <a href="https://www.businesswire.com/news/home/20231109597814/en/SOLA-Biosciences-Presents-Preclinical-Proof-of-Concept-Data-for-SOL-257-a-Gene-Therapy-Targeting-Misfolded-TDP-43-in-ALS-at-Neuroscience-2023-and-ALS-One-Symposium">company press release</a>. “Demonstrating efficacy in two distinct genetic mouse models of ALS supports our confidence that by targeting misfolded TDP-43, SOL-257 holds the potential to treat a vast majority of ALS patients.&#8221;
Abnormally folded TDP-43 is a common feature in both <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic</a> and <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial</a> types of ALS. It&#8217;s observed in about 97% of all ALS cases.
TDP-43 is normally found in the nucleus, where it regulates the first step of protein production from a gene. In ALS, the protein can take an abnormal shape, one more prone to accumulate in the cytoplasm and form toxic clumps, leading to cell damage and death.
[recommended-reading id=86261]
<h3>What does SOL-257 do?</h3>
SOL-257 is designed to target the misfolded TDP-43 and either promote its proper folding or facilitate its degradation, which ishould reduce nerve cell damage and slow disease progression.
It was developed with Sola&#8217;s JUMP70 technology platform, which promotes the production of JUMP70, a protein that connects the misfolded proteins to the patient’s own HSP70 chaperones. Chaperones are proteins that help other proteins fold correctly or direct misfolded ones to be degraded.
The company is developing JUMP70-based therapies for <a href="https://www.sola-bio.com/pipeline-2/">a number of conditions</a> marked by abnormal protein folding and aggregation, including <a href="https://huntingtonsdiseasenews.com/what-is-huntingtons-disease">Huntington&#8217;s</a>, <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer&#8217;s</a>, and <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson&#8217;s diseases</a>, as well as <a href="https://cysticfibrosisnewstoday.com/cystic-fibrosis-overview/">cystic fibrosis</a>.
The therapies use a modified and harmless adeno-associated virus (AAV) to deliver the JUMP70 gene to cells. The resulting two-part protein is specific to both HSP70 and to each disease-causing misfolded protein.
With SOL-257, the protein is designed to bring together HSP70 and the misfolded TDP-43 proteins, while leaving functional TDP-43 alone to do its job.
In an earlier study, researchers showed <a href="https://alsnewstoday.com/news/als-gene-therapy-sol-257-targeting-tdp-43-shows-promise-mouse-model/">SOL-257 significantly extended the survival</a> of mice genetically modified to allow the controlled production of misfolded TDP-43.
<h3>SOL-257 effects on two mouse models of ALS</h3>
Sola showed additional data from that model along with another mouse model in which animals carried mutations in the C9ORF72 gene, whose defects are the most common <a href="https://alsnewstoday.com/als-and-genetics/">genetic cause of ALS</a>. These mutations are thought to trigger <a href="https://www.nature.com/articles/s41598-022-08724-w#:~:text=TDP%2D43%20pathology%20correlates%20well,this%20causes%20neuronal%20death17.">TDP-43&#8217;s movement out of the nucleus</a>, where it misfolds.
&#8220;I&#8217;m thrilled to announce SOL-257, a breakthrough gene therapy poised to tackle ALS by targeting TDP-43 pathology. Our compelling preclinical data highlights a significant step toward harnessing the body&#8217;s cellular defenses,&#8221; said Keizo Koya, PhD, Sola&#8217;s CEO. &#8220;Committed to excellence, we are advancing this promising therapy, striving to bring hope to the ALS community.&#8221;
In the first model, researchers showed that pretreatment with SOL-257 before abnormal TDP-43 production was induced suppressed the toxic clumps and significantly prolonged survival. All untreated animals died in the first eight weeks, but some treated ones lived for up to 17 weeks.
The intracerebroventricular injection, that is, one directly into the brain, that was used to deliver the viral vector carrying JUMP70 was well tolerated in mice, the researchers said.
To develop the C9ORF72 mouse model, mice were injected into the brain with a C9ORF72 gene carrying 149 repetitions of six specific DNA building blocks (GGGGCC) in its genetic sequence. In these animals, toxic TDP-43 clumps were found to build up over time and cause death.
The animals were treated with SOL-257 after letting the disease progress for three months. At this more advanced stage, the gene therapy also significantly reduced toxic TDP-43 clumps in the brain.
Mice were subjected to an open-field test, which uses the distance walked over a given time as a proxy to assess hyperactivity, a sign of neurodegeneration. Hyperactivity steadily declined between six and nine months after the SOL-257 injection, but increased in untreated mice.
Mice also underwent a wire hang test, which measures how long it takes to fall off a wire, to assess motor function and muscle strength. At nine months, untreated mice fell off significantly faster than SOL-257-treated mice.
The data supports the continued development of SOL-257 to treat ALS.
&#8220;The robust &#8230; proof-of-concept data makes me excited to complete the preclinical studies necessary to take SOL-257 into ALS clinical trials,&#8221; Gerry Cox, chief medical officer at Sola, said in an email to ALS News Today. &#8220;The unmet medical need in ALS remains high, despite the current therapeutic landscape, and the prospect of a broadly applicable, one-time therapy brings new hope to the ALS community.&#8221;

SOL-257 gene therapy improves outcomes in 2 ALS mouse models

<a href="https://www.arunabio.com/">Aruna Bio</a>&#8216;s investigational therapy <a href="https://www.arunabio.com/ab126intro">AB126</a> significantly eased inflammation in the spinal cord and extended survival in a mouse model of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), the company announced.
The therapy, which is expected to treat several other neurodegenerative and neuroinflammatory disorders, also significantly reduced the levels of neurofilament light chain (NfL), a biomarker of nerve cell damage.
“We are encouraged by our growing dataset demonstrating the potential of AB126 in its native form to address both acute and chronic neurological indications, including ALS,&#8221; Stephen From, CEO at Aruna Bio, said in a <a href="https://www.globenewswire.com/news-release/2023/09/07/2739775/0/en/Aruna-Bio-Announces-Preclinical-Results-from-Pilot-Study-Evaluating-AB126-for-the-Treatment-of-Amyotrophic-Lateral-Sclerosis.html">company press release</a>. “We look forward to building upon this pilot data and further exploring the therapeutic potential of AB126 for the treatment of ALS and expanding our AB126 platform to chronic [central nervous system] indications.&#8221;
ALS is caused by the progressive loss of motor neurons, the nerve cells that control voluntary movements, leading to the loss of the ability to control muscle movements. Inflammation in the brain and spinal cord is common with ALS and may contribute to the disease’s progression by aggravating cell death.
[recommended-reading id=85595]
<h3>What is AB126?</h3>
AB126 is an experimental therapy made of exosomes — small packets released by virtually all cells that contain proteins and other molecules important for cellular communication. Exosomes can transport cargo, such as therapeutic agents, to cells of interest, but most exosome-based therapies developed to date lack specificity to the nervous system.
The exosomes in AB126 are derived from neural stem cells and contain specific proteins at their surface that are crucial to cross the blood-brain barrier (BBB), a semi-permeable layer that regulates the entry of molecules from the blood into the brain. Crossing this barrier is often a challenge when developing therapies for neurological diseases.
Preclinical research has shown that AB126 can cross the BBB and accumulate in brain regions involved in motor movement, cognition, and procedural learning, which involves repeating a task until the activity doesn&#8217;t require conscious awareness, essential for developing motor and cognitive skills.
Once in those regions, the therapy should bring down inflammation by reducing levels of pro-inflammatory immune cells while increasing the anti-inflammatory ones and promote nerve cell protection by reducing oxidative stress — a type of cell damage — and stimulating nerve cell survival. It&#8217;s also designed to boost the proliferation of nerve stem cells to increase nerve cell growth and repair.
Researchers have tested the exosome-based therapy in a mouse model of ALS carrying mutations in the SOD1 gene — associated with up to 20% of <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a> cases and up to 2% of <a href="https://alsnewstoday.com/sporadic-als/">sporadic cases</a>. The findings suggest the treatment is working as intended, reducing inflammation and markers of nerve damage, and leading to an increase in the mice&#8217;s survival.
&#8220;In the current pilot study, we observed prolonged survival in AB126 treated mice due to significantly reduced inflammatory mediators in the spinal cord, as well as significant reductions in serum neurofilament light chain, an important biomarker of neurodegeneration,&#8221; From said.
The therapy can treat a range of neurodegenerative conditions with significant unmet medical needs, according to the company. The neural exosome platform can also serve as a system to deliver other therapeutic molecules into the brain.

Aruna Bio’s AB126 eased inflammation in ALS mouse model

Mutations in the KIF5A gene, associated with some cases of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), may lead to impairments in motor unit recovery that are exacerbated with age, according to a recent study.
Motor units — nerve cells involved in movement and the muscle fibers they interact with — showed poor recovery after injury in younger mice with KIF5A mutations. With age, motor unit maintenance and repair saw even further declines.
Altogether, the scientists believe that motor unit loss with age — a natural process — may be accelerated by KIF5A mutations in ALS patients.
“Our findings could lead to a better understanding of how ALS develops in people who have this mutation,” Stephen Kolb, MD, PhD, professor of neurology and biological chemistry and pharmacology at The Ohio State University and the study&#8217;s principal investigator, said in a <a href="https://wexnermedical.osu.edu/mediaroom/pressreleaselisting/study-examines-the-possible-role-of-kif5a-gene-in-als">university press release</a>.
The study, &#8220;<a href="https://www.sciencedirect.com/science/article/pii/S0969996123001626?via%3Dihub">Impaired motor unit recovery and maintenance in a knock-in mouse model of ALS-associated Kif5a variant</a>,&#8221; was published in <a href="https://www.sciencedirect.com/journal/neurobiology-of-disease">Neurobiology of Disease</a>.
KIF5A is a gene encoding the production of KIF5A, a protein that facilitates the transport of critical cellular cargo along nerve cell projections, or axons.
Large-scale <a href="https://alsnewstoday.com/news/large-scale-international-study-links-kif5a-to-als/">genetic studies</a> have identified that mutations in KIF5A are associated with ALS, a neurodegenerative disease marked by the progressive loss of motor nerve cells. These mutations tend to impact the region of the protein that binds to its cargo, impairing axonal transport, and also make the protein more prone to forming clumps.
[recommended-reading id=84545]
<h3>Mouse model with KIF5A variant tested</h3>
Now, the U.S. researchers aimed to learn more about the mechanisms by which these mutations might contribute to development of the neurodegenerative disease. They genetically engineered a new mouse model, which housed a previously identified ALS-associated mutation, or variant, in KIF5A.
The scientists found that one-year-old mice, an age corresponding to adulthood, with either one or two copies of the variant showed normal survival rates, weight, and motor function relative to control mice without the variant.
However, the engineered animals exhibited signs of impaired motor unit recovery following a nerve injury.
Normally, motor units in mice at that age will be lost in response to a nerve injury, but will recover. Consistently, healthy mice had completely restored motor units four months after injury — a significant difference from mice with the KIF5A mutation, which still had diminished motor units at that time.
After injury, mutant mice exhibited reduced nerve cell size and reorganization of the neuromuscular junction, the site at which nerve and muscle cells meet to communicate.
Such an incomplete recovery, &#8220;suggests a KIF5A-dependent process may be required for full recovery,&#8221; the researchers wrote.
The researchers also found that, as KIF5A mutant mice aged, they began to have reductions in motor units independent of injury, indicating decreased maintenance and resilience. Older animals also have even more incomplete recovery after injury than they did at a younger age.
<h3>KIF5A mutations, aging process indicated as drivers of neurodegeneration</h3>
Altogether, the findings indicate that an interaction between KIF5A mutations and the aging process may be responsible for driving neurodegeneration in ALS patients.
“Humans who have ALS-associated KIF5A variants appear healthy for decades before the onset of symptoms,” Kolb noted. “Our findings suggest that the onset of disease in these individuals might result from the accumulation of stressors such as nerve damage and changes due to aging, resulting in a failure by axons to repair the damage and maintain motor units.”
While the scientists believe their new mouse model is representative of the human ALS mutation — and could thus be an important research tool — they noted the mice don&#8217;t exhibit the same overt nerve cell degeneration that patients do.
According to Kolb, that issue isn&#8217;t unique to this mouse model, and is &#8220;a perennial challenge in ALS research.&#8221;
Still, &#8220;future work in these mice is warranted,&#8221; the researchers wrote, noting that such studies should test potential therapeutic approaches for targeting KIF5A in ALS.

KIF5A mutations, age may drive neurodegeneration in ALS: 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.

Tag: ALS mouse model

Blocking MAP4Ks proteins extends survival in ALS mouse model

SOL-257 gene therapy improves outcomes in 2 ALS mouse models

Aruna Bio’s AB126 eased inflammation in ALS mouse model

KIF5A mutations, age may drive neurodegeneration in ALS: Study

ATH-1105 prolongs survival in mouse model of ALS