Biogen, Roche, Takeda, and Vertex Pharmaceuticals have exited the AAV capsid field. Meanwhile, Pfizer has completely abandoned all work in gene therapy.

This is very unfortunate for the neurodegenerative disease field, where many familial cases could, in theory, be cured with such technologies.

Many gene therapies have received regulatory approval. Most of these approaches use adeno-associated viruses (AAVs) and lentiviruses for gene delivery, in vivo and ex vivo, respectively.

The scientific foundation is solid (we understand how to design vectors and deliver genetic payloads), but industrialization faces many bottlenecks. Manufacturing costs per patient remain very high—hundreds of thousands of dollars.

Since gene therapies primarily target rare diseases, the patient populations are small. Companies cannot rely solely on scaling to lower costs. After the initial cohort is treated, the market shrinks dramatically.

While academia can demonstrate that gene therapies work on a small scale, industry needs to prove that these therapies are reliable, scalable, safe, and financially sustainable—much higher standards. This explains why many promising academic results lead to companies retreating when confronted with the challenges of large-scale production and commercialization.

Alternatives such as mRNA, antisense therapies (ASO), and protein drugs offer different balances of feasibility, durability, safety, and economic viability.

Huntington’s Disease and C9orf72 ALS: Shared Mechanisms and Therapeutic Hopes

Approximately 70,000 people have been diagnosed with Huntington’s disease (HD) in the U.S. and Europe, with hundreds of thousands more at risk of inheriting the condition. Despite the clear genetic cause of HD, there are currently no approved therapies that delay onset or slow progression.

Both Huntington's disease and C9orf72-linked ALS, while clinically distinct, share a common hallmark: long, abnormal repetitions of DNA bases. The success of antisense oligonucleotides (ASOs) in spinal muscular atrophy (SMA, SMN1 gene) in 2017, followed by gene therapy in 2019, gave researchers confidence to pursue similar strategies in HD and C9orf72 ALS. Progress in treating one of these repeat expansion diseases may provide hope for others.

1. Genetic Basis

1.1 Huntington’s disease (HD)

HD is caused by an expanded CAG trinucleotide repeat in the HTT gene. - Normal alleles: up to approximately 26 repeats - Pathogenic threshold: 36 or more repeats

CAG encodes glutamine, leading to a mutant protein with an expanded polyglutamine (polyQ) tract. This toxic protein disrupts neuronal function and accumulates throughout the body, contributing not only to neurodegeneration but also to systemic issues like muscle atrophy, cardiac problems, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.

1.2 C9orf72 ALS/FTD

C9orf72-related ALS and frontotemporal dementia (FTD) are caused by an expanded GGGGCC (G4C2) hexanucleotide repeat in the C9orf72 gene. - Normal alleles: up to approximately 30 repeats - Pathogenic alleles: hundreds to thousands

The expansion causes disease through several mechanisms: - Reduced C9orf72 protein levels - Formation of toxic RNA foci - Production of abnormal dipeptide repeat proteins via repeat-associated non-ATG (RAN) translation

1.3 Other repeat expansion diseases

• Spinocerebellar ataxias (SCAs) – many caused by CAG expansions
• Fragile X syndrome – CGG expansion in FMR1
• Myotonic dystrophy – CTG expansion in DMPK

2. Therapeutic Approaches: Shared Strategies

2.1 Antisense oligonucleotides (ASOs)

ASOs aim to reduce toxic transcripts. - HD: ASOs targeting HTT mRNA have reached clinical trials (e.g., Roche/Ionis). - C9orf72 ALS: ASOs targeting repeat-containing transcripts are in early-stage trials.

2.2 Gene silencing/editing

The most advanced approach in HD is uniQure’s AMT-130 gene therapy: - Uses an AAV vector to deliver microRNAs designed to silence mutant HTT. - Administered through MRI-guided stereotactic neurosurgery directly into the striatum. - Clinical trials (U.S. and Europe) are ongoing, with promising early results showing up to 75% slowing in disease progression in high-dose patients over 36 months.

These approaches are not yet cures, but they show that disease modification is possible. Advances in vector design (AAVs, lipid nanoparticles) are directly transferable to other repeat expansion disorders.

2.3 Targeting RNA structures

Small molecules that bind abnormal RNA structures (hairpins, G-quadruplexes) are under development for C9orf72 ALS and myotonic dystrophy, with potential extension to CAG-repeat disorders like HD.

2.4 Modulating protein homeostasis

Strategies to boost autophagy, proteasome activity, or molecular chaperones could reduce toxic protein aggregates in both HD and C9orf72 ALS.

3. Translating Progress Across Diseases

Research tools—such as assays for RNA foci, protein aggregation, and repeat instability—are shared across laboratories working on different repeat expansion disorders. Breakthroughs in one disease can therefore be rapidly tested in others.

Delivery challenges are also common: therapies must reach neurons in the brain and spinal cord. Advances in intrathecal ASO delivery or viral vector engineering benefit all disorders in this family.

In summary: Huntington’s disease and C9orf72 ALS/FTD are distinct conditions, but they share a unifying principle: DNA repeat expansions that disrupt RNA and protein homeostasis. Therapeutic strategies—including antisense oligonucleotides, RNA-targeting drugs, and gene-editing technologies—are broadly applicable across these diseases. Progress in one field accelerates progress in others, offering shared hope for patients facing these devastating neurodegenerative disorders.

A tool for ALS or FTD gene carriers.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases. A significant number of cases are linked to a hexanucleotide repeat expansion in the C9orf72 gene, making it the most common known genetic cause of both conditions.

Genetic counseling is essential in informing families about their risk, especially for those with a family history of the disease. Currently, children of C9orf72 mutation carriers are often told they have a 50% chance of inheriting the mutation. While technically correct based on Mendelian inheritance, this figure overlooks a critical factor: age-related penetrance.

Penetrance describes the likelihood that someone carrying a disease-causing gene will develop the disease. In cases of C9orf72-related ALS/FTD, penetrance increases with age, peaking around 58 years old. This means that simply knowing you carry the mutation does not give the full picture of your personal risk.

A new study addresses this limitation by developing a more precise method for calculating risk and providing an online tool for families.

The tool is available here: https://lbbe-shiny.univ-lyon1.fr/ftd-als/

While other research has focused on identifying genetic modifiers of disease risk, this study centers on a readily available and easily measurable factor: age.

The researchers used a Bayesian approach, a statistical method that updates probabilities with new evidence. In this case, the evidence includes the individual's age and family history. By integrating age-related penetrance data, the researchers created a model to estimate the probability of carrying the C9orf72 mutation and developing ALS or FTD within a specific timeframe. This approach is especially relevant for asymptomatic relatives, such as children, siblings, grandchildren, and niblings of mutation carriers.

Importance of this work:

This research is significant because it moves beyond the simplified 50% risk figure, offering a more personalized and accurate risk assessment for individuals at risk of C9orf72-related ALS/FTD. It helps inform decisions about genetic testing and could influence lifestyle choices or participation in clinical trials. As testing for C9orf72 becomes more common, the need for nuanced interpretation of results increases. The findings are highly relevant for families affected by ALS/FTD, providing a more realistic understanding of their individual risk profiles.

Originality:

The study offers original insights beyond the basic concept. Although age-related penetrance is a known idea, this research presents a concrete, mathematically sound method to incorporate it into risk calculations. The online simulator further enhances its practical use. The novelty is in applying a Bayesian framework to refine risk estimates in C9orf72-related ALS/FTD, providing a more sophisticated and personalized approach than traditional Mendelian risk assessments.

Conclusion:

This study makes a valuable contribution to ALS/FTD genetics. By offering a more detailed and personalized risk assessment, it can improve genetic counseling, aid in clinical trial recruitment, and deepen the understanding of the disease. The online simulator makes this complex information accessible to clinicians and families, increasing its practical impact.

Two FDA-approved small-molecule drugs, riluzole and edaravone, are currently available on the market; the antisense oligonucleotide tofersen was also recently approved. However, none blocks disease progression, making it crucial to investigate new therapeutic routes to overcome ALS.

Several products are known to slightly slow ALS progression, but they are not pursued by the pharmaceutical industry and academics because they lack patentability. One of the best-known among these products is TUDCA, while two lesser-known ones are Acetyl-L-Carnitine and Alpha-Lipoic Acid.

There are many forms of ALS, and each will likely require different therapeutics. Most forms are characterized by aggregates of misfolded TDP-43 fragments, an important protein. Various theories exist regarding how these aggregates form; one posits that they are a form of stress granules.

Numerous teams from diverse backgrounds collaborated to find a drug capable of dissolving these aggregates.

They screened many drug candidates and found that one, closely related to Alpha-Lipoic Acid, holds good prospects for future use as a drug. Indeed, it will likely be modified to enhance its bioavailability and thus could be patented.

The scientists screened a library of 1,600 small molecules to identify compounds that affect stress granule formation, using HeLa cells expressing FUS–GFP, a fusion protein that localizes to stress granules under stress. I remain cautious about findings from in vitro experiments, especially those involving immortalized cells of cervical cancer, whose biology often differs from that of normal cells. So consider yourselves warned, dear readers. The researchers specifically focused on molecules that could reduce or reverse stress granule formation, particularly those that act directly on stress granule proteins and may be useful as therapeutic agents. From the initial screening, lipoamide emerged as a novel, potent modulator of stress granules. Once lipoamide was identified as a hit, the researchers sought to determine its effects in cells regarding specificity, potency, intracellular localization, and its effects on other cellular condensates.

It's beneficial to understand the underlying mechanism of action, even if it's often challenging to achieve in biology. Thus, the authors evaluated the structure–activity relationships (SAR). Understanding which chemical features are critical for its function will assist in enhancing the potency of a future drug. The authors thus aimed to clarify its mechanism of action—whether it alters the physical properties of condensates, binds to specific proteins, or acts via redox chemistry.

Lipoamide was found to prevent stress granule formation when added before stress and to dissolve existing stress granules when added afterward.

Lipoamide's effect was also specific to stress granules, without impacting other cellular condensates or general protein synthesis. This specificity is crucial as it minimizes the risk of adverse effects.

Proteins stabilized by lipoamide are enriched in intrinsically disordered regions (IDRs) with high arginine and tyrosine content—characteristics typical of stress granule proteins. These effects suggest that lipoamide interacts with these IDR-rich proteins to modulate condensate behavior, likely through nonenzymatic redox interactions.

In conclusion, the authors identified lipoamide as a promising small molecule that selectively and reversibly modulates stress granule formation. It does so not through conventional binding to a specific target, but likely via redox-sensitive interactions with disordered proteins, altering the physical properties of condensates.

This may have therapeutic implications for ALS and other neurodegenerative diseases linked to stress granule dysfunction. However, this research is not yet at the pre-clinical trial stage, which we know unfortunately provides limited information about success in human trials. This study is in vitro with cells that possess biology mostly alien to living beings. These cells are not motor neurons, so it's somewhat odd to see so many references to ALS in the text; it's probably a bait for investors.

There are many articles on statins and ALS, and in general the results show that statin use does not influence the progression of ALS.

Statins are commonly used to manage cholesterol levels and reduce the risk of cardiovascular disease, but their safety in amyotrophic lateral sclerosis (ALS) has long been questioned by both patients and their caregivers. Since the mid-1990s, weight loss has been identified as a contributing factor for patients with ALS, leading to a 7.7-fold increased risk of death. Many individuals worry that statins may accelerate the progression of ALS or exacerbate symptoms, and reports from drug monitoring systems suggest a potential link between a diagnosis of ALS and statin use; however, these reports have yet to be validated in epidemiological studies. In contrast, findings from more recent studies indicate that high LDL cholesterol and elevated LDL/high-density lipoprotein ratios occurring well before the onset of ALS may be associated with an increased risk of developing the disease.

A new Norwegian study on this topic confirms that statin use does not impact the progression of ALS.

https://pubmed.ncbi.nlm.nih.gov/40034089/

The researchers analyzed data from four Norwegian health surveys spanning the years from 1972 to 2003. They linked these surveys to national registries to track ALS diagnoses, mortality, and medication use. Specifically, they examined whether statin use before and after an ALS diagnosis influenced survival time.

The researchers included 524 ALS patients in the analysis. They compared statin use before and after diagnosis and adjusted for various factors, including age, sex, smoking status, BMI, cholesterol levels, and use of riluzole (the main ALS drug).

Their work found no association between statin use and ALS survival. Interestingly, 21% of ALS patients stopped taking statins in the year before their diagnosis. This group had a poorer prognosis, perhaps because of worsening general health, but the fact they stopped using statins did not appear to have improved ALS survival.

The study therefore suggests that routinely stopping statins in ALS patients is not necessary. Since statins do not appear to have a negative impact on survival, stopping them solely because of an ALS diagnosis may deprive patients of their cardiovascular benefits.

Two recent studies highlight the complex interplay between metabolic dysregulation and ALS progression.

The first study investigated energy balance and glucose control in TAR DNA-binding protein 43 (TDP-43)Q331K mice, which serve as a model for ALS, during both the early and late symptomatic stages of the disease. It suggests the presence of compensatory mechanisms that regulate glucose metabolism differently in this form of ALS. Thus, targeting metabolic pathways, such as insulin signaling and oxidative stress, could provide new therapeutic approaches for ALS.

The etiology of ALS is complex, involving mechanisms such as neuroinflammation, protein aggregation, and energy metabolism dysfunction. The origin of hypermetabolism in amyotrophic lateral sclerosis remains unknown; however, metabolic perturbations in skeletal muscle may be a determining factor, including an increase in the expression of pyruvate dehydrogenase kinase 4 (PDK4), which plays a central role in regulating the oxidation of glucose.

Both sporadic and familial ALS cases commonly exhibit metabolic disturbances, including weight loss, increased resting energy expenditure, and hypermetabolism, which are associated with poorer disease outcomes. Interestingly, a higher body mass index (BMI) at disease onset is linked to increased survival, and high-calorie, high-fat diets have shown some benefits in ALS patients and mouse models, suggesting that metabolic interventions could influence disease progression.

Insulin resistance has been implicated in the progression of ALS. Some studies indicate that diabetes mellitus increases the risk of ALS, while others suggest that type 2 diabetes may delay the onset of the disease. This discrepancy highlights the need for further research into how energy homeostasis and insulin signaling are affected in ALS. Previous studies on SOD1G93A mice, a model of familial ALS, revealed increased energy expenditure and enhanced glucose uptake through insulin-independent pathways, along with glucagon intolerance.

The discrepancy between studies may stem from differences in tissue-specific glucose uptake, as ALS patients exhibit increased glucose uptake in denervated muscles but decreased uptake in the central nervous system.

Building on these findings, the first study investigated metabolic perturbations in the TDP-43Q331K mouse model, which mimics the neuropathological and metabolic hallmarks of human ALS, including TDP-43 pathology, a common feature in both familial and sporadic ALS.

TDP-43Q331K mice exhibited significantly increased daily energy expenditure (DEE) from the early symptomatic stages of the disease. This hypermetabolism was accompanied by a transient increase in food intake, which helped maintain fat mass initially but was insufficient in later stages, leading to fat mass reduction.

During the later stages of the disease, TDP-43Q331K mice showed improved glucose clearance, independent of insulin. Despite reduced circulating glucagon levels, these mice maintained normal fasting blood glucose levels, suggesting alternative mechanisms for glucose regulation.

Unlike SOD1G93A mice, TDP-43Q331K mice did not exhibit insulin or glucagon intolerance. Insulin sensitivity remained unchanged, and while glucagon levels were reduced, the mice maintained normal blood glucose levels, indicating the involvement of other regulatory mechanisms.

Consistent with other ALS models, TDP-43Q331K mice experienced a reduction in lean mass during both early and late disease stages. Regression analysis confirmed that the increased energy expenditure was independent of changes in body mass.

The TDP-43Q331K mutation drives significant metabolic changes, including hypermetabolism and altered glucose uptake, which are not observed with wild-type TDP-43.

The increased glucose uptake in later disease stages is insulin-independent, highlighting the activation of alternative metabolic pathways in response to the disease.

The ability of TDP-43Q331K mice to maintain fasting blood glucose levels despite reduced glucagon suggests the existence of compensatory mechanisms that regulate glucose metabolism differently in this ALS model.

• The second study, a phase 2a clinical trial, explored the pharmacodynamic response of trimetazidine, a partial fatty acid oxidation inhibitor, on oxidative stress markers and energy expenditure in amyotrophic lateral sclerosis. This publication highlights how it's difficult and inconclusive to conduct an ALS clinical trial as twenty-one participants received trimetazidine but only 19 completed the treatment period. While trimetazidine is a well known drug, usually well tolerated, the assessment of energy expenditure may have been uncomfortable. While there were 57 adverse events, the conclusion was, as usual, that the drug was well tolerated! While the publication recounts that trimetazidine was beneficial for patients (this is not a phase III trial), for me the results section does not show conclusive results. For example, the results improved only during the wash-out period.

The authors tell that the on-treatment period may have been too short, or the sample size too small to detect a disease-relevant change, if one exists. Moreover, in this study, they simply used the approved dose for angina pectoris. Therefore, it remains unclear whether dosing was appropriate and whether a different dose would have resulted in more substantial reductions. Finally, the response in the oxidative stress markers may also be explained by external factors that influence metabolism, such as concomitant medication use and smoking, which cannot be completely ruled out in this uncontrolled study.

While the study was limited by its short duration and lack of a control group, the findings suggest that trimetazidine may help mitigate the hypermetabolic state in ALS and improve disease outcomes. Larger, randomized controlled trials are needed to confirm these results and determine the optimal dosing regimen.

These findings suggest that targeting metabolic pathways, such as insulin signaling and oxidative stress, could offer new therapeutic avenues for ALS. Future research should focus on understanding the underlying mechanisms of metabolic dysregulation, exploring the potential of antidiabetic agents, and conducting larger clinical trials to evaluate the efficacy of metabolic modulators like trimetazidine in ALS patients.

SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation. SUMOylation is to signal to other cellular mechanisms that the protein attached must be processed. There are at least 4 SUMO isoforms in humans; SUMO-1, SUMO-2, SUMO-3, and SUMO-4. SUMO proteins are involved in a variety of cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability. Transactive response DNA-binding protein 43 (TDP-43) is a nuclear RNA binding protein (RBP) involved in RNA metabolism. TDP-43 has a high propensity to aggregate because of its low solubility in cells and in vitro. The aggregation propensity of TDP-43 is increased by ALS/FTD-linked mutations and upon exposure to stress and has been observed in patients with C9orf72 hexanucleotide repeat expansion, the most common genetic cause of sporadic and familial.

Stress conditions trigger the accumulation of TDP-43 in cytosolic stress granules. The role of stress granules in modulating TDP-43 aggregation is ambiguous. Functionally, SUMO2/3-ylation has been shown to maintain stress granules in a dynamic state: SUMOylation inhibition impairs stress granule disassembly, but the underlying mechanism is still unknown.

In this paper, the authors report that upon oxidative stress (induced by sodium arsenite), TDP-43 becomes modified by SUMO2/3 protein chains and moves from the nucleus to cytoplasmic stress granules. This conclusion is probably also valid for other stress conditions, so this study is of great interest. When researchers blocked SUMOylation, TDP-43 became less mobile within the cell, stress granules took longer to disassemble, and TDP-43 was more likely to form insoluble aggregates. Yet this is not a study on humans, the authors used various immortal cell lines, motor neuron cells, and Caenorhabditis elegans worms. Furthermore, the authors used genetic therapies to infect cells to express or repress PIAS4. This is easy to do in vitro but most probably hard to achieve in a seriously ill patient.

Because TDP-43 aggregation is central to familial and sporadic ALS, approaches aimed at preventing TDP-43 aggregation hold promise for future treatments. How cells control TDP-43 aggregation is poorly understood. Modifiers of TDP-43 solubility include molecular chaperones and posttranslational modifications. Besides ubiquitination, which is a key posttranslational modification required to clear aggregation-prone proteins, phosphorylation of TDP-43 is emerging as a protective response to counteract its misfolding. Phosphorylation of TDP-43 decreases its assembly into condensates and suppresses TDP-43 aggregation and toxicity.

Under normal growth conditions, cells prefer to modify proteins with SUMO1, while during cellular stress, SUMO2 and SUMO3 are usually conjugated in the form of SUMO2/3 chains (referred to as SUMO2/3-ylation). TDP-43 when SUMO1-ylated stays in the nucleus, does not aggregate in the cytoplasm, and its splicing activity is modified.

Using experiments in cells, the authors show that conjugation of TDP-43 with SUMO2/3 coincides with stress granule assembly. Pharmacological inhibition of TDP-43 SUMO2/3-ylation triggers TDP-43 aggregation inside stress granules.

E3 SUMO-protein ligase PIAS4 is one of several protein inhibitors of activated STAT (PIAS) proteins. PIAS proteins act as transcriptional co-regulators with at least 60 different proteins to either activate or repress transcription. The transcription factors STAT, NF-κB, p73, and p53 are among the many proteins that PIAS interacts with. PIAS4 has been shown to recruit proteins to the site of the DNA damage and promote repair.

The authors found that PIAS4 helps attach SUMO2/3 to TDP-43. - PIAS4-mediated SUMO2/3-ylation increases the solubility of TDP-43 and prevents its aggregation in the cytoplasm. - Depleting PIAS4 leads to TDP-43 aggregation In motor neurons from the human spinal cord in familial ALS cases with TDP-43 and C9orf72 mutations, reduced cytoplasmic PIAS4 correlates with increased TDP-43 aggregates.

RNA binding appears to compete with SUMOylation: When cells are not subjected to stress, TDP-43 is mainly localized inside the nucleus, binding with high affinity to RNA. When TDP-43 is bound to RNA, it's less likely to be SUMOylated. When cellular RNA levels are low, there's increased SUMO2/3 modification This suggests SUMOylation may be a protective mechanism when TDP-43 isn't bound to RNA

The authors conclude that modification with SUMO2/3 chains maintains the solubility of RNA-free TDP-43 during stress.

There are many studies on reducing TDP-43 aggregates in ALS, but this one looks much more sophisticated than the previous ones. Yet this is mostly an in-vitro study. Long pre-clinical studies must be conducted on mammals to verify if a simple and safe agonist of PIAS4 (which does not exist today) could improve the health of ALS patients.

A few years ago I tried to model the course of ALS using SBML, a systems biology tool now abandoned by scientists.

At the time there was no model of ALS, but since then there have been very interesting attempts, for example, this one:enter link description here

However, few scientists and almost no doctors use models based on differential equations today, we live in an era where statistical models are all the rage. In addition, biology as it is practiced is essentially qualitative, which makes it not very suitable for modeling and which attracts the mockery of "soft science", because by nature it is not capable of making consistent predictions. One only has to look at the colossal failure rate of clinical trials to be convinced of this.

The publication reviewed in this post focuses on understanding the regulatory dynamics of amyotrophic lateral sclerosis (ALS) using the widely used SOD1-G93A transgenic mouse model.

ALS is a multifactorial disease, and previous studies have often focused on isolated aspects rather than its complex and interconnected nature.

The study suggests that ALS regulation may be hypervigilant, meaning that the system overcorrects in response to stress, leading to damaging oscillatory behavior that contributes to disease progression. The study uses an innovative and integrative framework to model the regulatory dynamics of wild-type (WT) and SOD1-G93A ALS mice. The models are based on first-order ordinary differential equations (ODEs) that describe how the system output evolves over time. The research uses dynamic meta-analysis to synthesize experimental data from the literature and parameter optimization based on genetic algorithms to infer missing data. Indeed, to build a model, data are needed and here these are obtained from results reported in the literature on SOD1-G93A ALS mouse models.

The study shows that SOD1-G93A mice with ALS exhibit unstable physiological regulation, characterized by oscillatory behavior due to hypervigilant regulation. This instability intensifies near disease onset and worsens with progression.

Computational models of the physiological dynamics of wild-type (WT) and transgenic SOD1-G93A mice were constructed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate the dynamics of ALS pathology and their response to treatments in silico. The model simulates the functional molecular mechanisms of apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using data curated from published SOD1-G93A mouse experiments. Time-course measures of disease progression (rotarod, grip strength, body weight) were used to validate the results from the literature.

The health of untreated SOD1-G93A ALS mouse models cannot be maintained due to oscillatory instability. The onset and magnitude of homeostatic instability corresponded with disease onset and progression. Oscillations are associated with high feedback gain due to hypervigilant regulation.

Multiple virtual treatments combined were able to stabilize the dynamics of SOD1-G93A ALS mice to near-normal WT homeostasis. However, treatment timing and effect size are critical for stabilization to match therapeutic success. The most common unidirectional stabilizing treatment was pro-proteomics, while the most common bidirectional stabilizing treatment was energy consumption and anti-apoptosis. The authors cite anti-apoptosis factors such as caspase-9 inhibitor, caspase-3 inhibitor, Bax inhibitor, and Bcl-2 homolog BCL-XL.

A major drawback is that this type of ALS only affects less than 2% of ALS cases and if it is still largely overrepresented in the literature, it is because the association of this type of mutation with ALS is historically the first to have been discovered during the boom in genetics and for almost 15 years no other association has been found.

Another important point is that we do not know what mechanisms cause this disease, or even if it is a single disease. Models of this type therefore make many assumptions and their results are less robust than they appear.

The study highlights the multifactorial nature of ALS, which involves various molecular mechanisms, such as apoptosis, bioenergetics, excitotoxicity, inflammation, oxidative stress, and proteomics. These mechanisms are interconnected, and their dysregulation contributes to disease progression.

The study also explores the potential of combination therapies to stabilize the regulatory dynamics of ALS. Previous studies focusing on single therapeutic targets have often been inadequate, but combination treatments have shown success in the management of other complex diseases such as cancer, COVID-19, and HIV. The study suggests that precisely timed combination therapies targeting multiple pathways may be necessary to achieve meaningful results in ALS.

Code and data are not available at the indicated Github address.

The authors acknowledge that first-order feedback models may not fully capture the complexity of biological systems, including phenomena such as bistability and hysteresis. But for now, we are still in the prehistory of biological systems modeling, the field needs to be developed before focusing on its imperfections.

I fear that this publication will go way over the heads of health professionals working in the field of ALS.