Posts tagged: ALS - Padirac Innovations' blog

Stress granules are believed to play a critical role in modulating gene expression programs in response to environmental and nutrient stresses. However, it has been unclear how changes in cellular activity regulate stress granule formation and composition. The authors of a recent article, shown that Sam1 is recruited to yeast stress granules in response to a specific nutrient stress.

S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throughout the body, most SAM-e is produced and consumed in the liver. It is made from adenosine triphosphate (ATP) and methionine by methionine adenosyltransferase.

The scientists found that the product of Sam1, AdoMet, regulates stress granule formation in both yeast and human cells (HeLa and U2OS). This suggests that the connections between metabolism and stress granule assembly might be broader than previously believed. Their focus on the product of Sam1, AdoMet, uncovered parallels between how metabolites regulate metabolism and stress granule formation/composition. Most provocatively, AdoMet administration to iPSC-derived motor neurones cells, suppressed stress granule formation that expressed mutated forms of TDP-43 and FUS found in ALS patients. AdoMet was effective in blocking stress granule assembly in these disease models.

Cells deploy a variety of mechanisms to fine-tune biochemical processes in response to environmental stressors. One of these mechanisms is the formation of stress granules. Stress granules assemble in response to a variety of nutrient and metabolic stresses and are believed to provide a mechanism for coupling metabolic stress to post-transcriptional gene regulation.

Furthermore, stress granules act as centers to regulate cell signaling outputs and protein folding, highlighting stress granules as global integrators of the stress response. stress granules are transient and require tight regulation of both assembly and disassembly for cell function and viability. For example, disruption of stress granule formation decreases cell survival when the stress is removed.

In addition to their role in integrating the cellular stress response, stress granules have been implicated in a variety of neurodegenerative disorders. Dysregulation in stress granule dynamics in ALS patients results in accumulation of atypical cytoplasmic, stress granule-like protein aggregates in dying neurons of the brain and spinal cord. These results argue that understanding how stress granules assemble in response to metabolic or nutrient stresses is critical for both understanding the pathophysiology of ALS and FTD and developing treatment strategies focused on disrupting the formation of aberrant stress granules.

Given the linkage between stress granules and several neurodegenerative diseases, the composition of the stress granule proteome has been a subject of intense focus to identify potential therapeutic targets. Unfortunately, large-scale biochemical studies have found that stress granule composition is not only stress specific, but also organism and cell type specific. Although different techniques have helped identify which components reside within each phase, the relative role of stress granule core proteins and shell proteins in stress granule formation and pathogenesis remains unclear.

Despite the fact that stress granule formation and composition is stress specific, there has been surprisingly little exploration of the connections between metabolism and stress granule assembly. To date, only a few metabolic enzymes have been shown to be enriched or localized to stress granules via proteomic and/or targeted studies. This deficit is likely due to the limited number of stress conditions that have been used in stress granule proteomic studies. Interestingly, the localization of one metabolic enzyme, pyruvate kinase (Cdc19), to stress granules has been shown to be crucial for reactivation of growth-promoting pathways upon removal of stress. This suggests that stress granules can play a critical role in regulating metabolic enzymes in response to stress.

There are also limited examples of the reverse mode of regulation: metabolic intermediates that modulate stress granule assembly. Whereas stress granules can assemble upon the removal of glucose or amino acids, only one metabolite from intermediate metabolism, acetyl-CoA, has been implicated in regulating stress granule formation. Thus, the identification of metabolic enzymes that are recruited to stress granules in a stress-specific manner would identify new linkages between stress granule formation and metabolism as well as provide a novel set of potential therapeutic targets for ALS and FTD.

In this article the researchers have identified 17 metabolic enzymes that are recruited to yeast stress granules in a stress-specific manner. S-adenosylmethionine (AdoMet), the product of one these enzymes, is a regulator of stress granule assembly and composition.

The regulation of yeast stress granule formation by AdoMet is biphasic, with chronic changes altering stress granule composition and acute elevation of AdoMet suppressing stress granule assembly. Additionally, acute elevation of AdoMet suppresses stress granule formation in motor neurones, demonstrating conserved metabolite regulation of stress granule assembly from yeast to humans. The suppressive effect of AdoMet on stress granule formation also occurs in induced pluripotent stem cell (iPSC)-derived motor neurones from ALS patients.

AdoMet blocks the recruitment of cytoplasmic TDP-43 to remnant stress granules in this cell culture, implying that AdoMet can modify the pathogenic accumulation of stress granule material. Together, these results argue that metabolic activity controls both the composition and extent of stress granule formation and provide a framework for the identification of lead compounds that can modify or suppress stress granule formation.

Recent work on the stress granule proteome suggests that stress granule composition can vary depending on the cell type and the nature of the stress. Because many of the stresses that trigger stress granule assembly are thought to alter metabolic activity, either directly or indirectly, one might expect metabolic enzymes to be a common component of stress granules. However, few metabolic enzymes have been identified in proteomic and targeted studies of Saccharomyces cerevisiae stress granules. Their identification of 17 metabolic enzymes that are recruited to stress granules in response to physiological nutrient stresses, but are not recruited to stress granules in response to multiple acute stresses, argues that stress granule composition is tailored to the nature of the stress and that chronic stresses might require reorganization of the metabolic network.

This result also helps to explain why no metabolic enzymes have been identified in previous proteomic studies of mammalian stress granules. All of the stresses that are traditionally used to induce mammalian stress granules, such as sodium azide, do not trigger the recruitment of metabolic enzymes to yeast stress granules. Thus, one might expect to observe metabolic enzymes only in stress granules that assemble in response to the mammalian equivalent of a stationary-phase nutrient stress.

As a final thought: Whose ALS patient, have not dream of a simple drug that would alleviate their symptoms? AdoMet is interesting to investigate.

Scientists from Korea and Germany, shown that human fibroblasts can be converted into induced motor neurons (iMNs) by sequentially inducing POU5F1(OCT4) and LHX3. This is a radical simplification in the process to induce fibroblasts in morphing into motor neurons. Fibroblasts are a common cell type found in conjonctive tissue. In addition the scientists transplanted those iMNs in a rodent spinal cord injury model. The iMNs promoted locomotor functional recovery.

La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative fatale caractérisée par une dégénérescence progressive des motoneurones supérieur et inférieur. Le pronostic est très variable, allant de quelques mois à plus de 30 ans. Les taux sanguins de vitamine D 25OH (Calcifediol) ont été associés à un pronostic aggravé de la SLA, mais ces résultats restent controversés. En médecine, le test sanguin de 25-hydroxy vitamine D (calcifediol) est utilisé pour déterminer la quantité de vitamine D présente dans le corps. La concentration sanguine de calcifediol est considérée comme le meilleur indicateur du statut en vitamine D. Les patients atteints d'ostéoporose, d'insuffisance rénale chronique, de malabsorption, d'obésité et de certaines autres infections peuvent présenter un risque élevé.

Des scientifiques de Montpellier, en France, ont abordé cette question scientifique au moyen d'une étude sur l'influence des facteurs pronostiques cliniques connus de la maladie dont le niveau de calcifediol.

Cette cohorte prospective de patients SLA a contacté 127 patients, et 105 d'entre eux répondaient aux critères d'inclusion. Tous les patients SLA ont été inclus suivis trimestriellement au centre SLA de Montpellier, selon les recommandations nationales françaises. L'âge moyen d'apparition des symptomes était de 62 ans, 32% des sujets avaient une SLA de type bulbaire. Les données de 22 patients ont été exclus de l'étude.

Alors que la plage normale de calcifediol est de 30,0 à 74,0 ng / mL, le niveau moyen de calcifediol dans la cohorte de patients SLA était de 26,8 et était similaire entre hommes et femmes. Le score de gravité de la SLA à l'inclusion dans l'étude était plus élevé chez les patients bulbaires.

Les patients avec les niveaux de vitamine D les plus bas avaient reçu un pronostic de sclérose latérale amyotrophique aigüe. Lorsque les patients eurent été classé en trois groupes en fonction du niveau de calcifediol (<15,> 15 et <30, et> 30 ng / ml), l'âge, la capacité vitale lente (SVC) et la perte de poids au début de l'étude n'étaient pas significativement différents entre ces trois groupes. Les patients avec des niveaux de Calcifediol <15 ng / ml avaient un score de gravité de la SLA significativement plus élevé à l'inclusion dans l'étude que les autres patients.

Le score de gravité de la SLA à la fin du suivi n'a pas été trouvé corrélé aux niveaux initiaux de calcifediol, mais il était corrélé avec les niveaux de Calcifediol à la fin du suivi, la durée de la SLA à l'inclusion, la capacité vitale lente (SVC) à l'inclusion et la perte de SVC.

Certaines limites doivent cependant être soulignées. Les scientifiques n'ont pas observé ici une influence des niveaux de calcifediol sur la survie. Une raison potentielle de cette différence pourrait être les changements récents dans la pratique médicale. Dans les travaux antérieurs des chercheurs, près de 30% des patients SLA présentaient une carence grave en vitamine D, par exemple inférieure à 15 ng / ml. Dans la présente étude, seuls 19 patients sur 105 (18%) avaient des niveaux de Calcifediol aussi bas.

Les médecins semnlent désormais davantage conscients de l'importance de la supplémentation en vitamine D, ce qui peut expliquer la proportion plus faible de patients gravement déficients.

Un point important serait de savoir si les patients avec une supplémentation en vitamine D ont un pronostic meilleur ou pire.

Une autre limite du travail actuel est la faible taille de l'échantillon de la population.

Une autre limite potentielle à cette étude, est que plusieurs facteurs, liés à la vie quotidienne, peuvent influencer les concentrations sanguines, telles que la prise de nourriture ou l'exposition au soleil. À mesure que la maladie progresse, les patients limitent leurs activités de plein air et peuvent donc avoir des niveaux de Calcifediol plus bas.

Même si les niveaux de Calcifediol sont associés au score de gravité de la SLA à la fin de l'étude, dans cette cohorte, il n'y a pas d'arguments solides, à ce jour, pour proposer une supplémentation systématique en vitamine D aux patients atteints de la SLA.


Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of the upper and lower motor neurons. The prognosis is very variable, ranging from a few months to over 30 years. Blood levels of vitamin D 25OH (Calcifediol) have been associated with an worse prognosis for ALS, but these results remain controversial. In medicine, the 25-hydroxy vitamin D (calcifediol) blood test is used to determine the amount of vitamin D in the body. The blood level of calcifediol is considered the best indicator of vitamin D status. Patients with osteoporosis, chronic renal failure, malabsorption, obesity and certain other infections may be at high risk.

Scientists from Montpellier, France, addressed this scientific question by means of a study on the influence of known clinical prognostic factors of the disease, including the level of calcifediol.

This prospective cohort of ALS patients contacted 127 patients, and 105 of them met the inclusion criteria. All ALS patients were included prospectively and examined up quarterly in the ALS center of Montpellier. The average age of onset of symptoms was 62, 32% of subjects had bulbar type ALS. Data from 22 patients were excluded from the study.

While the normal range for calcifediol is 30.0 to 74.0 ng / mL, the average level of calcifediol in the cohort of ALS patients was 26.8 and was similar between men and women. The ALS severity score on inclusion in the study was higher in bulbar patients.

Patients with the lowest 25OH Vitamin D Levels have the worst Amyotrophic Lateral Sclerosis prognosis. When the patients were classified into three groups according to the level of calcifediol (<15,> 15 and <30, and> 30 ng / ml), age, slow vital capacity (CVS) and weight loss at study start were not significantly different between these three groups. Patients with Calcifediol levels <15 ng / ml had a significantly higher ALS severity score at baseline than the other patients.

The ALS severity score at the end of follow-up was not found to be correlated with the initial levels of calcifediol, but it was correlated with the levels of Calcifediol at the end of the follow-up, the duration of ALS at inclusion, slow vital capacity (SVC) at inclusion and loss of SVC.

Certain limitations must however be underlined. Scientists have not observed here an influence of calcifediol levels on survival. A potential reason for this difference could be recent changes in medical practice. In the researchers' previous work, almost 30% of ALS patients had a serious vitamin D deficiency, for example less than 15 ng / ml. In the present study, only 19 out of 105 patients (18%) had such low Calcifediol levels.

Doctors now seem to be more aware of the importance of vitamin D supplementation, which may explain the lower proportion of severely impaired patients.

An important point would be whether patients with vitamin D supplementation have a better or worse prognosis.

Another limitation of current work is the small sample size of the population.

Another potential limitation to this study is that several factors, linked to daily life, can influence blood levels, such as food intake or exposure to the sun. As the disease progresses, patients limit their outdoor activities and therefore may have lower Calcifediol levels.

Even if Calcifediol levels are associated with the ALS severity score at the end of the study, in this cohort, there is no solid argument, to date, for proposing systematic vitamin D supplementation to patients with ALS.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Repeated expansion of DNA in the C9orf72 region causes amyotrophic lateral sclerosis and frontotemporal dementia. The protein C9orf72 is localized in many regions of the brain, in the cytoplasm of neurons as well as in the presynaptic terminals. This protein regulates endosomal trafficking and autophagy in neuronal cells and primary neurons. Mutations causing repeat reading frames of this gene were discovered in 2011 by two independent research teams, led by Rosa Rademakers of Mayo Clinic and Bryan Traynor of the National Institutes of Health.

Preventive treatment with antisense oligonucleotides improved the disease in C9orf72 mouse models but would require regular intrathecal injection. Active vaccination is a promising approach to reduce the severity of the disease or even prevent ALS and FTD in people with the C9orf72 mutation.

As in other FTLD / ALS variants, the intracellular inclusions characteristic of improperly folded proteins define the pathology C9orf72. The proteins in these C9orf72-linked inclusions were identified in 2013 by the team of Dieter Edbauer in Munich in Germany.

They found that most of these characteristic inclusions contain proteins with repeats of poly-(Gly-Ala) dipeptide and, to a lesser extent poly-(Gly-Pro) and poly-(Gly-Arg) dipeptides (collectively called Poly-GA repeats in this text).

As we have often pointed out, the genetic origin of familial forms of ALS in the elderly raises questions. Why is this delay of several decades, when similar neurodegenerative diseases like SMA, strike children from an early age? One can also ask how a genetic origin of the disease can explain the progressive nature of ALS, how can it first attack only one hand or ankle and then gradually spread to the whole body, while all cells in the body have the same genetic heritage?

In 2016 Westergard et al. examined cell-to-cell propagation of C9orf72-linked dipeptide repeat proteins in vitro and in animal models. Westergaard and colleagues suggested that transcellular transmission may explain the progressive neurodegeneration of these diseases. This article was highly appreciated by the scientific community, but other explanations were also proposed and a consensus was not reached.

A particular case of this problem concerns the relationship between the pathology specific to C9orf72 and the pathology TDP-43. Understanding this relationship could greatly improve our knowledge of these two diseases (ALS and FTD), or even why not indicate a therapeutic path.

enter image description here

Scientists in Dieter Edbauer's team, recently showed that the extra cellular circulation of Poly-GA repeats promotes poor cytoplasmic localization and aggregation of TDP‐43.

Since the Poly-GA repeats are transmitted between cells, researchers from Dieter Edbauer's team studied the therapeutic potential of antibodies against Poly-GA repeats by vaccinating mice modeling C9orf72 ALS.

To overcome the poor immunogenicity, the researchers used ovalbumin as an adjuvant, which induced a strong response against Poly-GA repeats. Vaccine immunization largely saved motor function in 149-CFP transgenic mice.

Analysis of the transcriptome showed less neuroinflammation in mice, which was corroborated by a semi-quantitative and morphological analysis of microglia / macrophages. In addition, the poor cytoplasmic localization of TDP‐43 and the light chain levels of neurofilaments have been reduced, suggesting that neuroaxonal damage is reduced.

These data suggest that immunotherapy may be a viable primary prevention strategy for ALS / FTD in carriers of the C9orf72 mutation.

An immunogenic carrier protein such as ovalbumin can significantly improve the immunogenicity of the Poly-GA repeats and can cause a high level antibody response which would be difficult to maintain with regular intravenous injection of monoclonal antibodies.

Although the distribution of antibodies across the blood-brain barrier is limiting, antibody engineering could, however, increase antibody delivery.

The safety profile of lifelong administration of highly immunogenic carriers should be studied before general application. Researchers have not noticed any side effects such as T-cell infiltration or other signs of meningoencephalitis, but unfortunately, experiments in mice cannot sufficiently predict the T-cell response in humans.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

L'expansion répétée de l'ADN dans la région du C9orf72 provoque une sclérose latérale amyotrophique et une démence frontotemporale. La protéine C9orf72 se localise dans de nombreuses régions du cerveau, dans le cytoplasme des neurones ainsi que dans les terminaux présynaptiques. Cette protéine régule le trafic endosomal et l'autophagie dans les cellules neuronales et les neurones primaires. Des mutations causant des répétition des cadres de lecture de ce gène ont été découvertes en 2011 par deux équipes de recherche indépendantes, dirigées par Rosa Rademakers de Mayo Clinic et Bryan Traynor des National Institutes of Health.

Un traitement préventif avec des oligonucléotides antisens a amélioré la maladie dans les modèles de souris C9orf72 mais nécessiterait une injection intrathécale régulière. Une vaccination active est une approche prometteuse pour réduire la gravité de la maladie ou même prévenir la SLA et la FTD chez les personnes porteuses de la mutation C9orf72.

Comme dans d'autres variantes FTLD / ALS, les inclusions intracellulaires caractéristiques des protéines mal repliées définissent la pathologie C9orf72. Les protéines dans ces inclusions ont été identifiées en 2013 par l'équipe de Dieter Edbauer à Munich en Allemagne.

Ils ont constaté que la plupart de ces inclusions caractéristiques contiennent des protéines ayant des répétitions de dipeptide poly-(Gly-Ala) et, dans une moindre mesure des dipeptides poly-(Gly-Pro) et poly-(Gly-Arg).

Comme nous l'avons souvent souligné, l'origine génétique des formes familiales de la SLA chez les sujets agés pose question. Pourquoi ce délai des plusieurs dizaines d'années, alors que des maladies neurodégénérescentes similaires comme la SMA, frappent les enfants dès le plus jeune âge? On peut aussi ce demander comment une origine génétique de la maladie peut expliquer le caractère progressif de la SLA, comment peut-elle d'abord n'attaquer qu'une main ou une cheville puis s'étendre progressivement à tout le corps, alors que toutes les cellules du corps possèdent le même patrimoine génétique?

En 2016 Westergard et al. ont examiné la propagation de cellule à cellule des protéines de répétition du dipeptide liées à C9orf72 in vitro et dans des modèles animaux. Westergaard et ses collègues ont suggéré qu'un transmission transcellulaire peut expliquer la neurodégénérescence progressive de ces maladies. Cette article a été très apprécié par la communauté scientifique, mais pendant d'autres explications ont été proposées sans qu'un consensus ne se soit dégagé.

Un cas particulier de cette problématique concerne la relation entre la pathologie spécifique au C9orf72 et la pathologie TDP-43. Comprendre cette relation pourrait grandement améliorer nos connaissances sur ces deux maladies (SLA et FTD), voire pourquoi pas indiquer une voie thérapeutique.

enter image description here

Des scientifiques dans l'équipe de Dieter Edbauer, ont montré récemment que la circulation de manière extra cellulaire de répétitions Poly-GA favorise la mauvaise localisation cytoplasmique et l'agrégation du TDP‐43.

Puisque la répétition Poly-GA est transmise entre les cellules, les chercheurs de l'équipe de Dieter Edbauer ont étudié le potentiel thérapeutique des anticorps à l'encontre des répétitions Poly-GA en vaccinant des souris modélisant la SLA C9orf72.

Pour surmonter l'immunogénicité médiocre, les chercheurs ont utilisé l'ovalbumine comme adjuvant, ce qui a induit une forte réponse à l'encontre des répétitions Poly-GA. L'immunisation par vaccin a largement sauvé la fonction motrice chez les souris transgéniques (GA) 149-CFP.

L'analyse du transcriptome a montré moins de neuroinflammation chez les souris, ce qui a été corroboré par une analyse semi-quantitative et morphologique des microglies / macrophages. De plus, la mauvaise localisation cytoplasmique du TDP‐43 et les niveaux de la chaîne légère des neurofilaments ont été réduits, ce qui suggère que les dommages neuroaxonaux sont réduits.

Ces données suggèrent que l'immunothérapie peut être une stratégie de prévention primaire viable pour la SLA / FTD chez les porteurs de mutation C9orf72.

Une protéine porteuse immunogène telle que l'ovalbumine peut améliorer considérablement l'immunogénicité du la répétition Poly-GA et peut entraîner une réponse en anticorps de haut niveau qui serait difficile à maintenir avec une injection intraveineuse régulière d'anticorps monoclonaux.

Bien que la distribution d'anticorps à travers la barrière hémato-encéphalique soit limitante, l'ingénierie des anticorps pourrait toutefois permettre d'augmenter la livraison d'anticorps.

Le profil de sécurité de l'administration à vie de porteurs hautement immunogènes devra être étudié avant une application généralisée. Les chercheurs n'ont remarqué aucun effet indésirable tel qu'une infiltration de cellules T ou d'autres signes de méningo-encéphalite, mais malheureusement, les expériences chez la souris ne peuvent pas suffisamment prédire la réponse des cellules T chez l'homme.


Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.

We have presented on several occasions a summary of drugs that can be used in the fight against the progression of Amyotrophic Lateral Sclerosis. Here is a list of drugs that are currently (mid-2020) undergoing phase III clinical trials. When reading this list you should be aware of the following limitations:

  • None of these drugs can stop the progression of the disease, let alone reverse its course.
  • Most of these drugs have a dose-related effect. For example, a beneficial effect at low doses can become harmful at high doses. Of course, the concept of dose is very vague, it depends on the weight but also on other factors such as insulin resistance, which are rarely taken into account.
  • Our pharmacological imagination is shaped by our childhood illnesses where the administration of oral pills allows healing within a few days. However, the oral route is one of the least effective methods of administration, particularly for diseases of the central nervous system.
  • An adult has little experience of illness lasting longer than a few days. The drugs presented here do not have visible effects, they just slow the progression of the disease. Psychologically it is difficult to take medication and to continue to observe a deterioration in his condition.
  • A drug can completely have a beneficial action on a tissue and have a harmful action on one or more other tissues ("side" effects). The very term "medication" is therefore misleading, it is the result of a temporary compromise that is specific to the patient.
  • There are surprisingly several drugs known to bring a 30% improvement in life expectancy after diagnosis of ALS, that is to say several months, but it is at the cost of adverse effects which make the prospect unattractive.
  • Although the disease is referred to as ALS, there are multiple subcategories of ALS that only have in common the fact they are motor neuron diseases. For example below BIIB067 is a gene therapy that only targets patients with a mutation in the SOD1 gene (~ 2% of cases). The only point common to most cases of ALS is malformed TDP-43 protein granules located in the cytoplasm instead of the nucleus. But these granules are also observed in other neurodegenerative diseases. it is not known whether it is a protective mechanism like stress granules, or a cause of the disease.

  • BIIB067

  • Tauroursodeoxycholic Acid
  • Ravulizumab
  • Levosimendan
  • Arimoclomol
  • Deferiprone
  • Ibudilast
  • Memantine Hydrochloride
  • Cu(II)ATSM


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Nous avons présenté à plusieurs reprises une synthèse des médicaments pouvant être utilisé dans le cadre de la lutte contre la progression de la Sclérose Latérale Amyotrophique. Voici une liste de médicaments qui sont actuellement (mi-2020) en cours d’essai clinique de phase III. En lisant cette liste il faut être conscient des limitations suivantes :

  • Aucun de ces médicaments n’est capable de stopper la progression de maladie, encore moins d’inverser son cours.
  • La plupart de ces médicaments ont un effet qui est lié à la dose. Par exemple un effet bénéfique à faible dose, peut devenir néfaste à haute dose. Bien sur la notion de dose soit très flou, elle dépend du poids mais aussi d’autres facteurs comme la résistance à l’insuline, qui sont rarement pris en compte.
  • Notre imaginaire pharmacologique est façonné par nos maladies infantiles où l’administration de pilules par voie orale permet une guérison en quelques jours. Cependant la voie orale est l’un des moyens d’administration les moins efficaces qui soient, particulièrement pour les maladies du système nerveux central.
  • Un adulte n’a guère d’expérience de maladies durant plus longtemps que quelques jours. Les médicaments présentés ici n’offrent pas d’effets visibles, ils ralentissent juste la progression de la maladie. Psychologiquement il est difficile de prendre un médicament et de continuer à observer une détérioration de son état.
  • Un médicament peut tout à fait avoir une action bénéfique sur un tissu et avoir une action néfaste sur un ou plusieurs autres tissus (les effets « secondaires »). Le terme même de « médicament » est donc trompeur, c’est le résultat d’un compromis temporaire qui est spécifique au patient.
  • Il y a de façon surprenante plusieurs médicaments connus pour apporter une amélioration de 30 % de l’espérance de vie après diagnostic de la SLA, c’est-à-dire plusieurs mois, mais c’est au prix d’effets indésirables qui rendent la perspective peu attrayante.
  • Bien que l’on désigne la maladie sous le nom de SLA, on peut faire de multiples sous-catégories de la SLA qui n’ont en commun que d’être des maladies des moto-neurones. Par exemple ci-dessous BIIB067 est une thérapie génique qui n’adresse que les patients ayant une mutation du gène SOD1 (~2 % des cas). Le seul point commun à la plupart des cas de SLA ce sont des granules de protéine TDP-43 mal-formés et localisés dans le cytoplasme au lieu du noyau. Mais ces granules sont aussi observés dans d'autres maladies neurodégénérescentes. on ne sait pas s'il s'agit d'un mécanisme de protection comme les granules de stress, ou alors d'une cause de la maladie.

  • BIIB067

  • Tauroursodeoxycholic Acid
  • Ravulizumab
  • Levosimendan
  • Arimoclomol
  • Deferiprone
  • Ibudilast
  • Memantine Hydrochloride
  • Cu(II)ATSM


Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.

Several studies have demonstrated diverse pathological effects of ALS' cerebrospinal fluid in different in vivo and in vitro models. The cerebrospinal fluid is very roughly similar to the lymphatic system, as it drains waste products from the brain metabolism and they are removed into the bloodstream as CSF is absorbed.

Recently an article by Jean-Pierre Julien's group was published on transmission of ALS pathogenesis by the cerebrospinal fluid and we reported it here.

This new article, from Stefan Bräuer and al, is both similar and different to those other articles. On one hand the German scientists from Dresden and Rostock tell that ALS CSF degrades motor neurons, but on the other hand it did report of proteinopathies. It is also a study done in dish versus studies done on living animals.

enter image description here

In other studies a multitude of phenotypes linked to ASL-CSF had been observed, including aggregation of transactive response DNA binding protein 43 kDA (TDP-43) in the case of ALS-frontotemporal dementia (FTLD)-CSF, neurofilament abnormalities, gliosis, endoplasmic reticulum (ER)-stress, mitochondrial dysfunction and Golgi fragmentation.

Interesting is the fact that ALS-CSF is able to induce Golgi fragmentation and the inhibition of ER-Golgi trafficking. But this study was not able to induce any proteopathy. enter image description here

The term Golgi fragmentation describes the dispersion of this cisternal structure across the cell. Golgi fragmentation in motoneurons themselves has been reported in different in vitro and in vivo ALS models. It is also present in postmortem sections of ALS patients.

Moreover, Golgi fragmentation is reported in several other neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease. There is convincing evidence that Golgi fragmentation is an early event in the disease process and not only a consequence of apoptosis but rather inducing it.

Thus, similar to other neurodegenerative disease conditions, Golgi fragmentation in ALS could be an event that takes place before seeding of the aggregates, axon degeneration and manifestation of clinical symptoms occurs.

This new study aimed at learning how ALS-CSF derived from sporadic ALS patients, induces motor neuronal degeneration in human patient-derived induced pluripotent stem cell (iPSC)-derived motoneurons. Only one aspect of ALS (namely a model for spinal cord degeneration), and thus there might be differences when analyzing other neuronal cell populations affected, e.g., cortical neurons.

CSF was collected from 19 patients. The ALS group consisted of 11 patients (3 women and 8 men) with a mean age of 63 years. The group of 8 control patients (3 women and 5 men) had a mean age of 47 years.

The authors did not observe significant neuronal network degeneration, motoneurons-loss or protein aggregates containing SOD1, FUS or TDP-43, which is a bit surprising Since Golgi fragmentation is expected to be an early event in the pathophysiological cascade, it is plausible that it occurs prior to further changes, which could develop either later or under additional stress conditions.

Additionally they did not observed pathological protein mislocalization or aggregate formation when treating monogenetic ALS-patient-derived motoneurons with ALS-CSF

A major concern regards the cellular age. Because iPSC-derived neurons do resemble fetal neurons and are not as old as the ones normally affected in ALS patients, human development takes much longer.

This study does not explain what is the pathologic agent in the CSF. However it is another study that hints that the etiology of ALS is of extracellular origin.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

ProMIS Neurosciences is a biotechnology company focused on the discovery and development of antibody therapeutics intended for neurodegenerative diseases. This biotech has just released an update on several new programs including using intrabodies.

Until now their vaccine platform could rapidly and cost-effectively identify peptide antigens (MHC) and create specifically tailored antibody drugs, diagnostic tools and vaccines. They had work on such a vaccine for SOD1 ALS on the premise that ALS is a prion like disease where a prion like protein moves from cell to cell.

A vaccine is not really applicable to neurons as it would accelerate the progression of the disease, by making the immune system kill any defective neuron. Indeed from birth to death we use the same neurons. As most neurons do not reproduce, if they die, the host would die. So such a vaccine could only apply to the glial cells which are cells that reproduce every few hours.

We can see that making a vaccine for ALS is even more difficult than designing a molecular drug that targets a cell receptor.

Clearly any vaccine designer that wants to address the ALS has to experience a paradigm shift. The problem then is no more to kill the defective cell, but how to heal it.

Intrabodies are somewhat similar to antibodies.

An intrabody (from intracellular and antibody) works within the cell to bind to an intracellular protein. The antibody then activates some cellular mechanism, for example moving the binded protein from one place in the cell to another place, operating some transformation upon it or signaling it as to be recycled.

Intrabodies could be designed to promote degradation of toxic species of TDP-43 while preserving normal forms of the protein. Normal TDP-43 is essential for proper cell function.

One problem is how to introduce the intrabody in the cell. An intrabody is too huge to enter a cell via one cellular pore. A classical solution is to modify the DNA of cells to make the cell produce the intrabodies themselves. Many articles have described the use of gene therapy vectors to introduce intrabodies in a cell and at least two have described this technology for ALS.

An alternative solution is to use a cell penetrating peptide that, when inside the cell, has similar properties to intrabodies.

We have proposed a gene therapy against misfolded TDP-43 early in 2019, following articles by several teams in this area.

This therapy is also presented in our book on ALS research. An alternative with Cell Penetrating Peptides has been presented by the end of 2019.

We had the chance to discuss briefly such mechanisms in a few emails exchanged with Dr. Neil Cashman, ProMIS Neurosciences’ Co-Founder and Chief Science Officer in late November 2019.

ProMIS has now generated several highly selective intrabodies that bind to toxic TDP-43 protein aggregates within cells and promote their degradation without affecting normal TDP-43. This represent a promising first step in the eventual development of a safe and effective therapy for ALS, FTD and other TDP-43-driven disorders. Indeed those intrabodies still need to be introduced in the target cell with some gene therapy vector.

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