During 2019 January I thought a TDP-43 therapy was really missing and the next month I wrote a plea to develop a TDP-43 therapy. I am not sure it had any effect, but I sent emails to nearly 250 scientists the next months. A flurry of patents have been written which indicates it is now an active research topic. Now we are at a phase where there are even clinical trials targeting TDP-43.

Reducing the TDP-43 misfolded mislocated aggregates may stop ALS progression and it could help as well in other neurodegenerative diseases.

Now I think that a part of the set of drugs needed to really recover (in addition to TDP-43 therapies) is something targeting faulty UPR (Unfolded Protein Response). Here is a list of natural products targeting the UPR signaling to tilt it towards pro-survival. Some, it will not surprise you, have been discussed since a long time on Internet forums. (source doi: 10.1007/s11010-021-04223-0)


Name of compound / Mode of action / References


  • Ginkgolide / K(GK) Reduce ER by accentuating the IRE1/XBP1 activity. / [136]

  • Elatoside C / Inhibit ER stress induced genes like GRP78, CHOP, caspase-12 and JNK, reduce apoptosis. / [137]

  • Sulforaphane (SFN) /Inhibit GRP78,CHOP and caspase-12 by activating the SIRT1 pathway.SIRT1 decrease ER induced apoptosis by deacetylating eIF2α / [138]

  • Resveratrol / Reduce ER stress mediated apoptosis by downregulating the expression of GRP78, GRP94 and CHOP and upregulating the expression of Bcl-2 and Bax. Lowers the expression of GRP78 and CHOP in doxorubicin treated H9c2 cell. / [139–141]

  • Baicalin / Target the CHOP/eNOS/NO pathway by inhibiting CHOP and thus reducing apoptosis / [142]

  • Berberine / Decrease apoptosis by decreasing the phosphorylation rate of PERK and eIF2α and downregulating the expression of ATF4 and CHOP / [143]

  • Anisodamine / Downregulate the expression GRP78, CHOP, and cleaved caspase 3 and thus reduce cell death / [144, 145]

  • Rare ginsenoside-standardized extract (RGSE) / Inhibit the overexpression of GRP78, GRP94 and CHOP as well as decrease the phosphorylation level of PERK and IRE1α / [146]

  • Panax quinquefolium saponin (PQS) Improve ventricular remodeling by downregulating the expression of GRP78, CHOP, and Bax protein as well as increasing the expression of Bcl-2 protein, thus reducing apoptosis. Also inhibits apoptosis by targeting the PERK-eIF2α- ATF4- CHOP pathway / [147–149]

  • Notoginsenoside R1 (NGR1) Protect cells from acute ER stress by delaying the onset of ER stress by decreasing the expression of GRP78, p-PERK, ATF6, IREα. Inhibit the expression of CHOP, caspase-12, and p-JNK. Scavenges free radicals, thereby increasing the activity of antioxdidases / [150]

  • Paeonol / Relieve ER stress by activating AMPK/PPARδ pathway which in turn results in down regulation GRP78, eIF2α as well as lower ROS overproduction / [151]

  • Tournefolic acid B / Accentuate the phosphorylation of P13K and AKT as well as it downregulates the expression CHOP, caspase-12 thus inhibiting apoptosis during ER stress via PI3K/AKT pathways / [152]

  • Crocetin / Impair the function of nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 signaling. Loss of Nrf2 activity was in turn shown to attenuate the expression of ER stress associated proteins / [153, 154]

  • Salvianolic acid B / Exert its cardioprotective role by improving cellular survival and reducing ER stress mediated apoptosis / [155, 156]

  • Flavonoids of astragalus (TFA) / Restores the mRNA and protein level of ER chaperone calumenin, rescues the interaction between SERCA2 and calumenin thus restoring ER homeostasis / [157]

  • Curcumin and masoprocol / Rescue Protein disulfde isomerase (PDI). Reduces the ROS generated ER stress by increasing the expression of GRP98 and inhibiting the activation of caspase-12 / [158]

  • SP600125 / Ameliorate the expression of CHOP in cardiomyocytes, reduce apoptosis [159] Panax Notoginseng Saponins (PNS) Protects cardiomyocytes against ER stress mediated mitochondrial injury by augmenting the autophagic response / [160]

  • Inonotus obliquus (IO) / Protects heart against Myocardial I/R injury by activating SIRT1 which in turn inhibits ER stress induced apoptosis - [161]

  • Fuziline Imparts its cardioprotective role by attenuating isoproterenol induced ER stress by targeting the PERK/eIF2α/ATF4/CHOP signaling axis / [162]

  • Protocatechualdehyde Imparts its anti-apoptotic role during oxygen–glucose deprivation/reoxygenation (OGD/R) mediated myocardial ischemic injury via targeting the PERK/ATF6α/IRE1α signaling molecules / [163]

  • Beta carotene / Exhibits its cardioprotective role in advanced glycation end products (AGEs)-induced cardiomyocyte apoptosis during diabetic cardiomyopathy by decreasing hyperactive ER stress molecules CHOP, ATF4 and GRP78 / [164]

  • Qishen granule (QSG) / Imparts its cardioprotective role during myocardial ischemia by augmenting the inositol requiring enzyme 1 (IRE-1)-αBcrystallin (CRYAB) signaling pathway thereby decreasing cardiac apoptosis / [165]


[136]. Wang S, Wang Z, Fan Q, Guo J, Galli G, Du G, Wang X, Xiao W (2016) Ginkgolide K protects the heart against endoplasmic reticulum stress injury by activating the inositol-requiring enzyme 1α/X box-binding protein-1 pathway. Br J Pharmacol 173(15):2402–2418. https://doi.org/10.1111/bph.13516

[137]. Wang M, Meng XB, Yu YL, Sun GB, Xu XD, Zhang XP, Dong X, Ye JX, Xu HB, Sun YF, Sun XB (2014) Elatoside C protects against hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes through the reduction of endoplasmic reticulum stress partially depending on STAT3 activation. Apoptosis 19(12):1727–1735. https://doi.org/10.1007/s10495-014-1039-3

[138]. Li YP, Wang SL, Liu B, Tang L, Kuang RR, Wang XB, Zhao C, Song XD, Cao XM, Wu X, Yang PZ, Wang LZ, Chen AH (2016) Sulforaphane prevents rat cardiomyocytes from hypoxia/reoxygenation injury in vitro via activating SIRT1 and subsequently inhibiting ER stress. Acta Pharmacol Sin 37(3):344–353. https:// doi.org/10.1038/aps.2015.130

[139]. Lin Y, Zhu J, Zhang X, Wang J, Xiao W, Li B, Jin L, Lian J, Zhou L, Liu J (2016) Inhibition of cardiomyocytes hypertrophy by resveratrol is associated with amelioration of endoplasmic reticulum stress. Cell Physiol Biochem 39(2):780–789. https:// doi.org/10.1159/000447788

[140]. Hubbard BP, Sinclair DA (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 35:146–154. https://doi.org/10.1016/j.tips.2013. 12.004

[141]. Lou Y, Wang Z, Xu Y, Zhou P, Cao J, Li Y, Chen Y, Sun J, Fu L (2015) Resveratrol prevents doxorubicin-induced cardiotoxicity in H9c2 cells through the inhibition of endoplasmic reticulum stress and the activation of the Sirt1 pathway. Int J Mol Med 36(3):873–880. https://doi.org/10.3892/ijmm.2015.2291

[142]. Shen M, Wang L, Yang G, Gao L, Wang B, Guo X, Zeng C, Xu Y, Shen L, Cheng K, Xia Y, Li X, Wang H, Fan L, Wang X (2014) Baicalin protects the cardiomyocytes from ER stressinduced apoptosis: inhibition of CHOP through induction of endothelial nitric oxide synthase. PLoS ONE 9(2):e88389. https://doi.org/10.1371/journal.pone.0088389

[143]. Zhao GL, Yu LM, Gao WL, Duan WX, Jiang B, Liu XD, Zhang B, Liu ZH, Zhai ME, Jin ZX, Yu SQ, Wang Y (2016) Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress. Acta Pharmacol Sin 37(3):354–367. https://doi.org/10. 1038/aps.2015.136

[144]. Jia LJ, Chen W, Shen H, Ji D, Zhao XM, Liu XH (2008) Efects of anisodamine on microcirculation of the asystole rats during the cardiopulmonary resuscitation. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 20(12):737–739

[145]. Yin XL, Shen H, Zhang W, Yang Y (2011) Inhibition of endoplasm reticulum stress by anisodamine protects against myocardial injury after cardiac arrest and resuscitation in rats. Am J Chin Med 39(5):853–866. https://doi.org/10.1142/s0192415x1 1009251

[146]. Wang L-C, Zhang W-S, Liu Q, Li J, Alolga R, Liu K, Liu B-L, Li P, Qi L-W (2015) A standardized notoginseng extract exerts cardioprotection by attenuating apoptosis under endoplasmic reticulum stress conditions. J Funct Foods 16:20–27. https://doi. org/10.1016/j.jf.2015.04.018

[147]. Liu M, Wang XR, Wang C, Song DD, Liu XH, Shi DZ (2013) Panax quinquefolium saponin attenuates ventricular remodeling after acute myocardial infarction by inhibiting chop-mediated apoptosis. Shock 40(4):339–344. https://doi.org/10.1097/shk. 0b013e3182a3f9e5

[148]. Liu M, Wang XR, Wang C, Song DD, Liu XH, Shi DZ (2012) Panax quinquefolium saponins reduce myocardial hypoxia-reoxygenation injury by inhibiting excessive endoplasmic reticulum stress. Shock 37(2):228–233. https://doi.org/10.1097/shk.0b013 e3182a3f9e5

[149]. Liu M, Xue M, Wang XR, Tao TQ, Xu FF, Liu XH, Shi DZ (2015) Panax quinquefolium saponin attenuates cardiomyocyte apoptosis induced by thapsigargin through inhibition of endoplasmic reticulum stress. J Geriatr Cardiol 12(5):540–546

[150]. Yu Y, Sun G, Luo Y, Wang M, Chen R, Zhang J, Ai Q, Xing N, Sun X (2016) Cardioprotective efects of Notoginsenoside R1 against ischemia/reperfusion injuries by regulating oxidative stress- and endoplasmic reticulum stress- related signaling pathways. Sci Rep 6:21730. https://doi.org/10.1038/srep21730

[151]. Choy KW, Mustafa MR, Lau YS, Liu J, Murugan D, Lau CW, Wang L, Zhao L, Huang Y (2016) Paeonol protects against endoplasmic reticulum stress-induced endothelial dysfunction via AMPK/PPARdelta signaling pathway. Biochem Pharmacol 116:51–62. https://doi.org/10.1016/j.bcp.2016.07.013

[152]. Yu Y, Xing N, Xu X, Zhu Y, Wang S, Sun G, Sun X (2019) Tournefolic acid B, derived from Clinopodium chinense (Benth.) Kuntze, protects against myocardial ischemia/reperfusion injury by inhibiting endoplasmic reticulum stress-regulated apoptosis via PI3K/AKT pathways. Phytomedicine 52:178–186. https:// doi.org/10.1016/j.phymed.2018.09.168

[153]. Yang M, Mao G, Ouyang L, Shi C, Hu P, Huang S (2020) Crocetin alleviates myocardial ischemia/reperfusion injury by regulating infammation and the unfolded protein response. Mol Med Rep 21(2):641–648. https://doi.org/10.3892/mmr.2019.10891

[154]. Wang X, Yuan B, Cheng B, Liu Y, Zhang B, Wang X, Lin X, Yang B, Gong G (2019) Crocin alleviates myocardial ischemia/ reperfusion-induced endoplasmic reticulum stress via regulation of miR-34a/Sirt1/Nrf2 pathway. Shock 51:123–130. https://doi. org/10.1097/shk.0000000000001116

[155]. Xu L, Deng Y, Feng L, Li D, Chen X, Ma C, Liu X, Yin J, Yang M, Teng F, Wu W, Guan S, Jiang B, Guo D (2011) Cardioprotection of salvianolic acid B through inhibition of apoptosis network. PLoS ONE 6(9):e24036. https://doi.org/10.1371/journ al.pone.0024036

[156]. Chen R, Sun G, Yang L, Wang J, Sun X (2016) Salvianolic acid B protects against doxorubicin induced cardiac dysfunction via inhibition of ER stress mediated cardiomyocyte apoptosis. Toxicol Res (Camb) 5(5):1335–1345. https://doi.org/10.1039/c6tx0 0111d

[157]. Zhou X, Xin Q, Wang Y, Zhao Y, Chai H, Huang X, Tao X, Zhao M (2016) Total favonoids of astragalus plays a cardioprotective role in viral myocarditis. Acta Cardiol Sin 32(1):81–88. https:// doi.org/10.6515/acs20150424h

[158]. Pal R, Cristan EA, Schnittker K, Narayan M (2010) Rescue of ER oxidoreductase function through polyphenolic phytochemical intervention: implications for subcellular trafc and neurodegenerative disorders. Biochem Biophys Res Commun 392:567–571. https://doi.org/10.1016/j.bbrc.2010.01.071

[159]. Cheng WP, Wang BW, Shyu KG (2009) Regulation of GADD153 induced by mechanical stress in cardiomyocytes. Eur J Clin Invest 39:960–971. https://doi.org/10.1111/j.1365-2362.2009. 02193.x

[160]. Chen J, Li L, Bai X, Xiao L, Shangguan J, Zhang W, Zhang X, Wang S, Liu G (2021) Inhibition of autophagy prevents panax notoginseng saponins (PNS) protection on cardiac myocytes against endoplasmic reticulum (ER) stress-induced mitochondrial injury, Ca2+ homeostasis and associated apoptosis. Front Pharmacol 12:620812. https://doi.org/10.3389/fphar.2021. 620812

[161]. Wu Y, Cui H, Zhang Y, Yu P, Li Y, Wu D, Xue Y, Fu W (2021) Inonotus obliquus extract alleviates myocardial ischemia/reperfusion injury by suppressing endoplasmic reticulum stress. Mol Med Rep 23(1):77. https://doi.org/10.3892/mmr.2020.11716

[162]. Fan CL, Yao ZH, Ye MN, Fu LL, Zhu GN, Dai Y, Yao XS (2020) Fuziline alleviates isoproterenol-induced myocardial injury by inhibiting ROS-triggered endoplasmic reticulum stress via PERK/eIF2α/ATF4/Chop pathway. J Cell Mol Med 24(2):1332– 1344. https://doi.org/10.1111/jcmm.14803

[163]. Wan YJ, Wang YH, Guo Q, Jiang Y, Tu PF, Zeng KW (2021) Protocatechualdehyde protects oxygen-glucose deprivation/ reoxygenation-induced myocardial injury via inhibiting PERK/ ATF6α/IRE1α pathway. Eur J Pharmacol 891:173723. https:// doi.org/10.1016/j.ejphar.2020.173723

[164]. Zhao G, Zhang X, Wang H, Chen Z (2020) Beta carotene protects H9c2 cardiomyocytes from advanced glycation end productinduced endoplasmic reticulum stress, apoptosis, and autophagy via the PI3K/Akt/mTOR signaling pathway. Ann Transl Med 8(10):647

[165]. Zhang Q, Shi J, Guo D, Wang Q, Yang X, Lu W, Sun X, He H, Li N, Wang Y, Li C, Wang W (2020) Qishen Granule alleviates endoplasmic reticulum stress-induced myocardial apoptosis through IRE-1-CRYAB pathway in myocardial ischemia. J Ethnopharmacol 252:112573. https://doi.org/10.1016/j.jep.2020. 112573

Biogen announced the first results of its pivotal phase 3 VALOR study in tofersen (BIIB067), an experimental antisense oligonucleotide (ASO) under evaluation for people with amyotrophic lateral sclerosis (ALS) who carry a mutation on the SOD1 gene.

The results are depressing.

enter image description here

The VALOR study showed that there was no slowing of disease progression, as measured by the overall score of the ALSFRS-R scale.

However, improvements have appeared on specific points or technical aspects.

In particular, the therapy has achieved its technical goal, although this does not translate into clinical terms. The production of SOD1 protein was indeed reduced, as differences were observed between the Tofersen and placebo groups of 38% and 26% in the faster and slower progressing populations respectively.

Regarding the baseline value of the plasma neurofilament light chain (NfL), a potential marker of neuronal degeneration, differences were observed between the tofersen and placebo groups of 67% and 48% in the more rapidly progressing populations. and slower respectively.

In the fastest growing population, respiratory function evolved somewhat slower than expected (SVC); difference of 7.9%). This is also the case for muscle strength.

However, serious neurological events have been reported in one in twenty patients receiving Tofersen, including 2 cases of myelitis (2.0%). One death was reported in the Tofersen group in the VALOR study, which was determined to be unrelated to Tofersen.

Tofersen binds to SOD1 mRNA, allowing its degradation by RNase-H1 to reduce the synthesis of mutant SOD1 protein production.

The idea that the production of a mutated gene should be reduced is very common among biologists, but it is medically counter-intuitive. Indeed our genes would not have been constantly selected through a billion year if they were useless, and if we could put them "KO" without serious consequences. SOD1 is a gene that is essential for survival. It is present in most organisms. So it's not surprising cases of myelitis appear when SOD1 production was inhibited. It happened as well in other clinical trials.

Moreover, an ASO is only effective for a certain type of mutation, but there are more than a hundred known mutations for SOD1, some with very rapid progression, others on the contrary almost harmless.

If the problem was due to a "gain of function" of the mutated protein, then it was not enough to reduce its production, it had to be corrected, or to increase the production of SOD2. Even the key 1993 article on SOD1 involvement in ALS suggested something similar.

Hopefully this failure will trigger a global strategic reflection at Biogen, which has stopped all research on ALS in general a few years, to concentrate on ALS subsets deemed (at the time) less risky through licenses with Ionis Pharmaceuticals.

This failure is not only that of an ALS therapy, it is the overall failure of research on neurodegenerative diseases which is unable to produce results despite colossal investments (more than 500 unsuccessful clinical trials for ALS, nearly 2,500 unsuccessful clinical trials for Alzheimer's). These numbers are dizzying and insane.

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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.

Biogen a annoncé les premiers résultats de son étude pivot de phase 3 VALOR sur le tofersen (BIIB067), un oligonucléotide antisens expérimental (ASO) en cours d'évaluation pour les personnes atteintes de sclérose latérale amyotrophique (SLA) et porteuse d'une mutation sur le gène SOD1.

Les résultats sont déprimants.

L'étude VALOR a montré qu'il n'y avait aucun ralentissement de la progression de la maladie, tel que la mesure le score global de l'échelle ALSFRS-R.

Cependant des améliorations sont apparues sur des points particuliers ou des aspects techniques.

En particulier la thérapie a bien atteint son but technique, même si cela ne se traduit pas en terme cliniques. La production de protéine SOD1 a bien été réduite, des différences ont été observées entre les groupes Tofersen et placebo de 38 % et 26 % dans les populations à progression plus rapide et plus lente respectivement.

En ce qui concerne la valeur initiale de la chaîne légère des neurofilaments plasmatiques (NfL), un marqueur potentiel de dégénérescence neuronale, des différences ont été observées entre les groupes tofersen et placebo de 67 % et de 48 % dans les populations à progression plus rapide et plus lente respectivement.

Dans la population qui progresse le plus rapidement, la fonction respiratoire a évoluée un peu moins vite que prévu (SVC) ; différence de 7,9 %). C'est aussi le cas pour la force musculaire.

Des événements neurologiques graves ont cependant été rapportés chez un patient sur vingt recevant du Tofersen, dont 2 cas de myélite (2,0 %). Un décès a été signalé dans le groupe traité au Tofersen dans l'étude VALOR, qui a été déterminé comme n'étant pas lié au Tofersen.

Tofersen se lie à l'ARNm de SOD1, permettant sa dégradation par la RNase-H1 pour réduire la synthèse de la production de protéines SOD1 mutantes.

L'idée qu'il faille réduire la production d'un gène muté est très courante chez les biologistes, elle est cependant contre-intuitive sur le plan médical. En effet nos gènes n'auraient pas été sélectionnés s'ils étaient inutiles, et qu'on pouvait les mettre "KO" sans conséquences graves. SOD1 est un gène qui est indispensable à la survie. Il est présent dans la plupart des organismes.

Par ailleurs, un ASO n'est efficace que pour un certain type de mutation, or il y a plus d'une centaine de mutations connues pour SOD1, certaines à progression très rapide, d'autres au contraire quasi inoffensives.

Si le problème était dû à un "gain de fonction" de la protéine mutée, alors il ne suffisait pas de réduire sa production, il fallait la corriger, ou augmenter la production de SOD2.

Tofersen est également à l'étude dans l'étude de phase 3 ATLAS, qui est conçue pour évaluer la capacité de Tofersen à retarder l'apparition clinique lorsqu'elle est initiée chez des individus présymptomatiques présentant une mutation génétique SOD1 et des preuves biomarqueurs de l'activité de la maladie.

Espérons que cet échec va déclencher une réflexion stratégique globale chez Biogen qui a déjà arrêté toute recherche sur la SLA en général, pour ce concentrer sur des segments jugés (à l'époque) moins risqués à travers des licenses avec Ionis Pharmaceuticals.

Cet échec n'est pas seulement celui d'une thérapie de la SLA, c'est globalement l'échec d'une recherche sur les maladies neurodégénérative qui est incapable de produire des résultats malgré des investissements colossaux (plus de 500 essais cliniques infructueux pour la SLA, près de 2500 essais cliniques infructueux pour Alzheimer). Les chiffres sont vertigineux et insensés, un sorcier Vaudou aurait statistiquement de meilleurs résultats.

Il est temps d'arrêter de recruter des "meilleurs élèves" ou des leaders d'opinion comme scientifiques, la société a besoin de personnes innovantes pas de scientifiques courants après leur carrière ou les plateaux de télévision.

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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.

Alzheimer may be a comorbidity of ALS

- Posted in English by

As observed in other neurodegenerative conditions, mixed pathologies also exist in ALS. In similar fashion to TDP-43 pathology playing a role in Alzheimer disease, Shuangwu Liu, Chuanzhu Yan and colleagues suggest here that Alzheimer disease pathology also plays a role in ALS. Indeed they found alterations at early stage in the subiculum, which is located in the temporal lobe of the brain, a region different from the frontal lobe which hosts the motor cortex which is classically implicated in ALS.


enter image description here Source: Wikipedia. The temporal lobe is shown in green, while the motor area is in the frontal lobe in blue


ALS is now considered a multisystemic disorder in which almost half of patients present with varying degrees of cognitive deficits, yet unfolded TDP-43 aggregates in cytosol are found in most ALS cases.

TDP-43 pathology in ALS can be divided into four stages (Braak stages): it begins focally, and then spreads persistently in sequential and regional patterns that typically originate from the motor cortex and extend to the prefrontal cortex, thalamus and eventually, the hippocampus.

However neuroimaging studies of hippocampal volumes in patients with amyotrophic lateral sclerosis (ALS) have reported inconsistent results. The group of Chinese scientists from 10 institutions, aimed to demonstrate that such discrepancies are largely due to atrophy of different regions of the hippocampus that emerge in different disease stages of ALS and to explore the existence of co-pathology in ALS patients.

They used King’s clinical staging system for ALS to classify patients into different disease stages. The scientists then investigated in vivo hippocampal atrophy patterns across subfields and anterior-posterior segments in different King’s stages using structural MRI in 76 ALS patients and 94 health controls.

The thalamus, corticostriatal tract and perforant path were used as structural controls to compare the sequence of alterations between these structures and the hippocampal subfields.

In summary:

  • ALS patients at King’s stage 1, had lower volumes in the bilateral posterior subiculum and presubiculum;
  • ALS patients at King’s stage 2 exhibited lower volumes in the bilateral posterior subiculum, left anterior presubiculum and left global hippocampus;
  • ALS patients at King’s stage 3 showed significantly lower volumes in the bilateral posterior subiculum, dentate gyrus and global hippocampus. Thalamic atrophy emerged at King’s stage 3.

White matter tracts remained normal in a subset of ALS patients.

In the present study, the authors demonstrated that the earliest hippocampal alterations in ALS patients occurred in the posterior subiculum and presubiculum, and these alterations emerged at King’s stage 1. This indicates that subiculum atrophy occurs earlier and independent of TDP-43 pathology in ALS.


enter image description here Hagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, et al. 


Taken together, their data suggest that patients with ALS have additional pathologies that are independent of TDP-43 pathology.

Increasingly, studies have shown that at least 20% of ALS patients present significant Alzheimer disease pathology of both Aβ and tau proteins. Recently, Gómez-Pinedo and colleagues showed that in ALS patients, the amyloid cascade of the amyloid precursor protein is activated in the hippocampus of ALS patients, and cytoplasmic Aβ peptide and pTDP-43 expression levels are moderately correlated.

Thus the motor cortex and subiculum seem to represent two independent centres of ALS during the early stages of the disease, which represent TDP-43 pathology and Alzheimer disease pathology, respectively, and these pathologies may converge as the disease progresses toward advanced stages.

If these findings are confirmed in further studies, they will have a profound effect on the understanding of the aetiology and pathogenic mechanisms underlying ALS and other neurodegenerative diseases.

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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.

Modeling neurodegenerative diseases is difficult because of poor access to human samples. Animal models fail to to model the disease due to critical differences between humans and other mammals.

The advent of human-induced pluripotent stem cell (hiPSC) technology now allow disease modeling using human samples that can be used for drug discovery.

Bosutinib and ropinirole are two candidate anti-ALS drugs recently identified in iPSC-based drug screens and are now under clinical investigation.

Bosutinib is a tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia.

Bosutinib, an inhibitor of Src/c-Abl, has been found to increase the survival of ALS iPSC-derived MNs by inducing autophagy and reducing misfolded SOD1 and TDP-43 proteins.

Furthermore, bosutinib has been shown to delay disease onset and prolong survival of SOD1-mutant mice.

A Spanish group reported in 2018 that 2 ALS patients in whose Src/c-ABL seemed to have a beneficial effect.

A 12-week phase I dose-escalation open label trial has been initiated in early 2021 in ALS subjects (UMIN000036295) to evaluate the safety and tolerability of bosutinib at 4 levels (100, 200, 300 or 400 mg/day).

The results of this clinical trial had been announced. Some patients may have stopped progressing.

Of the nine patients who drank 100-300 milligrams of bosutinib daily for 12 weeks, five stopped progressing. Of the nine, the remaining four remained progressing at the same pace. Professor Inoue explains, "A phenomenon that is not normally seen has occurred."

Examination of the blood before taking the drug also revealed that the five people who stopped progressing produced biomarkers than the four who where still progressing. It can be an indicator of whether the drug is likely to work.

The results of this clinical trial will be announced online at the "25th World Neurology Conference".

Extreme caution is required, we saw many “breakthrough” announcements in ALS without any concrete result. It's an open label trial (without control arm), with a few patients and for a short time.

And the reason why it was beneficial for some patients and not for others is unknown.

In addition making specific (to avoid side effects) c-Abl inhibitors is a challenging task, and companies have tried and abandoned some past efforts for lack of success.

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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.

It has been known for several decades that Cu(II)ATSM belongs to a class of molecules with anti-inflammatory and antioxidant effects. enter image description here By Jynto via Wikipedia

In 2016 the synthetic copper-containing compound, CuATSM, was proposed as yet another drug candidate for the treatment of amyotrophic lateral sclerosis (ALS).

Scientists in the Beckman group in Australia, were studying transgenic mice with a double mutation, SOD1 and CCS. They decided to try the compound Cu(II)ATSM in a transgenic mouse, which is unable to stand up at the end of its short lifespan.

The researchers dissolved Cu(II)ATSM in dimethylsulfoxide and spread it on the neck of the little animal, where it was quickly absorbed through the skin. A few hours later, the mouse was again able to move.

The researchers shown that with continuous treatment, the mice can live 18 months, that is to say almost half of the average life of non-transgenic laboratory mice, instead of dying after three months.

The media ans social networks were, as usual, dithyrambic about Cu(II)ATSM.

This 2016 article had an unusual style, for example it nearly suggested that it deserved the Prize4Life.

However, scientific publications, here and there from 2011 and 2013 had already shown the benefits of Cu(II)ATSM for ALS (1 ). In fact Cu(II)ATSM belongs to a class of molecules that have been identified very early as being useful in SOD1-related diseases.

« I'm not sure that this will have an impact on sporadic diseases » said Lucie Bruijn of the ALS Association. Bruijn noted that Cu(II)ATSM-based therapy worked best in mice overexpressing both mSOD1 and CCS, and weakly in animals overexpressing only mSOD1.

The same was true of Jeffrey Rothstein, another prominent ALS scientist.

Beckman said that if Cu(II)ATSM proved to be safe and effective, he considered that it could become a prophylactic drug that a person with a SOD1 mutation could take for decades.

Unscrupulous people then illegally sold on Internet the complex (or a counterfeit compound) to desperate people.

In September 2019, Collaborative Medicinal Development, a company of Cthulhu (sic) Ventures LLC started a clinical trial (NCT04082832) where Cu(II)ATSM is administrated orally as a suspension powder. As results obtained from Phase I clinical trials observed that 8/14 patients receiving the highest dose of CuATSM (> 72 mg/day) exhibited reversible transaminitis (an indicator of liver dysfunction), consequently leading to the recommended Phase II dose set at 72 mg/day (2 bottles) on an empty stomach each day before breakfast. The clinical trial end date was supposed to be December 2020, but as of mid-2021 for obvious reason, no results are yet released.. There are two other clinical trials at Macquarie University.

In this new study Australian scientists assessed CuATSM in SOD1 G93A mice (an ALS animal model), treating at 100 mg/kg/day by gavage, starting at 70 days of age. https://www.nature.com/articles/s41598-021-98317-w

This dose in this specific model has not been assessed previously.

The authors reported that a subset of mice initially administered CuATSM exhibited signs of clinical toxicity, that necessitated euthanasia in extremis after 3-51 days of treatment. It is unclear why only a subset of mice exhibited signs of toxicity. Of the seven CuATSM affected mice, the authors were able to obtain plasma samples for two, which subsequently showed elevated alanine aminotransferase (ALT) levels, which is consistent with what happened to the Phase I patients.

Following a 1-week washout period, the remaining mice resumed treatment at the reduced dose of 60 mg/kg/day.

At this revised dose, treatment with CuATSM slowed disease progression and increased survival relative to vehicle-treated littermates.

This work provides evidence that CuATSM produces positive disease-modifying outcomes in high copy SOD1 G93A mice, which might not mean much for humans, an provides an upper limit for the dose.

This is however an unlikely high dose, as when it is converted to the dose for a human weighting 100kg (220lbs), it means a daily dose of 6.7 mg/kg/day, thus 670 mg per day for this 100kg (220lbs) person.

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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.

A new version of my book on ALS research

- Posted in English by

The previous revision of this book was done in February 2021. The new version has fewer pages because it focuses on research and less on clinical trials.

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At that time, we were still awaiting the results of clinical trials with Arimoclomol. What a disappointment after that of Nurown! There may be a few lessons in this debacle, that a small molecule cannot help stop the progression of ALS (the corollary being that ALS is not due to single molecular dysfunction like a failed cell receptor) and that a single drug cannot be effective in the face of the diversity of cases encountered in a clinical trial.

There has been little news on the research front in 2021, especially compared to 2020.

On a regulatory front, what is a bit surprising is the turnaround of the FDA decision on AMX0035 under. the pressure of public opinion. AMX0035 is not a cure, during a clinical trial it can extend life expectancy by 6 months, which is both a lot and too little.

The only therapy that would be effective in stopping the progression of most cases of ALS is a TDP-43 therapy. A number of these therapies have been designed in laboratories for a few years, but no company has taken the risk of doing a clinical trial. Instead, companies prefer to bet on new compounds made from existing drugs, which helps speed up the passage of regulatory hurdles. A godsend for any investor including, curiously, some NGOs.

This once again illustrates how disorganized our pharmaceutical industry is. The biotechs care little about academic research, which is of poor quality anyway. Biotechs just want a quick payoff as they are essentially a gamble for investors, but they have a high death rate anyway. Large companies wait for successful biotechs, but generally do not research rare diseases because they are deemed unprofitable.

The new version of the book has also been updated in the last part which deals with the generation of new motor neurons in-vivo. This is the only way to restore health. Yet we have learned that new motor neurons derived from the patient's astrocytes are also carriers of the disease, so there is a phenomenon here that is not well understood.

Perhaps ALS and other neurodegenerative diseases belong to a spectrum of diseases where cells are not functional, for example because they are in a perpetual UPR / ISR state. An Italian clinical trial hints at something like this, let's hope Sephin1 / IFB-088 will be tried soon and give good news.

The French book is still not updated.

Otherwise the best advice ALS patients could be given in 2021 is still to keep their BMI at 27.

Jean-Pierre Le Rouzic Please do not hesitate to send me any feed-back

The ability to generate in-vivo spinal cord motor neurons from human pluripotent stem cells would be a major milestone in motor neuron-based diseases such as ALS. enter image description here

A key step in the design of human pluripotent stem cells differentiation strategies aiming to produce in-vitro motor neurons involves induction of the appropriate anteroposterior (A-P) axial identity, an important factor influencing motor neuron subtype specification, functionality, and disease vulnerability.

The anterior grey column contains motor neurons that affect the skeletal muscles while the posterior grey column receives information regarding touch and sensation. The anterior grey column is the column where the cell bodies of alpha motor neurons are located.

In-vitro generation of neural progenitors from human pluripotent stem cells holds a great promise for the development of cell-therapy-based approaches and the study of the specification of lineages and hence has attracted a considerable amount of research interest.

The protocols reported in literature generally are based on a multistep process that includes multiple neural induction, differentiation and maturation phases. This multistep process last weeks.

Scientists have previously described the generation of neural crest populations corresponding to various levels along the anteroposterior (A-P) axis from human pluripotent stem cells, including vagal neural crest (Frith et al., 2018). Yet stem cell derived motor neurons are often functionally immature.

Neural crest is a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia. The ectoderm is the outermost layer of the three primary germ layers formed in early embryonic development.

To date, differentiation strategies have either implemented human pluripotent stem cells in the presence of EGF, FGF signals (Li et al., 2018; Workman et al., 2017) or employed a monolayer differentiation approach that relies on transforming growth factor β (TGF-β) signaling suppression, bone morphogenetic protein (BMP) signaling regulation and WNT pathway stimulation to generate an neural crest like population (Barber et al., 2019; Lau et al., 2019).

Patterning of the in vitro derived neural crest to a vagal axial identity is routinely achieved by retinoic acid (RA) addition while further commitment has been mediated by co-culture with intestinal/colonic organoids (Lau et al., 2019), gut tissue explants (Li et al., 2018), or further differentiation following culture in neurotrophic medium (Barber et al., 2019; Lau et al., 2019).

An efficient method of directed differentiation, generates progenitors from human pluripotent stem cells via the combined WNT signaling stimulation and TFG-β pathway inhibition together with precise levels of bone morphogenetic protein signaling.

Most current protocols for induction of motor neurons from human pluripotent stem cells produce predominantly cells of a mixed hindbrain/cervical axial identity marked by expression of Hox paralogous group (PG) members 1-5, but are inefficient in generating high numbers of more posterior thoracic/lumbosacral Hox PG(8-13)+ spinal cord motor neurons.

Here, the authors describe a protocol for efficient generation of thoracic spinal cord cells and motor neurons from human pluripotent stem cells. This step-wise protocol relies on the initial generation of a neuromesodermal-potent axial progenitor population, which is differentiated first to produce posterior ventral spinal cord progenitors and subsequently to produce posterior motor neurons exhibiting a predominantly thoracic axial identity.

Japanese scientists, including the famous ALS specialist Makoto Urushitani, as well as the first author Ryutaro Nakamura, wanted to study whether hypermetabolism, but also lipid metabolism, could predict the prognosis of patients with Early amyotrophic lateral sclerosis (ALS), with different nutritional profiles when they are hospitalized.

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Indeed, many elements show the importance of non-pharmacological treatment which can improve quality of life, decrease progression or increase survival time in ALS.

The early introduction of non-invasive positive pressure ventilation, especially with cough assistants, would prolong the life of ALS.

In addition, a high calorie diet effectively slows the progression of ALS, especially in patients with rapid progression.

Surprisingly, in rapidly progressing ALS, a fat-dominant high calorie diet inhibits the elevation of serum neurofilament-L (NFL), a convincing biomarker of neuronal damage.

A body mass index (BMI) of less than 18.5 on the first visit to neurologists is recognized as a factor of poor prognosis.

Despite these clinical evidence, and although many studies have shown that age and BMI are the best biomarkers for predicting the course of ALS, these studies encounter a sort of consensus narrative barrier that says ALS is a disease of the upper motor neurons and the loss of muscle mass is exclusively due to the lack of activation by the lower motor neurons.

Similarly while scientists say that TDP-43-like proteopathy is present in all cells of the body of patients, particularly in skeletal muscles (those involved in ALS) in 97% of cases, it seems it is unlikely that ALS would target only certain cells and only in the brain and spinal cord.

Finally, more than half of ALS patients have hypermetabolism, that is, to perform a certain task, their body needs more energy than the body of a healthy person.

Patients with ALS have impaired glucose tolerance from an early stage, and free fatty acids are higher in these patients than in those with normal glucose tolerance. The energy production pathway has been reported to switch from glycolytic metabolism to lipid metabolism during disease.

This indicates that lipids could be the primary fuel in malnourished patients as well as in ALS mice, although no studies have examined changes in metabolism in response to nutritional status in humans.

Elevated levels of total and low density lipoprotein (LDL) cholesterol and a higher LDL / high density lipoprotein (HDL) cholesterol ratio have been associated with longer survival, which could indicate a metabolism primarily using lipids rather than glucose.

Therefore, Ryutaro Nakamura and colleagues retrospectively reviewed the available information on forty-eight patients (25 men; 23 women) over 49 years of age with ALS admitted to Shiga University of Medical Sciences Hospital. from March 2018 to February 2021.

The aim of the scientists was to test the hypothesis that the impact of hypermetabolism on survival might differ depending on nutritional status. enter image description here

Fig. 1: Comparison of the survival rate between the hypermetabolic group and the normal metabolic group in all patients (a), the normal weight group (b), the malnutrition group (c). Kaplan-Meier analyzes and the log-rank test showed that there was no difference in all patients; however, the hypermetabolic group had a significantly shorter survival time in the normal weight group and a longer survival time in the malnutrition group, although the difference was not significant.

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Fig. 2: Comparison of survival rate between patients with amyotrophic lateral sclerosis stratified by excessive weight loss (a), body fat percentage (b) and low density lipoprotein (LDL) cholesterol (c). analyzes showed that patients with excessive weight loss and a low percentage of body fat had a significantly shorter survival time.

In this study, Japanese scientists explored the effect of hypermetabolism on survival versus nutritional status of patients with ALS, and found that hypermetabolic patients with normal weight had a shorter life, while survival was longer in hypermetabolic patients with malnutrition. They find that survival is correlated with LDL levels.

The low level of skeletal muscle and soft tissue mass, which is a factor of poor prognosis, could be the reason why the prognosis of the normal weight hypermetabolic group is worse than that of the other groups.

Surprisingly, hypermetabolism was a better prognostic factor in the malnutrition group (Fig. 1). Lipid biomarkers were characteristic in this group, which may contribute to longer survival.

The hypermetabolic malnutrition group had the highest median LDL value among all groups, and a higher body fat percentage, which were good prognostic factors in previous studies.

Indeed, patients with a high body fat percentage had a longer survival in their study (Fig. 2), and patients with high LDL showed a similar trend.

It should be noted that the respiratory quotient was less than 0.85 in eight of the nine patients in this group and that the fasting blood sugar was significantly higher in this group, which could indicate a change in lipid metabolism compared to the glucose hypothesis.

Respiratory quotient was associated with ALSFRS-R and time from onset, and it is interesting to hypothesize that a "fuel switch" may underlie metabolic profiles in progression. of ALS.

In addition, Steyn et al. reported that high fatty acid oxidation increases whole body energy expenditure and slows disease progression, which may support the findings described here and indicate the contribution of hyperlipid metabolism to longer survival. these results caution against measuring hypermetabolism as the only prognostic indicator.

Based on the possible involvement of skeletal muscle hypermetabolism in the prognosis of ALS, Japanese scientists propose the following equation "BMM = (BMI - 19.8) × (mREE / LSTM - 38)", which successfully predicted the prognostic factor regardless of nutritional status. BMM = BMI-muscle metabolism mREE = measured rest energy expenditure LSTM = lean soft tissue mass

In conclusion, these studies show that a weight loss of more than 10% was a factor of poor prognosis. The rate of weight loss was faster in the high BMM group; thus, the BMM index could be a valuable indicator for considering aggressive nutritional intervention, including PEG (percutaneous endoscopic gastrostomy), at an early stage of clinical practice.

Calorie supplementation high in fat or carbohydrate is still a matter of debate. Some reports suggest that high-fat calorie supplementation is a better nutritional treatment in patients with ALS, while others recommend high-carbohydrate calorie supplementation.

For patients with chronic obstructive pulmonary disease who have reduced CO2 emissions, a high fat diet is recommended because lipid metabolism produces less carbon dioxide. Based on their finding that the tendency to alter lipids might contribute to a better prognosis, a high fat intake might be an attractive option in a high calorie diet for ALS. Of course, the choice of nutrition should be made with caution, depending on the metabolic profiles of the patients.

The definition the authors adopted for hypermetabolism is a high mREE / LSTM, rather than the popular world index, mREE / pREE, as the PRE estimated by the Harris-Benedict equation would not be appropriate for the assessment. metabolic rate of the Japanese.

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