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.

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.

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.

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.

Voir notre post sur les résultats ici.

Deep brain stimulation (DBS) is an established therapy for patients with Parkinson's disease. In silico computer models for DBS allow to pre-select a set of potentially optimal stimulation parameters. If efficacious, they could further carry insight into the mechanism of action of DBS and foster the development of more efficient stimulation approaches. In recent years, the focus has shifted towards DBS-induced firing in myelinated axons, deemed particularly relevant for the external modulation of neural activity.

The scientists in this new medRxiv publication, use the concept of pathway activation modeling, which incorporates advanced volume conductor models and anatomically authentic fiber trajectories to estimate DBS-induced action potential initiation in anatomically plausible pathways that traverse in close proximity to targeted nuclei.

Then the scientists applied the method on a retrospective dataset with the aim of providing a model-based prediction of clinical improvement following DBS (as measured by the motor part of the Unified Parkinsons Disease Rating Scale).

Based on differences in outcome and activation rates for two DBS protocols in a training cohort, the authors computed a theoretical 100% improvement profile and enhanced it by analyzing the importance of profile matching for individual pathways.

Finally, the authors validated the performance of authors' profile-based predictive model in a test cohort.

As a result, the authors demonstrated the clinical utility of pathway activation modeling in the context of motor symptom alleviation in Parkinsons patients treated with DBS.

Read the original article on medRxiv

Another interesting article was published by Alzforum. Alzforum is a quality news website dedicated to Alzheimer’s disease and other neurodegenerative disorders. It is a subsidiary Fidelity Management & Research. In Alzheimer disease, aggregation of Aβ42 peptide into amyloids is conceived as the pathogenic trigger of a cascade leading to tau accumulation into neurofibrillary tangles, neuronal loss, and clinical dementia. However, while most of the 40 anti-amyloid clinical trials over the past two decades have successfully reduced the burden of brain amyloid, corresponding benefits for the patients have never materialized.

Moreover, brain amyloidosis does not invariably predict dementia: by the age of 85, the prevalence of brain amyloidosis is approximately 60% whereas that of dementia is only of 10%.

This new study makes the revolutionary hypothesis that high levels of natively-folded, soluble Aβ42 are associated with normal cognition in the setting of brain amyloidosis.

In a cross-sectional analysis of 598 brain amyloid-positive individuals participating in the Alzheimer's Disease Neuroimaging Initiative, higher levels of soluble Aβ42 were associated with normal cognition.

Higher soluble Aβ42 levels were also associated with better neuropsychological performance and larger hippocampal volume, with a larger effect size yielded by changes in soluble Aβ42 than in insoluble (brain amyloid) Aβ42.

“The main premise on which Alzheimer’s and all neurodegenerative diseases are conceived, is essentially the idea that proteins are toxic. It should end,” Alberto Espay, University of Cincinnati, told Alzforum.

Espay and Ezzat want their findings to inspire a paradigm shift on how we view neurodegenerative disease. “Our key message is that neurodegenerative diseases, in general, are associated with loss of protein,” said Espay. He contends that yes, aggregates accumulate, but total soluble protein goes down and that is what leads to disease. Tau protein levels falls in tauopathies, as synuclein in falls in Parkinson’s, Aβ in Alzheimer's disease, and progranulin in FDD/ALS.

The situation in Parkinson's disease mirrors what the scientists found in Alzheimer's disease. Most cases of Parkinson's disease have no specific known cause. A small proportion of cases, however, can be attributed to known genetic factors. Environmental toxins, herbicides, pesticides, and fungicides, as well as some medical and recreational drugs have been associated with the risk of developing PD. Vascular events such as stroke can cause Parkinson's disease. As for ALS, there are many conditions that look similar to Parkinson's disease. The motor symptoms of the disease result from the death of cells in the substantia nigra, a region of the midbrain.

For several generations of neurologists, the alpha-synuclein protein has been at the center of the Parkinson's disease universe. Alpha-synuclein is exists in the same form since prehistoric genomes. While the function of a protein molecule generally depends on its correct shape, wouldn't adopting an “incorrectly shaped” beta sheet aggregate make it impossible for it to function?

The central event was the discovery in 1997 that autosomal dominant Parkinson's disease was caused by a point mutation in the SNCA gene. Alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.

The elegant work of Braak and colleagues on the brains of patients under 50 with Parkinson's disease has shown that alpha-synuclein aggregates in a stereotypical pattern, conspicuously first appearing in the peripheral nervous system, then into the central nervous system.

As with the beta-amyloid protein in Alzheimer's disease, the elimination of alpha-synuclein in young mice makes no difference and actually protects them from the effects of MPTP, a mitochondrial toxin. Surprisingly, knockout mice, where the SNCA gene has been turned off, develop deficits when they get old!

One of the curious things about Lewy bodies is that the proportion of substantia nigra neurons containing Lewy pathology remains relatively constant regardless of how many neurons are already lost, which invalidates the classic belief that it is Lewy bodies that cause cell death in the substancia nigra.

Is it really the higher level of proteins, normal or mutated, that ultimately leads to 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. 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.

Mitochondria are organelles that have their own genomes, which are small and only encode 13 proteins, compared to around 20,000 for the genome of human cells. By National Human Genome Research Institute - via Wikipedia

More than 1000 proteins are used by the mitochondria to perform their functions, the mitochondria therefore rely on the importation of proteins encoded in the nucleus of the host cell. The majority of mitochondrial proteins are synthesized in the cytosol and must be actively transported to the mitochondria, a process that occurs via a sophisticated system.

In many neurodegenerative diseases, there are dysfunctions in the management of proteins. This is called proteopathies. Proteopathies are found in diseases such as Creutzfeldt-Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, ALS and a wide range of other disorders.

Since proteins share a common structure known as the polypeptide backbone, all proteins have the potential to fold badly under certain circumstances. Mitochondrial defects might be responsible in part for those misfolded proteins that accumulate in the cytosol.

However, it is still unclear whether mitochondrial defects appear as a consequence of neurodegeneration, or if they contribute to it, or both. Since the accumulated mitochondrial protein precursors can form toxic aggregates, host cells have a mechanism to respond to and cope with them properly.

In an excellent eLife publication, Urszula Nowicka and colleagues at the University of Warsaw hypothesized that mitoprotein-induced stress induces a general response to precursor proteins which then accumulate in the cytosol and this contributes to the onset and progression neurodegenerative disorders. In this study, the authors propose a new mechanism of proteostasis.

Studies have shown that specific mitochondrial proteins that are functionally related to oxidative phosphorylation are downregulated by transcription in Alzheimer's disease. In the present study, scientists at the University of Warsaw investigated why these proteins are downregulated.

They used yeast homologues of these proteins to show the consequences of this cytosolic accumulation as well as of C. elegans worms. They applied mutations to the import machines, overexpression of mitochondrial proteins and CCCP (a decoupler of oxidative phosphorylation). They studied two disease-relevant aggregation models - α synuclein and Amyloid beta aggregation.

They found that importation of compromised mitochondrial proteins caused overall changes in the levels of transcriptome and proteins, especially chaperones, including Hsp104 and Hsp42, ABC transporters and mitochondrial proteins, which can lead to growth defects. (yeast) and decreased motility (C. elegans).

This new hypothesis complements the recent findings very well that unprocessed (but imported!) Precursor proteins aggregate in the mitochondrial matrix and initiate an mtUPR-like response.

These proteins trigger a molecular chaperone response specific to the host cell that aims to minimize the consequences of protein aggregation. However, when this rescue mechanism is insufficient, these aggregates stimulate cytosolic aggregation of other mitochondrial proteins and lead to downstream aggregation of non-mitochondrial proteins.

The present study showed that a group of mitochondrial proteins that are downregulated in Alzheimer's disease (i.e. Rip1, Atp2, Cox8 and Atp20) can aggregate in the cytosol and that the overexpression of these proteins upregulates Hsp42 and Hsp104, two molecular chaperones. Cellular stress responses induced by mitochondrial proteins mitigate the danger.

Urszula Nowicka's findings indicate why and how metastable mitochondrial proteins can be downregulated during neurodegeneration to minimize the imbalance in cellular protein homeostasis caused by their poor targeting.

Several stress response pathways have recently been identified to counteract import defects in mitochondrial proteins. It is not known, however, whether they act independently or whether simultaneous actions of all of these stress responses are necessary to ensure balanced homeostasis of cellular proteins.

It is likely that the study of the mechanisms of protection against stress, whether at the cellular level or at the mitochondrial level, will make it possible to better understand neurodegenerative diseases and to develop drugs to treat them.

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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.