Results of Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

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Tofersen is an investigational antisense oligonucleotide designed to reduce protein superoxide dismutase 1 (SOD1) synthesis through the degradation of SOD1 mRNA. This seems to me counterproductive for ALS patients, and facts seem to agree with me.

A phase 1 clinical trial (NCT01041222) tested four different doses of tofersen in 33 patients. The most common side effects were post-lumbar puncture syndrome, also known as spinal headache, injection-related back pain, and nausea. Subsequently, a second larger phase 3 trial (NCT02623699) named VALOR was initiated. Yet, in October 2021, it was announced that in this Phase 3 VALOR study, the primary endpoint measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) did not reach statistical significance.

Surprisingly (or maybe unsurprisingly), the principal investigator stated that "The results from the VALOR study are encouraging as they show reduction of SOD1 protein, reduction of neurofilament, a potential biomarker for neurodegenerative disease, and positive signals across multiple key endpoints including measures of important aspects of the daily lives of SOD1-ALS patients”.

In particular, finding encouragement in the reduction of the SOD1 protein is bizarre at best. The SOD1 protein is what protects the central nervous system against the toxicity of metabolic end products. Indeed, in this case, these patients have SOD1 mutations, but why wasn't Torfersen engineered to modulate the mutated SOD1 gene by alternative splicing, functionally converting it to a normal SOD1 gene?

Another study was planned for 2022, which, as usual for recent ALS studies, was supported by famous ALS scientists such as Merit E Cudkowicz, Albert C. Ludolph or Pamela J Shaw.

In this phase 3 trial, the scientists randomly assigned adults with amyotrophic lateral sclerosis SOD1 in a 2:1 ratio to receive eight doses of tofersen or a placebo over a 24-week period. Eight doses is a lot when it's given intrathecally. Intrathecal drug delivery is the introduction of a therapeutic substance into the cerebrospinal fluid by injection into the subarachnoid space of the spinal cord to bypass the blood-brain barrier. It's an odd choice to deliver an ALS drug because it punctures the barrier that protects the central nervous system. We know that in 3% of cases, intrathecal administration of chemotherapy leads to paralysis! In this case, this barrier was perforated eight times, which means that the risk of paralysis is much higher. Serious neurological adverse events occurred in 7% of Tofersen recipients.

The primary endpoint was the change from baseline to week 28 in total score on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale among participants with more rapidly progressing disease predicted. Secondary endpoints included changes in total cerebrospinal fluid SOD1 protein concentration, plasma neurofilament light chain concentration, slow vital capacity and portable dynamometry in 16 muscles.

A combined analysis of the randomized component of the trial and its 52-week open-label extension compared outcomes in participants who started tofersen at entry into the trial with those in participants who switched from placebo to drug at week 28. A total of 72 participants received tofersen and 36 received placebo.

Morally and ethically, this means that 36 patients received eight intrathecal injections of placebo. Not only were they losing time, but they risked further health degradation by this procedure.

As in the first phase III clinical trial in the more rapidly progressing subgroup, the change at week 28 in the ALSFRS-R score (primary endpoint) was -6.98 with tofersen and -8.14 with the placebo. Administration of Tofersen also resulted in greater reductions in cerebrospinal fluid SOD1 and plasma neurofilament light chains than placebo, but overall results for secondary clinical endpoints did not differ significantly between the two groups.

At the end of the trial, 95 of the participants went on to open label extension which will last up to four and a half years. All expansion participants receive tofersen.

An analysis six months after the start of the extension found a significant difference in motor function between those who had been on tofersen from the start and those who had been on a placebo for six months before starting tofersen. After a year on the drug, the participants showed a stabilization of muscle strength and this is a remarkable finding, according to the researchers. Some scientists have even gone so far as to claim that "most of the course participants on our site regained and/or maintained a number of their activities of daily living". We see these kinds of marketing claims in all ALS clinical trials, but no one has ever encountered these lucky patients.

From a business perspective, it's hard to see Biogen's interest in Torfensen. The SOD1 gene is only mutated in about 2% of ALS patients, and there are hundreds of SOD1 mutations, so Torfensen, if effective, would be usable for less than 2% of patients.

And indeed Torfensen is not effective in ALS: If in 28 weeks the change is only 1.16 point, that means absolutely nothing in terms of improvement. Simply taking a new medication to make swallowing easier or wearing better-fitting clothing could improve the ALSFR by one or two points.

Biogen changed its strategy a few years ago in order to increase the chances of success of the clinical trials it funds. This was at a time when molecular biologists were promising wonders. Biogen could change strategy again. It would be a welcome change if human physiology were better considered in future studies.

Does ApoB mediate motor neuron degeneration in sporadic amyotrophic lateral sclerosis?

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A new publication by Jamie K Wong, and colleagues including two well known ALS scientists argues apolipoprotein B-100 in sporadic amyotrophic lateral sclerosis CSF is the putative agent responsible for inducing motor disability, motor neuron degeneration and pathological translocation of TDP-43.

While there are publications with similar claims about every week, this one sounds impressive, the scientists here have really worked hard to make sure they haven't left any stone unturned.

For a layperson like me, at first glance, this publication makes sense as there is a special relation between ALS and lipid metabolism. Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph. There are multiple classes of apolipoproteins and several sub-classes

ApoD level increases in nervous system with a large number of neurologic disorders inclusive of Alzheimer's disease, schizophrenia, and stroke. ApoE has been implicated in dementia and Alzheimer's disease.

So why not ApoB and ALS? Moreover overproduction of apolipoprotein B can result in lipid-induced endoplasmic reticulum stress and insulin resistance in the liver. ER stress leads to mislocalized misfolded proteins in cytosol, and half of ALS patients exhibit insulin resistance. In addition patients with ALS have higher levels of LDL-C, ApoB, and ApoB/ApoAI ratio already 20 years before diagnosis.

Yet this is not a study on humans but on mice and motor neurons in-vitro, and as usual a lot could be said about mice animal models of ALS. So maybe their claim, that ApoB is the agent responsible for inducing sporadic ALS, needs more work.

In addition a recent publication claimed that ALS patients that have elevated levels of ApoB in blood are associated with a lower risk of death. ApoB is also correlated with LDL (the "bad" cholesterol). Another study claimed the contrary. Yet another study did not find any evidence of association between lipoprotein or apolipoprotein levels and clinical findings.

There is also a lack of associations of cholesterol-lowering drugs (which lowers ApoB), antihypertensive drugs, and antidiabetics with the risk of ALS.

So we must remain cautious again, anyway even if this finding about ApoB and ALS was true, a commercial drug would be available only in 10 or 20 years.

Synucleinopathy in Amyotrophic Lateral Sclerosis?

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I have for long thought that subtle distinctions between neurodegenerative diseases were blurring the understanding instead of making thing clearer.

In particular we know that ALS and FTD have something in common (TDP-43 aggregates), that Parkinson, dementia with Lewy bodies and Multiple System Atrophy are related (Alpha-synuclein aggregates (αSyn)), even some case of Alzheimer are related to ALS and FTD (Limbic-predominant age-related TDP-43 encephalopathy).

Yet an article to be published soon pushes the boundaries by hinting that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43.

Around 50 cases of ALS/Parkinson commorbidities have already been described such this one, yet suggesting there is something fundamental behind ALS and Parkinson have never been suggested.

Many neurogenerative diseases are accompanied by accumulation of protein aggregates such as extracellular amyloid-β (in Alzheimer’s disease), intraneuronal hyper-phosphorylated tau (in Alzheimer’s disease), or α-synuclein (in Parkinson’s disease).

TDP-43 pathologies are widely varied and affects different cell types and brain regions. TDP-43 was reported to co-localize with other protein species characteristic in other neurogenerative diseases, namely Huntington’s disease, Parkinson’s disease, dementia with Lewy bodies, and Alzheimer’s disease. One reason may be that TDP-43 has regions of low complexity such its C-terminal domain, which could easily bind to other proteins.

The authors found a growing body of evidence that suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. They discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.

This does not explain the colocation of those proteins. An article published a year ago might point to a little discussed suspect: Karyopherins.

Karyopherins are proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. Most proteins require karyopherins to traverse the nuclear pore.

Karyopherins can act as importins (i.e. helping proteins get into the nucleus) or exportins (i.e. helping proteins get out of the nucleus). Energy for transport is derived from the Ran gradient.

Upon stress, several karyopherins stop shuttling between the nucleus and the cytoplasm and are sequestered in stress granules, cytoplasmic aggregates of ribonucleoprotein complexes...

Synucleinopathy in Amyotrophic Lateral Sclerosis?

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I have long thought that the subtle distinctions between neurodegenerative diseases blur the understanding instead of making things clearer.

In particular we know that ALS and FTD have something in common (TDP-43 aggregates), that Parkinson, dementia with Lewy bodies and Multiple System Atrophy are related (Alpha-synuclein aggregates (αSyn)), even some case of Alzheimer are related to ALS and FTD (Limbic-predominant age-related TDP-43 encephalopathy).

Yet an article to be published soon pushes the boundaries by hinting that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43.

Around 50 cases of ALS/Parkinson commorbidities have already been described such this one, yet suggesting there is something fundamental behind ALS and Parkinson have never been suggested.

Many neurogenerative diseases are accompanied by accumulation of protein aggregates such as extracellular amyloid-β (in Alzheimer’s disease), intraneuronal hyper-phosphorylated tau (in Alzheimer’s disease), or α-synuclein (in Parkinson’s disease).

TDP-43 pathologies are widely varied and affects different cell types and brain regions. TDP-43 was reported to co-localize with other protein species characteristic in other neurogenerative diseases, namely Huntington’s disease, Parkinson’s disease, dementia with Lewy bodies, and Alzheimer’s disease. One reason may be that TDP-43 has regions of low complexity such its C-terminal domain, which could easily bind to other proteins.

The authors found a growing body of evidence that suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. They discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.

This does not explain the colocation of those proteins. An article published a year ago might point to a little discussed suspect: Karyopherins.

Karyopherins are proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. Most proteins require karyopherins to traverse the nuclear pore.

Karyopherins can act as importins (i.e. helping proteins get into the nucleus) or exportins (i.e. helping proteins get out of the nucleus). Energy for transport is derived from the Ran gradient.

Upon stress, several karyopherins stop shuttling between the nucleus and the cytoplasm and are sequestered in stress granules, cytoplasmic aggregates of ribonucleoprotein complexes...

Can Terazosin be Repurposed to Treat ALS?

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There were 35 clinical trial of Terazosin, most recents are related to various neurodegenerative diseases. enter image description here

Terazosin, is normally used to treat symptoms of a (non cancerous) enlarged prostate and high blood pressure. It was recently discovered to increase energy levels (in the form of ATP molecules) in the brain by enhancing glycolysis.

Hypertension is prevalent in obese and diabetic patients. As soon as 1991, scientists hypothesized that people with hypertension are also likely to suffer from insulin resistance, glucose intolerance, and hyperinsulinemia.

They noted that commonly used antihypertensive agents, such as thiazide, thiazide-like diuretics, and beta-blockers, are associated with glucose intolerance and increased insulin resistance. In contrast, angiotensin-converting enzyme inhibitors, calcium antagonists, and peripheral alpha-blockers (such as prazosin and terazosin) do not adversely affect glucose tolerance or insulin sensitivity.

Yet Terazosin is not without side effects: Orthostatic hypotension, asthenia, dizziness, faintness and syncope.

Insulin stimulates glycolysis. glycolysis is an anaerobic pathway to make ATP (as opposed to the usual Krebs-cycle way, the citric acid cycle and oxidative phosphorylation).

Fixing the underlying insulin resistance would be nice, but we don't actually understand the biochemical mechanisms behind it enough to do that directly yet. Metformin is probably the closest thing, and it has several other beneficial effects as well, but we don't really understand its mechanism(s) of action either.

In 2019 Terazosin suddenly leapt into a growing pool of drugs that might have a repurposed role in Parkinson’s disease, such as exenatide, salbutamol, ursodeoxycholic acid, nilotinib, deferiprone, and ambroxol.

An article with contributors from many laboratories tell that as Terazosin stimulates glycolysis and increases cellular ATP levels, it may change the course of Parkinson’s disease. In toxin-induced and genetic Parkinson's disease models in mice, rats, flies, and induced pluripotent stem cells, Terazosin increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function.

The scientists also interrogated 2 distinct human databases and found slower disease progression, decreased Parkinson's disease-related complications, and a reduced frequency of Parkinson's disease diagnoses in individuals taking Terazosin and related drugs.

So other teams of scientists tried to replicate this success with other neurodegenerative diseases, including ALS.

In this later case, they increased activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) using Terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.

The scientists found that targeting PGK1, indeed modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour.

Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43M337V, Terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.

The team is now inviting 50 patients from the Oxford MND Care and Research Centre to participate in a feasibility study to examine the impact of terazosin on key indicators of disease progression. If this proves successful and if they find financial sponsors, they will look to move forward into a full clinical trial.

As usual, ALS mice models are not realistic, they live only 25 days when an healthy mouse lives 2 years (30 times more). As ALS in humans strikes mostly after 50 years old, a realistic mice model should live 14 months before being ill. Indeed this would create insanely long experiments, slow publication rates, and it would be costly. As in the old joke, scientists prefer to look where it's easy even if they know that current neurodegenerative diseases mice models are useless.

Let's cross our fingers, who knows, this time it may work.

EU Awards €2.5M for Potential Vaccine for ALS Tied to C9orf72 Gene

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Intravacc, a contract development and manufacturing organization (CDMO) of preventive and therapeutic vaccines and the German Center for Neurogenerative Diseases (DZNE), have been awarded a funding of € 2.5 million from the European Union (EIC Transition Grant) to further develop a prototype C9orf72 ALS vaccine.

Mutations in C9orf72 gene causes excessive repeats of six nucleotides GGGGCC. These extra repeats lead to the production of abnormal proteins, called dipeptide repeat proteins (DPR). Moreover, excessive GGGGCC repeats in the C9orf72 gene also are one of the most common causes of frontotemporal dementia (FTD).

Researchers from the German Center for Neurogenerative Diseases hypothesized that using a vaccine to induce the production of such antibodies by the body’s immune system could be a potential therapy for ALS and FTD linked to C9orf72 gene mutations.

This is a concept close to ASO, but it would make the body continuously targeting those repeats, while ASO work only for a short time after administration.

In recent years, there has been increasing interest in the use of monoclonal antibodies to treat neurodegenerative disorders, with the goal of targeting misfolded intra- or extra-cellular proteins, such as amyloid beta peptide, tau, or alpha-synuclein.

Very recently, the U.S. FDA has approved Aducanumab, a recombinant monoclonal antibody against amyloid beta plaques, for the treatment of Alzheimer's disease patients.

Antibodies show a considerable number of advantages when used for therapeutic purposes. They possess a long half-life, and, due to their nature, they can efficiently target proteins in their physiological state, after post-translational modifications or in a misfolded conformation, with high specificity and affinity.

Yet there were many pre-clinical studies involving antibodies against SOD1 or TDP-43 without much success. In 2019 a study had more success with C9orf72.

Antibodies are big molecules and might pose difficulties in penetrating the CNS due to the natural defense structure of the blood-brain barrier (BBB). The use of single chain antibodies could overcome this issue since they are smaller in size and possess higher cellular penetration capacity.

Antibodies treatment starting at the pre-symptomatic stage often proves less effective when delivered at the symptomatic stage, corroborating the need to evaluate therapeutic efficacy when the pathology has already manifested itself. As sporadic ALS patients are diagnosed only years after the beginning of their symptoms, it is unclear how such therapies could be effective.

What strikes me, is that despite the high number of studies on ALS, all the attempts to make therapies seem to explore only rather improbable paths.

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Biogen stops working on BIIB100, one of its three amyotrophic lateral sclerosis (ALS) drug candidates

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Biogen is discontinuing BIIB100 (an XPO1 inhibitor) as one of its three amyotrophic lateral sclerosis (ALS) drug candidates. This is a sad news as Tofersen, an ASO, its most advanced of the three ALS programs, failed recently to hit the primary endpoint, even as Biogen has made the case for the asset and engaged with regulators about the next steps.

Biogen’s other clinical-phase ALS candidate is BIIB105, another antisense asset. BIIB105 is in a phase 1 clinical trial designed to assess its effect on two forms of ALS.

Biogen partnered on BIIB100 in 2018 with a biotech named Karyopharm Therapeutics which wanted to focus on their cancer pipeline. The idea was that if BIIB100 was successful, then Biogen would bought it for $207 million.

Biogen began a Phase 1 trial in 49 adults with ALS the following year to investigate whether reducing nucleoprotein export by inhibiting the nuclear transport factor XPO1 can prevent the formation of neuronal cytoplasmic inclusions and thus slow the sporadic progression of ALS.

Work on the study was completed in June 2021. On June 7, 2022, Biogen wrote to Karyopharm terminating the agreement, with Karyopharm notifying investors eight days later.

BIIB100 crosses the blood-brain barrier more readily than other selective inhibitors of nuclear export compounds. It's also supported by research suggesting it causes the binding and blocking of NF-κB, a protein involved in inflammation.

It's not clear to me why Biogen saw a great potential for a XPO1 inhibitor in ALS. XPO1 exports several hundreds of different proteins from the nucleus. XPO1 is involved in various viral infections and in many cancer.

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Quality of life was better with CNM-Au8 than with placebo nearly one year after the start of the ALS treatment.

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The RESCUE-ALS trial (NCT04098406) enrolled 45 people with early-onset ALS, who were assigned randomly to take CNM-Au8 (30 mg/day) or a placebo for 36 weeks (about nine months). Participants then had the option to enter an open-label extension study in which all were given CNM-Au8. Results were presented in November 2021.

It's a phase II trial, which means it was designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients.

The trial, did not meet its primary and a key secondary goal after 36 weeks of treatment: higher Motor Unit Number Index (MUNIX) scores — which measure the number, function, and health of motor neurons — and greater forced vital capacity (FVC), a measure of lung health. However, a trend toward better MUNIX scores was evident at 12 weeks among patients taking CNM-Au8.

In addition, quality of life at week 36 was significantly better in patients taking the investigational therapy, and there was evidence of benefit in long-term survival.

Over the eight-month trial, the therapy was also found to be relatively well-tolerated with no reported life threatening adverse events related to treatment.

It was followed by an open label trial. The data has accumulated and some new results of this open label trial were presented at ENCALS (2022 European Network to Cure ALS).

One poster (a low cost way to present results in scientific conferences) suggests that survival was improved by 24 weeks. Yet the phrasing is not very clear, it tells that early and continuous treatment with CNM-Au8 reduced mortality risk by 62% compared to delaying treatment. In one case one knows they can live longer, in the other case one can expect to be in the lucky people who would not die early.

A second poster is less bold, but clearly shows that quality of life was better with CNM-Au8 tha with placebo nearly one year after the start of the treatment. A third one reiterates that quality of life was better with CNM-Au8.

An ongoing platform clinical trial called HEALEY (NCT04297683) is testing the effectiveness of CNM-Au8 alongside several other potential ALS therapies. Results are expected later this year.

While all those good results are welcomed, one should reminds itself that in the world of biotechs it is common practice to make excessive announcements in order to attract investors. Here what could refrain enthusiasm is the lack of scientific publications on CNM-Au8, except those posters. Posters are usually presented by students, not by professional scientists.

Clene Nanomedicine claims that CNM-Au8 is a catalytic gold nanoparticule, which probably means it accelerates metabolic reactions. Usually nanoparticles are used to vehicle a drug, for example mRNA in COVID vaccines. So far CNM-Au8 has been demonstrated to be an efficient catalyst for metabolic energy reactions, converting the energetic metabolite nicotinamide adenine dinucleotide hydride (NADH) into NAD+ in proof-of-principle cell-free assays.

It's not clear what makes CNM-Au8 so successful in ALS. There is no publications on animal models of ALS. One can wonder why there is no more regulatory supervision on the organization of new clinical trials.

Let's hope these good results it will trigger more and more opened research in the area of nanoparticles for ALS.

ROS and Endoplasmic Reticulum Stress in Pulmonary Disease.

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Here is an interesting article, that reviews misfolded proteins in lungs. In our body, cells while available in ~200 types, share common characteristics, so it's not surprising that diseases that affect brain cells, also affect other organs. Misfolded and mislocated proteins are associated with most neurodegenerative diseases, yet we do not know if they are a cause or a consequence of the disease.

Lung disease is one of the leading causes of morbidity and mortality worldwide. Current studies show that although lung diseases possess unique pathophysiology and specific clinical manifestations, they still tend to exhibit common features, including accumulation of reactive oxygen species and disturbances in proteostasis leading to accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER).

The article is not really precise on these disruptions of proteostasis, how they emerge, nor how they cause the accumulation of unfolded or misfolded proteins. One can however imagine that the long way by which a protein is elaborated and which by the making of a messenger RNA, its use by a ribosome (stuck to a membrane of the ER) to generate an unfolded protein, its folding in the ER then its dispatch in vesicles on the operating site by the Golgi apparatus, is susceptible to many malfunctions.

The cellular response to proteostasis dysfunction is called UPR. This is a set of poorly understood mechanisms that globally decrease the production of proteins for the duration of the stressful event, but whose involvement in neurodegenerative diseases is increasingly suspected.

In fact, decreasing the production of proteins does not really help the survival of the biological host of these cells, these proteins are necessary for life, and each is involved in all kinds of biological reactions. The triggering of UPR is therefore a guarantee of future health problems for the host.

When the adaptive unfolded protein response fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to disruption of ER integrity and apoptosis, referred to as ER stress.

ER stress primarily includes accumulation of misfolded and unfolded proteins in the lumen and disturbance of Ca balance. ROS mediate several critical aspects of the ER stress response.

Here the authors summarize the latest advances in UPR and ER stress in the pathogenesis of lung disease and discuss potential therapeutic strategies aimed at restoring ER proteostasis in lung disease.

Hopefully this kind of publication will help to cross-fertilize research in UPR mechanisms in brain diseases, and they may also help shed a new look on muscle wasting in ALS, not as a consequence of motor neuron disease, but as an independent event occurring in a more global context.

Read the original article on Pubmed

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Efficacité de la méthylcobalamine à ultra-haute dose pour les patients atteints de SLA

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L'efficacité des médicaments actuellement approuvés pour la sclérose latérale amyotrophique est très limitée.

Plusieurs études (1) ont montré que la méthylcobalamine, une forme de vitamine B12, à ultra-haute dose était capable de ralentir la progression de la SLA.

La carence en vitamine B12, une voie biologique commune à la SLA, la maladie d'alzheimer, de Parkinson et la sclérose en plaque, est connue pour provoquer une toxicité mitochondriale en raison de l'inhibition du cycle de l'acide citrique (Toyoshima et al. 1996) et prédit une aggravation de la mobilité chez les patients atteints de la maladie de Parkinson (Christine et al. 2018 ).

Le cycle de Krebs (aussi appelé TCA ou cycle de l'acide citrique) est utilisé par les organismes qui respirent par opposition aux organismes qui fermentent pour générer de l'énergie, soit par respiration anaérobie, soit par respiration aérobie. De plus, le cycle fournit des précurseurs de certains acides aminés, ainsi que l'agent réducteur NADH, qui sont utilisés dans de nombreuses autres réactions. Dans les cellules eucaryotes, le cycle de l'acide citrique se produit dans la matrice de la mitochondrie.

Dans le but de valider l'efficacité et l'innocuité de la méthylcobalamine à ultra-haute dose pour les patients atteints de sclérose latérale amyotrophique inscrits dans l'année suivant leur apparition, [des scientifiques Japonais on mené un essai clinique][1] de phase III multicentrique, contrôlé par placebo, en double aveugle et randomisé avec une période d'observation de 12 semaines et une période randomisée de 16 semaines, menée du 17 octobre 2017 au 30 septembre 2019. Les patients ont été recrutés dans 25 centres de neurologie au Japon .

Le nombre cible de participants était de 64 dans les groupes méthylcobalamine et placebo. Les interventions ont consistées en l'injection intramusculaire de méthylcobalamine ou de placebo deux fois par semaine pendant 16 semaines (ce qui est une courte durée). Le critère d'évaluation principal de l'étude clinique était la modification du score total de la ALSFRS-R entre le départ et la semaine 16 dans l'ensemble d'analyse complet.

Au total, 129 patients étaient éligibles pour l'ensemble complet d'analyses et 126 ont terminé l'étape en double aveugle. Parmi ceux-ci, 124 patients sont passés à la période d'accès ouvert. La différence du score total de l'ALSFRS-R sur ces 4 mois de la période randomisée était supérieure de 1,97 point avec la méthylcobalamine par rapport au placebo. C'est réellement une différence importante qui est comparable aux meilleurs médicaments utilisés actuellement dans le cadre de la SLA.

L'incidence des événements indésirables était similaire entre les 2 groupes.

Il ne s'agit toujours pas d'un remêde miracle, mais certainement et comme plusieurs produits similaires, d'un médicament capable d'atténuer les effets de la SLA.

Identifiant ClinicalTrials.gov : NCT03548311.

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