This is another study about oxytocin role in autism. It reflects a view of autism as mainly about communication skills. Yet autism's diagnostic is not standardized, and as for some other diseases biomarkers are actively seeked as hopes for a genetic origin have been dashed.

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Studies have looked at oxytocin's role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, in-group bias, autism, and maternal behaviors.

As Oxytocin is believed to have a significant role in social learning, it has been implicated in the etiology of autism, with one report suggesting autism is correlated to a mutation on the oxytocin receptor gene (OXTR). Low levels of oxytocin could become a new biomarker for individuals that fall into the Autism Spectrum.

Yet clinical trials of the efficacy of oxytocin in autism spectrum disorder (ASD) have reported mixed results due in part to autism spectrum disorder complex etiology. The scientists here hypothesized that genetic and epigenetic variation contribute to variable endogenous oxytocin levels that modulate sensitivity to oxytocin therapy.

To test this hypothesis, the authors integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma oxytocin levels in 290 participants with autism spectrum disorder enrolled in a randomized controlled trial of oxytocin.

Their analysis shows subtle, but statistically significant association of plasma oxytocin levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. The scientists also identified genetic variants with novel association with plasma oxytocin, several of which reside in known autism spectrum disorder risk genes.

These findings broaden authors' understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of autism spectrum disorder and its interaction with oxytocin signaling and oxytocin-based interventions.

Read the original article on medRxiv

La prévalence des maladies neurodégénératives augmente et reste sans traitement modificateur (à défaut de cure) de ces maladie, et la plupart des essais de nouveaux médicaments échouent. Les solutions proposées consistent à viser en amont : cibler les causes profondes moléculaires de la maladie et tester les thérapies plus tôt, même à des stades pré-symptomatiques.

Des scientifiques du Massachusetts General Hospital ont cherché à comprendre à quels stades de leur maladie devenaient éligibles les patients qui désiraient s'inscrire dans des essais cliniques sur les maladies neurodégénératives au cours des dernières années et quelles cibles moléculaires ont été testées dans ces essais.

Ils ont trouvé que les critères d'éligibilité pour les essais se sont progressivement déplacés vers des stades plus précoces et plus bénins de la maladie, mais sont toujours massivement axés sur les patients symptomatiques, en particulier pour les essais de médicaments parrainés par l'industrie. Les médicaments ciblant les gènes associés à la maladie considérée ne représentent qu'une fraction de l'effort de développement de médicaments, et leur succès a peut être entravé par une concentration sur les patients symptomatiques, où la pertinence de la cible par rapport au taux de progression de la maladie est moins claire.

Les scientifiques ont travaillé sur les données de ClinicalTrials.gov pour la maladie d'Alzheimer, la maladie de Parkinson, la démence frontotemporale/sclérose latérale amyotrophique et la maladie de Huntington. De 2000 à 2020, 241 essais ont été organisés.

Les essais de médicaments parrainés par l'industrie, bien qu'étant une minorité (34 %) des essais mais représentant cependant la majorité (61 %) des années-patients, étaient plus susceptibles d'être terminés, d'avoir une méthodologie standard et d'avoir des groupes témoins placebo.

Le nombre moyen de critères d'inclusion et d'exclusion a plus que doublé au cours de cette période, et en cons&quence le nombre de patients éligibles a diminué. Les essais se sont déplacés vers des participants moins gravement atteints, mais de façon compréhensible, seulement 2,7 % des essais étaient ouverts aux personnes pré-symptomatiques.

16 nouvelles hypothèses thérapeutiques reposant sur un aspect génétique ont été testées dans des essais de médicaments, avec un décalage moyen de 13 ans entre la recherche fondamentale et le premier essai clinique. De façon extrêmement surprenante, les essais concernant de nouvelles hypothèses thérapeutiques ne représentaient que 18 % des années-patients. Alors que la période concernée (de 2000 à 2020) mettait l'accent sur la génétique et la biologie moléculaire, on voit ainsi que ce n'était pas perçu par l'industrie pharmaceutique comme une voie royale pour élaborer de nouveaux médicaments.

La perte synaptique survient tôt dans de nombreuses maladies neurodégénératives et contribue à une déficience cognitive même en l'absence d'atrophie macroscopique. Actuellement, pour les maladies humaines, il existe peu de modèles formels pour expliquer comment les réseaux corticaux sous-jacents à la cognition sont affectés par la perte synaptique.

Des scientifiques de l'université de Cambrige, préconisent que les modèles biophysiques de neurophysiologie offrent d'une part un pont entre les modèles cliniques et précliniques de pathologie, et d'autre part des tests quantitatifs pour la médecine expérimentale. De tels modèles biophysiques peuvent également révéler des dynamiques neuronales cachées pouvant être alors mises en évidence au moyen d'observations neurophysiologiques telles que l'électro- et la magnéto-encéphalographie (MEG).

Dans un nouvel article, les auteurs présentent un modèle amélioré de la fonction corticale humaine qui inclue des estimations de densité synaptique capturées par la tomographie par émission de positrons, et donnent un aperçu de la façon dont la perte de synapse régionale affecte la neurophysiologie.

Les scientifiques étudient en particulier la tauopathie primaire de la paralysie supranucléaire progressive (syndrome de Richardson), avec des corrélations clinicopathologiques élevées.

La paralysie supranucléaire progressive (PSP) est une maladie dégénérative d'apparition tardive impliquant la détérioration progressive et la mort de volumes spécifiques du cerveau. La maladie entraîne des symptômes tels qu'une perte d'équilibre, un ralentissement des mouvements, une difficulté à bouger les yeux et une déficience cognitive. La PSP peut être confondue avec d'autres maladies neurodégénératives telles que la maladie de Parkinson, la démence frontotemporale et la maladie d'Alzheimer. La cause de la maladie est incertaine, mais implique une accumulation de protéine tau dans le cerveau.

La paralysie supranucléaire progressive provoque une modification marquée de la neurophysiologie corticale en présence d'une atrophie légère et est associée à un déclin des fonctions cognitives associées au lobe frontal.

Les auteurs montrent que l'incorporation de la densité synaptique régionale dans leur modèle, suggère qu'une réduction de la densité synaptique dans le cortex frontal inférieur affecte l'excitation glutamatergique de la couche superficielle et granulaire.

Les différences individuelles de comportement ainsi prédites, démontrent le lien entre la perte synaptique, la neurophysiologie et les déficits cognitifs.

La méthode que les auteurs démontrent ne se limite pas à la paralysie supranucléaire progressive ou aux effets de la perte synaptique : de tels modèles causals dynamiques enrichis en pathologie peuvent être utilisés pour évaluer les mécanismes d'autres troubles neurologiques, avec diverses mesures non invasives de la pathologie, et conviennent tester les effets de la pharmacologie expérimentale.

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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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.

Contrary to appearances, there is some links in this post with neurodegenerative diseases. Alcoholic liver injury are one kind of cellular stress. All drugs that can treat cellular stress, and especially Endoplasmic Reticulum (ER) stress, can probably be used against most common neurodegenerative diseases. The same is true for drugs with free radicals scavenging activity.

Euscaphis konishii Hayata is a traditional medicinal plant in China, and its leaves are usually used to make dishes for hepatic or gastrointestinal issues by Chinese She nationality. Hepatocellular carcinoma (hepatoma) is the most common type of primary liver cancer in adults. Hepatocellular carcinoma causes 662,000 deaths worldwide per year about half of them in China.

Pharmacological analysis showed that E. konishii leaves contain high levels of flavonoids and chromones with favorable anti-hepatoma effect. 8 flavonoids and 2 chromones were recognized in the chromone-rich extract. Chromones are found throughout the plant kingdom, where they serve as essential components of a number of structural polymers, provide protection from ultraviolet light, defend against herbivores and pathogens, and also mediate plant-pollinator interactions as floral pigments and scent compounds.

Alcohol-fed mice disease model were used to assess the hepatoprotective effects of these chromone-rich extract.

Chromone-rich extract represented strong free radicals scavenging activity in vitro. With oral administration, chromone-rich extract dose-dependently decreased the serum levels of alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase in alcohol-fed mice.

Chromone-rich extract gradually increased the activity of superoxide dismutase and glutathione peroxidase in the alcohol-treated liver tissues. Chromone-rich extract also alleviated the hepatic inflammation, inhibited the hepatocyte apoptosis and lessened the alcohol-induced histological alteration and lipid accumulation in the liver tissues.

Chromone-rich extract administration inhibited the overexpression of endoplasmic reticulum chaperones signaling and unfolded protein response pathways to defense the ER-induced apoptosis. Pretreatment with chromone-rich extract also restored the mitochondrial membrane potentials andadenosine triphosphate levels, which in turn suppressed the Cytochrome C release and mitochondria-induced apoptosis.

Chromone-rich extract conferred great protection against alcoholic liver injury, which might be associated with its viability through suppressing reactive oxygen species stress and hepatocyte apoptosis.

It may be possible they also have positive effects in neurodegenerative diseases.

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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.

What's in a name? Is Flail leg syndrome a variant of ALS or another disease? There are many anomalies in medicine, for example cancer sufferers in Western Europe could have a much different life expectancy when moving abroad, even when the new country is very similar to the country of origin.

It's a bit similar in ALS, it looks like ALS is not exactly the same disease in US, EU or Asia. Sometimes there is a understandable reason for example the statistical frequency of SOD1 mutations is different in Asia from US. Sometimes it is simply a matter of different semantics, some neurologists tell ALS is both upper and lower motor neurons, others have different opinions.

"Flail leg syndrome" is a Asian variant of amyotrophic lateral sclerosis with the characteristics of slow progression and the symptoms confined to the lumbosacral region for extended periods. In US it would have probably been called "Progressive Muscular Atrophy".

Yet there is no genetic background behind Flail leg syndrome, so why is it a regional appellation? In this new publication the scientists astonishingly decided that a slow progressing disease must be called "Flail leg syndrome".

The objective of a new study was to determine a cutoff time of disease progression that could differentiate Flail leg syndrome from the typical lower limb onset Amyotrophic Lateral Sclerosis.

A cutoff point analysis was performed with maximally selected log-rank statistics in patients with lower limb onset Amyotrophic Lateral Sclerosis registered from 2009 to 2013.

Based on the cutoff duration from the lower limb onset to second region (14 months), all patients were divided into the slowly progressive subtype of lower limb onset Amyotrophic Lateral Sclerosis group and the typical lower limb-onset Amyotrophic Lateral Sclerosis group.

Unsurprisingly the FLS was characterized by slower progression, less and later respiratory dysfunction, and a more benign prognosis than the typical lower limb onset Amyotrophic Lateral Sclerosis.

Patients with FLS exhibited a median diagnostic delay of 25 months, a median duration of 24 months from lower limb onset to second region, a forced vital capacity abnormity rate of 12.5% at the first visit to authors' department, and a median survival time of 80 months, which were significantly different from those of patients with typical lower limb onset Amyotrophic Lateral Sclerosis. The 5-year survival rate of the FLS group was much higher than that of the other group.

Now what all this mean? That if you select patients with a slow progression, you find they have a slow progression, is it high quality science?

Read the original article on Pubmed