Pour être efficace contre la maladie d'Alzheimer, il semble évident qu'un médicament doit pouvoir exercer un effet sur le cerveau. Mais selon les résultats présentés lors de la 12e conférence des essais cliniques sur la maladie d'Alzheimer, qui s'est tenue du 4 au 7 décembre à San Diego, en Californie, une thérapie pourrait également influencer le cerveau sans jamais pénétrer la barrière hémato-encéphalique.

L'apabétalone est une petite molécule administrée par voie orale, qui a été créée par Resverlogix Corp. Des chercheurs ont rapporté lors de la 12e conférence des essais cliniques sur la maladie d'Alzheimer que l'apabétalone semblait ralentir le déclin cognitif, mais seulement chez les personnes les plus atteintes et après une année d'administration.

L'apabétalone bloque essentiellement l'association entre BET et les lysines acétylées, écrasant la transcription de centaines de gènes. Auparavant, les chercheurs avaient rapporté que les protéines BET stimulaient l'expression d'une myriade de gènes impliqués dans l'inflammation, le métabolisme lipidique et la fonction vasculaire, faisant de l'apabétalone un traitement candidat pour les maladies cardiovasculaires et autres maladies chroniques du vieillissement.

De nombreux gènes ciblés par l'apabétalone se trouvent en aval du facteur de nécrose tumorale α (TNFα), un maître régulateur de l'inflammation. Les résultats présentés par Ewelina Kulikowski de Resverlogix, suggèrent que l'apabétalone pourrait atténuer les réponses inflammatoires provoquées par le TNFα, apaiser l'inflammation vasculaire - et peut-être même limiter l'activation chronique des cellules gliales de l'autre côté de la barrière hémato-encéphalique.

L'essai multicentrique de phase III BETonMACE était conçu pour déterminer si l'apabétalone en association avec des statines pouvait diminuer les événements cardiaques par rapport au traitement avec des statines seules.

Les participants à l'essai avaient un diabète de type 2, un syndrome coronarien aigu et de faibles niveaux de lipoprotéines de haute densité (HDL). L'essai s'est poursuivi jusqu'à 250 événements cardiovasculaires. Bien que le médicament ait eu tendance à réduire les événements cardiovasculaires, l'effet n'a pas atteint la signification statistique.

Sur les 2425 personnes inscrites à l'essai, 469 personnes de plus de 70 ans ont participé à une sous-étude cognitive, le Montreal Cognitive Assessment (MoCA). Alors que les scores MoCA ont légèrement diminué ou sont restés stables dans les groupes sous traitement et sous placebo parmi les participants des deux groupes à MoCA élevé, au contraire ceux dont les scores MoCA étaient les plus bas ont semblé bénéficier du traitement.

Parmi les 97 participants de ce sous-groupe, ceux prenant de l'apabétalone se sont améliorés en moyenne de trois points sur le test entre la ligne de base et 27 mois, tandis que ceux sous placebo, curieusement, se sont améliorés de 1 point. Les chercheurs pensent que le médicament atténue les troubles cognitifs en ciblant l'inflammation du système vasculaire.

L'idée qu'un endothélium vasculaire enflammé - en particulier dans les vaisseaux qui composent la barrière hémato-encéphalique - pourrait endommager la santé du cerveau et diminuer les capacités cognitives, confirme les résultats d'études précédentes.

For therapies aimed at Alzheimer's disease, it seems obvious that an effective drug must act on the brain. But according to the results presented at the 12th conference of clinical trials on Alzheimer's disease, which was held from December 4 to 7 in San Diego, California, a therapy could also influence the brain without ever penetrating the blood-brain barrier.

Apabetalone is a small, orally administered molecule that was created by Resverlogix Corp. Researchers reported at the 12th Alzheimer's Clinical Trials Conference that apabetalone appears to slow cognitive decline, but only in those most affected and after one year of administration.

Apabetalone essentially blocks the association between BET and acetylated lysines, crushing the transcription of hundreds of genes. Previously, researchers had reported that BET proteins stimulate the expression of a myriad of genes involved in inflammation, lipid metabolism and vascular function, making apabetalone a candidate treatment for cardiovascular and other chronic diseases of aging.

Many genes targeted by apabetalone are found downstream of the tumor necrosis factor α (TNFα), a master regulator of inflammation. The results presented at the conference by Ewelina Kulikowski of Resverlogix, suggest that apabetalone could attenuate the inflammatory responses provoked by TNFα, soothe vascular inflammation - and perhaps even limit the chronic activation of glial cells on the other side of the blood-brain barrier.

The BETonMACE multicentre phase III trial was designed to determine whether apabetalone in combination with statins could decrease heart events compared to treatment with statins alone.

Participants in the trial had type 2 diabetes, acute coronary syndrome and low levels of high density lipoprotein (HDL). The trial continued for up to 250 cardiovascular events. Although the drug tended to reduce cardiovascular events, the effect did not reach statistical significance.

Of the 2,425 people enrolled in the trial, 469 people over the age of 70 participated in a cognitive sub-study, the Montreal Cognitive Assessment (MoCA). While the MoCA scores decreased slightly or remained stable in the treatment and placebo groups among participants in the two high MoCA groups, those with the lowest MoCA scores appeared to benefit from treatment.

Among the 97 participants in this subgroup, those taking apabetalone improved on average by three points on the test between the baseline and 27 months, while those on placebo, curiously, improved by 1 point . Researchers believe the drug alleviates cognitive impairment by targeting inflammation in the vascular system.

The idea that an inflamed vascular endothelium - particularly in the vessels that make up the blood-brain barrier, could damage brain health and decrease cognitive ability, confirms the results of previous studies.

Disturbances in glucose metabolism (insulin resistance and abnormal glucose tolerance) are frequently observed among ALS patients. In recent years, there has been growing interest in the elusive relationship between premorbid diabetes and ALS.

With regard to the risk of developing ALS, studies in European countries have demonstrated that premorbid type 2 diabetes protects people against ALS development. One exception was the study by Sun et al. , who found that premorbid type 2 diabetes increased the risk of ALS development in Asia (Taiwan, China). In addition, a 4 year delay in the onset of ALS was observed in ALS patients with premorbid type 2 diabetes.

The aforementioned literature demonstrated the distinctive effect of premorbid type 2 diabetes on ALS patients from Asia and Europe. The present study aims to provide evidence for the association between premorbid type 2 diabetes and ALS by evaluating the onset and prognostic value in our cohort of ALS patients.

Patients were recruited from the national referral Amyotrophic Lateral Sclerosis Clinic at the Department of Neurology, Peking University Third Hospital (PUTH), Beijing, between 1January 2013, and 31 December 2016. Among 1331 consecutive sporadic ALS patients, 100 (7. 5%) were labeled as ALS type 2 diabetes and 1231 were labeled as ALS control according to the presence or absence of premorbid type 2 diabetes

As in other studies, the authors found a 4. 4 year delay in the onset of ALS inpatients with premorbid type 2 diabetes after controlling for other ALS disease modifiers, including gender.

The prevalence of premorbid type 2 diabetes at base line in ALS patients was lower than the estimated rate among the Chinese population. The overall prevalence of premorbid type 2 diabetes at baseline among ALS patients was 100/1331¼7. 5%; however, the expected prevalence of type 2 diabetes in the general population (>18 years) in China is estimated to be over 11. 6% (95% CI, 11. 3% – 11. 8%). This observation also indicates a protective role of premorbid type 2 diabetes on ALS development. This result was consistent with what has been reported in other studies.

In this study, the mean age of onset of ALS symptoms was 52. 9 years (SD, 10. 2 years), which was lower than that reported in Japan (64. 8 years), Italy (64. 8 years), Europe (64. 4 years) and Germany (67. 0 years). The age of onset of Chinese patients with ALS is approximately a decade younger than that of European and Japanese patients with ALS.

It is noteworthy that the willingness to medically treat younger patients is much stronger than that of elderly patients. Since ALS is a relatively rare disease, ALS might be under recognized in older people because being weak or wasted may be regarded as a normal part of aging or because multiple medical problems may ALS diagnostic difficult. This may create bias.

A clear molecular explanation of the relationship between type 2 diabetes and ALS remains a challenge. Recently, several radiographic and molecular studies have demonstrated that structural and functional alterations in the hypothalamic melanocortin system are frequently observed at the preclinical stage of ALS patients. The essential role of melanocortins lies in the regulation of body weight and appetite. The hypothalamic melanocortin pathway is a critical center for monitoring, processing, and responding to peripheral signals, including hormones, such as ghrelin, leptin, and insulin.

In ALS patients, these alterations in the structure and function of the hypothalamic melanocortin system provide a mechanistic explanation for the abnormalities in food intake and metabolism observed inpatients with ALS. Increasingly, behavior related changes have been associated with improved survival. Similarly, these preclinical alterations in the hypothalamic melanocortin pathway, as compensatory changes for ALS development, could also be a potential explanation for ALS patients with insulin resistance and type 2 diabetes. High levels of glucose could reduce the damage to motoneurons caused by hypermetabolism in the preclinical and early stages of ALS, while in the middle and late stages of ALS, when the melanocortin system is in a decompensatory period, insulin resistance and type 2 diabetes have no beneficial effect on the progression or survival of ALS patients.

In Alzheimer disease, for example, clinical and epidemiological studies have shown that the risk of Alzheimer disease was almost doubled in type 2 diabetes patients compared to the general population. Insulin deficiency and insulin resistance, core features of type 1 diabetes and type 2 diabetes, were also observed in the brains of Alzheimer disease patients. Thus, researchers proposed the term “type 3 diabetes”, which reflects the fact that Alzheimer disease represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes and type 2 diabetes. However, the question of whether the observed insulin resistance is a cause or consequence of neuro-degeneration in Alzheimer disease remains open.

Finally, the anti type 2 diabetes drugs metformin and pioglitazone, which have been proven to be neuroprotective in Alzheimer disease and other neurodegenerative diseases, have unexpectedly failed to show beneficial effects on the progression or survival of ALS patients. It was found that, at later time points, the metformin induced trophic effects may have been overshadowed by advancing and aggressive SOD1G93A pathology and potentially negative drug effects. The cause of pioglitazone’s failed clinical translation remains elusive. It was even suggested that suboptimal glycemic control may be beneficial in ALS.

Most neurodegenerative diseases are proteopathies. Alleviating ER stress is a promising approach for treating a range of diseases. Heren researchers aimed to identify a potent chemical chaperone through High-Throughput Screening of a small molecule chemical library.

The endoplasmic reticulum (ER) is responsible for folding secretory and membrane proteins, but disturbed ER proteostasis may lead to protein aggregation and subsequent cellular and clinical pathologies. For example Tudca (see AMX00035 trial) has some efficiency in this area. Tudca is a chemical chaperone.

Chemical chaperones have recently emerged as a potential therapeutic approach for ER stress-related diseases. Scientists have identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen.

https://elifesciences.org/articles/43302

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) is called ER stress. The cell has an adaptive system against ER stress called the unfolded protein response (UPR), which is the coordinated transcriptional upregulation of ER chaperones and folding enzymes that prevents the aggregation of unfolded and incompletely folded protein.

To overcome ER stress-related diseases, the following two pharmacological strategies can be applied: the modulation of ER protein folding environments (by UPR modulators) and a reduction in the accumulation of unfolded or misfolded ER proteins (by chemical chaperones).

In contrast, several chemical chaperones that have shown therapeutic benefits in mouse disease models have also been developed. 4-Phenylbutyrate (4PBA) and taurourso-deoxycholic acid (TUDCA) have been reported to function as chemical chaperones and have shown therapeutic benefits for a wide variety of diseases, such as diabetes, ALS and Alzheimer's disease.

Biochemical and chemical biology approaches revealed that IBT21 directly binds to unfolded or misfolded proteins and inhibits protein aggregation. IBT21 prevented cell death caused by chemically induced ER stress and by a proteotoxin, an aggression-prone prion protein. Taken together, their data show the promise of IBTs as potent chemical chaperones that can ameliorate diseases resulting from protein aggregation under ER stress.

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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.

Amylyx Pharmaceuticals, Inc., a pharmaceutical company focused on developing new treatments for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, announced today that AMX0035 has demonstrated significant treatment advantage for people with of ALS in the CENTAUR study. In the study, participants taking AMX0035 had a statistically significant slowdown in the progression of ALS disease, as measured by the revised ALS functional rating scale (ALSFRS-R) compared to placebo.

AMX0035 is an orally available candidate therapy designed to minimize the mechanisms associated with nerve cell death. It is made up of two small molecules - tauroursodeoxycholic acid (TUDCA) and sodium phenylbutyrate (PB) - which target signals in the mitochondria and endoplasmic reticulum of a cell, two compartments strongly involved in cellular stress and death of nerve cells.

TUDCA and PB have been shown to prevent cell death and damage neuroinflammation in preclinical models of ALS.

According to Justin Klee, co-founder and president of Amylyx, the therapeutic strategy followed is somewhat unique in that it does not try to prevent the root cause of ALS, the process of which, in most cases, has occurred since long before a person is diagnosed; rather, it aims to preserve motor neurons.

"What ultimately causes the clinical decline of ALS is that the motor neurons in the brain and spine degenerate and die," said Klee. "What we designed was that if we could identify or develop a therapy that could intervene in cell death and degeneration, then maybe we could have a therapy that would work for ALS, as well as neurodegeneration as a whole. "

CENTAUR participants had the opportunity, after the trial, to enroll in an open-label extension study to receive treatment with AMX0035. Almost 90 percent of participants who have completed CENTAUR have chosen to enroll in the extension study. Intermediate data from the ongoing extension study will be presented in 2020.

Sabrina Paganoni, MD, PhD, Harvard professor leading the trial, explained that CENTAUR was designed to maximize the data that could be obtained using the least number of participants and in the least possible time. This involved the use of stringent enrollment criteria - essentially, only those individuals who were expected to have the most severe ALS with the fastest disease progression, were enrolled. "In other words, when we test the drug in the most severe patients - those who need it most - if we can stop or slow the disease in these patients, we expect to do the same in all patients . "

Paganoni added that if AMX0035 reaches the point of being approved by regulatory authorities for the treatment of ALS, it should be approved for all patients with ALS.

In addition, the company will provide an update on regulatory plans and more details on expanded access plans in early 2020.

Dr. Rudolph Tanzi, Ph.D., Professor Kennedy of Neurology, Massachusetts General Hospital, Chairman of the Cure Alzheimer's Fund research leadership group and Chairman of Amylyx SAB, shared: "The positive results of the CENTAUR study ALS demonstrate that the mechanism of AMX0035 could represent a new therapeutic approach not only for ALS, but for Alzheimer's disease. I am very excited about the proven benefits of AMX0035 in people with ALS and look forward to the results of the ongoing PEGASUS trial for people with Alzheimer's disease. "

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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.

Amylyx Pharmaceuticals, Inc., une société pharmaceutique axée sur le développement de nouveaux traitements pour la sclérose latérale amyotrophique (SLA) et d'autres maladies neurodégénératives, a annoncé aujourd'hui que l'AMX0035 avait démontré un avantage de traitement significatif pour personnes atteintes de SLA dans l'étude CENTAUR. Dans l'étude, les participants prenant AMX0035 ont eu un ralentissement statistiquement significatif de la progression de la maladie SLA, tel que mesuré par l'échelle de notation fonctionnelle révisée SLA (ALSFRS-R) par rapport au placebo.

AMX0035 est une thérapie candidate disponible par voie orale conçue pour minimiser les mécanismes liés à la mort des cellules nerveuses. Il se compose de deux petites molécules - l'acide tauroursodésoxycholique (TUDCA) et le phénylbutyrate de sodium (PB) - qui ciblent les signaux dans les mitochondries et le réticulum endoplasmique d'une cellule, deux compartiments fortement impliqués dans le stress cellulaire et la mort des cellules nerveuses.

TUDCA et PB se sont avérés efficaces pour prévenir la mort cellulaire et endommager la neuroinflammation dans des modèles précliniques de SLA.

Selon Justin Klee, cofondateur et président d'Amylyx, la stratégie thérapeutique suivie est quelque peu unique en ce qu'elle n'essaie pas de prévenir la cause profonde de la SLA, dont le processus, dans la plupart des cas, se produit depuis longtemps avant qu'une personne ne soit diagnostiquée; il vise plutôt à préserver les motoneurones.

"Ce qui provoque finalement le déclin clinique de la SLA, c'est que les motoneurones du cerveau et de la colonne vertébrale dégénèrent et meurent", a déclaré Klee. "Ce que nous avons conçu c’est que si nous pouvions identifier ou développer une thérapie qui pourrait intervenir au niveau de la mort cellulaire et de la dégénérescence, alors peut-être pourrions-nous avoir une thérapie qui fonctionnerait pour la SLA, ainsi que la neurodégénérescence dans son ensemble."

Les participants à CENTAUR ont eu la possibilité, après l'essai, de s'inscrire à une étude d'extension en ouvert pour recevoir un traitement avec AMX0035. Près de 90 pour cent des participants qui ont terminé CENTAUR ont choisi de s'inscrire à l'étude d'extension. Les données intermédiaires de l'étude d'extension en cours seront présentées en 2020.

Sabrina Paganoni, MD, PhD, professeur à Harvard qui dirige l'essai, a expliqué que CENTAUR a été conçu pour maximiser les données qui pourraient être obtenues en utilisant le moins de participants et dans le moins de temps possible. Cela impliquait l'utilisation de critères d'inscription rigoureux - essentiellement, seules les personnes dont on prévoyait qu'elles souffraient de la SLA la plus sévère avec la progression de la maladie la plus rapide, étaient inscrites. «En d'autres termes, lorsque nous testons le médicament chez les patients les plus sévères - ceux qui en ont le plus besoin - si nous pouvons arrêter ou ralentir la maladie chez ces patients, nous nous attendons à faire de même chez tous les patients.»

Paganoni a ajouté que si l'AMX0035 atteint le point d'être approuvé par les organismes de réglementation pour le traitement de la SLA, il devrait être approuvé pour tous les patients atteints de SLA.

En outre, la société fournira une mise à jour sur les plans réglementaires et de plus amples détails sur les plans d'accès élargis au début de 2020.

Le Dr Rudolph Tanzi, Ph.D., professeur Kennedy de neurologie, Hôpital général du Massachusetts, président du groupe de leadership de recherche Cure Alzheimer's Fund et président de l'Amylyx SAB, a partagé: «Les résultats positifs de l'étude CENTAUR ALS démontrent que le mécanisme de l'AMX0035 pourrait représenter une nouvelle approche thérapeutique non seulement pour la SLA, mais pour la maladie d'Alzheimer. Je suis très enthousiasmé par les avantages démontrés de l’AMX0035 chez les personnes atteintes de SLA et j’attends avec impatience les résultats de l’essai PEGASUS en cours pour les personnes atteintes de la maladie d’Alzheimer. »

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

You remember that in 2016, a group of scientists of Case Western Reserve University, Cleveland, found that in ALS, TDP-43 is mislocated in the mitochondria. TDP-43 is a protein which is involved in 95% of ALS cases, 1/3 of Alzheimer cases and in several other neurodegenerative diseases.

But not all neurodegenerative diseases are TDP-43 proteopathies, for example Parkinson is mainly a α-synuclein proteopathy. In Parkinson the intracellular inclusions, that contain aggregates of the intrinsically disordered protein α-synuclein, are called Lewy bodies.

Now a group of scientists in Switzerland and Sweden, have found that if the action of some chaperones (molecules that process proteins, including for protein folding) is impaired, then α-synuclein tended to accumulate in the mitochondria where it aggregated, forming clumps of protein that bear a striking resemblance to Lewy bodies.

The reseachers found that six highly divergent molecular chaperones commonly recognize a canonical motif in α-synuclein, consisting of the N terminus and a segment around Tyr39, and hinder the aggregation of α-synuclein.

Specific inhibition of the interactions between α-synuclein and the chaperone HSC70 and members of the HSP90 family, including HSP90β, results in transient membrane binding and triggers a remarkable re-localization of α-synuclein to the mitochondria and concomitant formation of aggregates.

Phosphorylation of α-synuclein at Tyr39 directly impairs the interaction of α-synuclein with chaperones, thus providing a functional explanation for the role of Abelson kinase in Parkinson’s disease. One mechanism that was invoked in Parkinson is apoptotic pathway activation via Abelson (c-Abl), so Tyrosine kinase inhibitors were envisaged to treat Parkinson. This mirrors their usage to treat ALS.

The results of the European scientists establish a master regulatory mechanism of α-synuclein function and aggregation in mammalian cells, extending the functional repertoire of molecular chaperones and highlighting new perspectives for therapeutic interventions for Parkinson’s disease.

If we return to ALS and the Case Western scientists, they similarly thought that chaperones were involved in the mislocalisation of TDP-43 in mitochondria:

Considering that molecular chaperones are usually needed to unfold protein before and during import, perhaps the final localization of TDP-43 in mitochondria depends on multiple factors, including, but not limited to, TOM and TIM22 complexes, ∆ψ and chaperones.

The article about α-synuclein : https://www.nature.com/articles/s41586-019-1808-9

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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.

Blood-brain barrier (BBB) ​​dysfunction is increasingly emerging as an early and important mechanism that may underlie some of the cognitive changes seen in the aging process and in the development of neurodegenerative diseases, including including Alzheimer's disease.

Source: Ben Brahim Mohammed, wikimedia.org/w/index.php?curid=12263975

A common denominator in studies on this subject is that the dysfunctional blood-brain barrier releases toxic products derived from blood in the brain, such as fibrinogen, thrombin, plasminogen, iron-containing proteins, albumin, etc., which disrupt normal neuronal function, possibly leading to neuronal and synaptic loss and/or cognitive decline in Alzheimer's disease.

In a series of experiments on mice and humans, Senatorov et al. show that BBB dysfunction occurs with aging and leads to hyperactivation of TGFβ signaling in astrocytes, which in turn leads to dysfunction of the neural network, particularly in the hippocampus. These dysfunctions could be corrected by intraperitoneal infusions of a small molecule TGFβR1 kinase inhibitor (IPW).

In a separate but related study, Milikovsky et al. show a link between electrographic anomalies - paroxysmal slow wave events (PSWE) - detected using EEG, and cognitive disorders. They show that PSWE are observed in a number of human and murine models of blood-brain barrier dysfunction, and that PSWE can be induced by exposing the mouse brain to albumin.

These two studies provide convincing evidence for a causal link between a deficiency of the blood-brain barrier and neuronal dysfunction. They suggest that this interaction may be mediated by specific astrocytic pathways, leading to electrographic dysfunction that can be quantified using EEG, and especially suggest that this pathological pathway may be a treatable therapeutic target.

Further studies are needed to determine the extent to which protein infusion (Aβ, tau, α-synuclein, TDP43) in the central nervous system contributes to the cognitive changes observed in aging and neurodegenerative diseases in humans, and what strategies to block astrocyte TGFβ signaling (eg using IPW or losartan) are feasible, safe and therapeutically useful for patients.

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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.