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

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

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.

Differentiating Slowly Progressive Subtype of Lower Limb Onset ALS From Typical ALS Depends on the Time of Disease Progression and Phenotype.

- Posted in Differentiating Slowly Progressive Subtype of Lower Limb Onset ALS From Typical ALS Depends on the Time of Disease Progression and Phenotype. by English by

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

Alterations in metabolic biomarkers and their potential role in amyotrophic lateral sclerosis.

- Posted in Alterations in metabolic biomarkers and their potential role in amyotrophic lateral sclerosis. by English by

Accumulating evidence suggests defective energy metabolism in ALS patients, which contributes to weight loss and a poor prognosis.

Lipid metabolism disorders have been widely reported in patients with ALS, presenting with hypercholesterolemia, hypertriglyceridemia, and other mixed dyslipidemias. Leptin, an adipokine, plays a neuroprotective role in neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Nagel et al. suggested that leptin concentrations were positively correlated with the survival rate in ALS patients, indicating protective effects of leptin in patients with ALS.

Serum leptin concentration is strongly correlated with body weight or BMI, which was also confirmed in this study written by scientists from Chinese Academy of Medical Sciences. And higher body weight and BMI have been found to be associated with a lower risk of ALS and better prognosis in ALS patients.

Adipokines are a group of factors released or secreted by adipose tissue and have many physiological functions, such as fat distribution, energy expenditure, appetite and satiety regulation, insulin secretion and sensitivity, and inflammation.

Previous studies on the biological functions of adiponectin provide some evidence that adiponectin is beneficial in ALS. As one of the most abundant adipokines secreted by adipocytes, adiponectin functions in multiple physiological processes, including insulin sensitization, glucose regulation, lipid metabolism, and anti-inflammatory and antiapoptotic activities.

Fifty-two subjects were recruited between October 2020 and January 2022 among patients newly diagnosed with ALS in the Neurology Department of Peking Union Medical College Hospital. The study also included 24 healthy participants to compare adipokines and other metabolic biomarkers.

When comparing adipokines in patients and controls, the authors, found significant differences in the levels of adiponectin, adipsin, resistin, and visfatin between the two groups.

ALS patients had higher levels of adipokines (adiponectin, adipsin, resistin, and visfatin) and other metabolic biomarkers [C-peptide, glucagon, glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide, and plasminogen activator inhibitor type 1] than controls.

Leptin levels in serum were positively correlated with body mass index, body fat, and visceral fat index.

Adiponectin was positively correlated with the visceral fat index and showed a positive correlation with the ALSFRS-R and a negative correlation with baseline disease progression.

Lower leptin and adiponectin levels were correlated with faster disease progression. After adjusting for confounders, lower adiponectin levels and higher visfatin levels were independently correlated with faster disease progression.

Berberine, an isoquinoline alkaloid, has been shown to increase adiponectin expression, which partly explains its beneficial effects on metabolic disturbances. Mice fed the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both omega-3 fatty acids, have also shown increased plasma adiponectin. Curcumin, capsaicin, gingerol, and catechins have also been found to increase adiponectin expression.

Read the original article on Pubmed

ALS, cellular stress and Inflectis' new drug.

- Posted in ALS, cellular stress and Inflectis' new drug. by English by

InFlectis BioScience received Orphan-Drug Designation from the U.S. Food and Drug Administration (FDA) for its investigational treatment for Amyotrophic Lateral Sclerosis (ALS), IFB-088.

IFB-088 or Sephin-1, is an improved version of Guanabenz, a medication to treat hypertension. enter image description here In a phase II clinical trial in Italy, Guanabenz offered a comparable level of protection to AMX0035 for people but specifically for patients with a bulbar onset.

IFB-088 as act as AMX0035 on the cellular stress response but in an different manner. IFB-088 as several action,

  1. It reduces mitochondrial stresses in ALS.
  2. IFB-088 is prolonging the protective effect of the Unfolding Protein Response (which trigger Integrated Stress Response) to prevent the production of new misfolded protein and increasing the stress response gene transcription to increase the cellular chaperones until the ER stress is resolved.

After the failure of many ALS drugs including Arimoclomol, and Biogen's two genetiic therapies for SOD1 and C9orf72, scientists are searching for new paradigms.

Research on ER cellular stress offers a clear mechanism of action, something lacking for almost all proposed drugs: When a new protein is built by a ribosome under the direction of mRNA, this protein is "flat", it has not acquired its final shape. This contorted shape makes it acquire new chemical properties.

Folding proteins is achieved in the Endoplasmic Reticulum (ER). Ribosomes are close to the ER so it's easy for proteins to enter the ER which is a very complex structure. At the exit of the ER folded proteins are sent to their final destinations by the Golgi apparatus.

If the ER is not working properly, then proteins built by ribosomes will not be able to be folded and will accumulate at the entrance of the ER, hence aggregates of misfolded, mislocated proteins.

While Sodium phenylbutyrate suppresses the cellular stress, Sephin-1 increases it. It is possible the two drugs might be useful at different stages of the disease course and for different populations.

Both drugs relative efficiency indicates that cell stress responses in neurodegenerative diseases are to be studied with much more attention than done previously.

Contact the author

Advertisement


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.

Targeted transcutaneous cervical spinal cord stimulation promotes upper limb recovery in spinal cord and peripheral nerve injury

- Posted in Targeted transcutaneous cervical spinal cord stimulation promotes upper limb recovery in spinal cord and peripheral nerve injury by English by

Long-term recovery of control of the upper limb is an unmet need in people with paralysis.

Recently, it has been demonstrated that spinal cord stimulation, when paired with intense physical therapy, can restore conscious control of upper limb in spinal cord injury (SCI).

Epidural administration involves the placement of a catheter into the epidural space

Epidural stimulation of the spinal cord has traditionally been demonstrated to be highly effective in restoring movement, potentially due to the ability of targeted activation of specific motoneuron pools. Yet epidural administration is an invasive procedure.

enter image description here However, transcutaneous spinal cord stimulation (tSCS) has recently shown equally promising results partly because can offer the same benefits with a non-invasive procedure.

Transcutaneous spinal cord stimulation (tSCS), like epidural stimulation, exerts its neuromodulatory effect on motoneurons trans-synaptically via activation of large-to-medium size sensory afferent fibers.

In this study, the authors from Northwell Health, a nonprofit integrated healthcare network in New York State, used a custom designed electrode patch and stimulator to enable targeted stimulation of specific spinal segments.

Targeted transcutaneous stimulation of the cervical spinal cord was paired with minimal physical therapy in two individuals classified as having a motor complete SCI and one individual with a peripheral nerve injury. enter image description here Stimulation was targeted to specific cervical levels using a custom electronically configurable electrode array, with each electrode having a small form factor (10 mm x 10 mm).

Modulating the spatial configuration of the stimulation electronically allowed the researchers to extensively map the recruitment profile of the upper-limb muscles based on the location of stimulation. This enabled them to choose the precise location of stimulation to achieve maximal recruitment of the muscle group of interest.

Even though participants received stimulation only once per week, the authors observed a rapid increase in both volitionally controlled muscle activity and force within a period of 5-6 weeks.

However, the observed gains were restricted to muscles that generated at least a measurable amount of force at the beginning of therapy.

In the subject with peripheral nerve injury leading to paralysis of the hand, the scientists observed rapid increase in functionality of the affected digits.

Read the original article on medRxiv

Keto diet and neurodegenerative diseases, caution is required

- Posted in Keto diet and neurodegenerative diseases, caution is required by English by

Introduction The ketogenic diet has been used since the beginning of the 20th century to reduce the incidence of epileptic seizures, and over time its application to other diseases has been studied.

This diet is characterized by a high content of unsaturated fatty acids, few carbohydrates and a normal protein content. While in a traditional diet there is about 55% of the energy value in the form of carbohydrates, about 30% fat and 15% protein, these proportions in the classic ketogenic diet are 8% for carbohydrates, 90% for lipids and about 7% for proteins. The most common form of the ketogenic diet includes mostly long-chain fatty acids.

The drastic changes induced by the ketogenic diet in eating habits are difficult to maintain in a long-term perspective. This is because high volumes of high fat components in the diet (cheeses, eggs, butter, oils, meat, etc.) can lead to nausea, vomiting, constipation and loss of appetite.

Adverse effects of the ketogenic diet The ketogenic diet, as a high-fat, low-carb diet, is associated with some insufficiency in the energy value of food portions and leads to metabolic effects that ultimately reduce body weight. People suffering from neurodegenerative diseases are at high risk of malnutrition and therefore this type of diet seems a priori to be contraindicated for them. People with neurodegenerative diseases suffer from sarcopenia which is often fatal.

According to current recommendations, people at risk should consume 1.0 to 1.2 g of protein/kg per day, or even more if they are physically active. The ketogenic diet, particularly when the energy value of the diet decreases, may therefore lead to a protein intake that is too low, although its contribution to the energy value of the diet may be normal or even higher than recommended. Such a situation can lead to the catabolism of structural proteins (especially in the muscles).

In individuals with insulin resistance, diabetic acidosis can be identified, which is a disease state with ketone body concentrations above 25 mmol/L, resulting from insulin deficiency with a simultaneous increase in glucose concentration ( > 300 mg/dL) and a decrease in blood concentration. pH (pH < 7.3), which can cause death.

Ketogenic diet and Alzheimer's disease It is not easy to formulate a ketogenic diet, in fact saturated fatty acids are present everywhere in large quantities, particularly in foods associated with pleasure, desserts, dairy products, chocolates. Eating a single meal high in saturated fat is enough to reduce our ability to concentrate, much more than if it is a meal high in unsaturated fat. Epidemiological studies show that a diet rich in saturated fatty acids increases the risk of Alzheimer's disease.

Studies conducted on an animal model of Alzheimer's disease, however, indicate a possible beneficial effect of the ketogenic diet for this medical condition.

Reger et al. concluded that oral administration of medium-chain triglycerides elevates plasma levels of ketone bodies and may improve cognitive functioning in older adults with memory impairment.

Henderson et al. administered medium-chain triglycerides to subjects with mild and moderate Alzheimer's disease. Administration of this type of fat resulted in improved cognitive functioning. It should be noted, however, that no effect of this type was observed in subjects carrying the APOEε4 genotype.

Ota et al. administered medium-chain triglycerides to 20 patients with mild to moderate Alzheimer's disease. After 8 weeks, patients showed significant improvement in their immediate and delayed logical memory tests compared to their baseline score. At 12 weeks, they showed significant improvement in the Numerical Symbol Coding Test and Logical Immediate Memory tests compared to baseline.

In the Ketogenic Diet Retention and Feasibility Trial, 15 patients with Alzheimer's disease maintained a ketogenic diet supplemented with medium-chain triglycerides (approximately 70% of energy as fat, including triglycerides at medium chain; 20% of energy as protein; and less than 10% of energy as carbohydrate). They have observed that when fully achieved ketosis, the mean score of the cognitive subscale of the Alzheimer's Disease Rating Scale improved significantly during the diet but returned to baseline at its termination.

Krikorian et al. applied a high carbohydrate diet to 23 subjects with mild cognitive impairment. After 6 weeks of intervention, the authors observed an improvement in verbal memory performance in subjects on a low carbohydrate diet. The authors concluded that even short-term use of a low-carb diet could improve memory function in older adults at increased risk for Alzheimer's disease. Although the observed effect may be partly attributable to the correction of hyperinsulinemia, other mechanisms associated with ketosis, such as reduced inflammation and improved energy metabolism, may also have contributed to the improved neurocognitive functioning.

Adapted from "Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer’s Disease and Parkinson’s Disease)" Dariusz Włodarek doi: 10.3390/nu11010169

Entrepreneurial activism, mannitol and Parkinson's disease

- Posted in Entrepreneurial activism, mannitol and Parkinson's disease by English by

A new article in the journal BioSocieties, published by Drs. Shlomo Guzmen-Carmeli and David A. Rier, from the Department of Sociology and Anthropology at Bar-Ilan University, tell the story of CliniCrowd, an Israeli company established to test the effectiveness of nutritional supplements like mannitol, cinnamon or cherries in Parkinson's or Alzheimer's disease.

CliniCrowd's model emphasizes speed, efficiency and creativity in dealing with a particular kind of unfinished science, involving potential orphan drugs which, of natural origin, cannot be patented.

Indeed, scientific questions do not all have the same chances of being explored by officially accredited scientists.

The term “unfinished science” refers in sociology to areas of research identified by societal movements as having potentially important social impacts which are however not funded, or incomplete or even completely ignored. This research, although often initiated, is ultimately not carried out for financial, theoretical, ideological or even political reasons.

The classic model of Parsons (1951) of the patient's role as patient supposes that all the action lies with the doctor (the expert), who acts on the passive patients who themselves remain passive, because a priori incompetent.

However, this evolved towards the end of the 20th century, in particular with the fight against AIDS. In 1987, the Community Based Research Initiative, a partnership of physicians and community patients, began a pivotal clinical trial of a treatment for pneumocystis pneumonia, then the main threat to AIDS patients.

The trial provided important clinical data, quickly influenced clinical practice, and was even used by the United States Food and Drug Administration (FDA) in the approval process.

Activists have also formed groups to identify and obtain (sometimes, via smuggling) potential treatment not available in the United States. They criticized drug companies for their high prices and inability to study a wider range of compounds. They particularly attacked the FDA's reliance on very slow and expensive randomized clinical trials (the traditional “gold standard”).

In 2004, the PatientsLikeMe community site was started by two brothers and a friend of a patient with amyotrophic lateral sclerosis (ALS). It opened in 2006 as an online platform, allowing patients with ALS to share their downloaded and anonymized clinical data, assess their own progress, exchange advice and support. , and to contribute more generally to emerging clinical knowledge on the disease.

Finally, PatientsLikeMe is currently a for-profit company, as it was acquired in 2019 by a large healthcare management company. They sell aggregated and anonymized data to academic and professional customers such as pharmaceutical and medical device companies.

In Israel, defense elites and high-tech start-ups are often considered some of the brightest and most innovative in society, trained to think creatively, collaborate and take risks.

Dan Vesely, is a retired Israeli general and high tech entrepreneur. Here's how he describes his response to his terrifying Parkinson's diagnosis in 2013: "If there’s a problem, deal with it. No crying over spilled milk or grieving about my misfortune, about what I ‘won’ [said cynically]. Come on, what do we do next? We think of solutions. [interview, January 24, 2018]"

Vesely, obviously dissatisfied with the treatment options available to him, then turned to acquaintances for help. A small group of entrepreneurs have gathered around him to research the published research on Parkinson's disease.

They quickly noticed the published - and forgotten - study on the possible effect of mannitol on patients with Parkinson's disease. Vesely and some partners contacted Professor Dan Segal of Tel Aviv University, who had co-led the research team, and asked to meet with him:

"It had not yet been tested on humans. So I made an appointment .... Prof. Segal told us his story, described the experiment, and said it's all simply been shelved, there's no incentive for the pharmaceutical companies. at each other and said, 'So we'll take it!' The professor said, 'Who exactly are you? You brash Israelis, who are you?' But it was clear to us that if you can't go through the door , you go through the window. [Vesely interview, Jan. 24, 2018]"

The heartbreaking story of the abandonment of the study born affected the group of friends. Vesely then resolved to test the mannitol on himself. However, its partners dissuaded it from being ineffective for the community because it was totally inconclusive. Instead, together they decided to test mannitol on a number of patients with Parkinson's disease.

In the absence of the support of a pharmaceutical company ready to invest in clinical research, they then sought to test mannitol as if it were a military operation.

They adopted a model, marrying patient self-experimentation with crowdsourcing techniques. Inspired by similar crowdsourcing projects like PatientsLikeMe, the group then planned to create a website for patients with Parkinson's disease who would agree to take mannitol regularly for an extended period.

This alternative is not, however, a real substitute for “* classic *” clinical trials. The survey platform would indeed lack a control group and patient monitoring would be carried out on site on a voluntary and independent basis, and not by a doctor. Nevertheless, this survey platform would generate preliminary data to justify the need for more formal clinical research which would be a result of great value in itself.

The founders of CliniCrowd initially considered marketing mannitol directly, but decided not to, to avoid conflicts with their research. But the founders of CliniCrowd nonetheless chose to register it as a company rather than a non-profit organization. This reflected their primary motivation to “get the job done” as quickly and efficiently as possible, through entrepreneurial tactics, rather than adopting the identity and tactics of social activism. In addition, Israeli non-profit organizations are more regulated than commercial companies.

So they created the company in August 2016. They recruited qualified staff with experience in planning and conducting clinical trials to create the company's platform, and then started recruiting patients using patient forums and media exposure.

At the start of 2021, 2,480 patients had registered on the platform dedicated to the research of mannitol for Parkinson's disease. Of these, 1,364 (55%) had completed questionnaires more than once. The platform allows patients to record and track data related to their disease and (while maintaining anonymity) compare this data with that of other members of the community. It is also possible to share the stored data with the attending physician.

CliniCrowd's efforts have unfolded in several stages. As Parkinson's patients on the platform began taking mannitol and regularly filling out questionnaires about their symptoms, the next step was to attract accredited scientists to conduct larger trials.

CliniCrowd's initial data helped generate public pressure, which in turn led to a formal clinical study, launched in 2018 at the Hadassah Medical Center in Jerusalem. This study (https://clinicaltrials.gov/ct2/show/NCT03823638), conducted with public funding, examines the effects of mannitol on Parkinson's disease. As of June 2021, the study was continuing, but had slowed down somewhat due to the coronavirus and its severe impact on the medical system. Additional studies, at universities and medical centers in the UK and US, are expected to begin shortly. As far as the authors of this article are aware, at the time of writing, however, these are limited studies.

Nonetheless, there has already been a major shift in the way scientists view mannitol research. As Vesely, the patient-founder of CliniCrowd, noted:

"It gives me great satisfaction that the studies we are currently talking about [the clinical research underway in Jerusalem and expected further studies] would not have taken place, nor would they have received funding or the attention of the medical establishment and the public, without the buzz and especially the clinical indications that CliniCrowd achieved in the wake of the surveys. [interview, July 7, 2019"

Researchers involved in planning the clinical trial confirmed in interviews with the authors that without public pressure, it is unlikely that a trial would have been initiated.

In fact, CliniCrowd's position vis-à-vis the biomedical establishment has evolved over the course of its short history. In early interviews, founders sharply criticized the pharmaceutical industry. For example, in the first interview with CEO Amir Sadeh, he describes the decision to start the business as follows:

"The goal is to create something that cannot be ignored and make available to the public what the pharmaceutical companies are trying to hide from us. Because they [such 'ignored' compounds] do not generate income, they do not make a profit, so it's better not to know about them at all. But now we're exposing them, showing their nakedness in public, telling them it's inexpensive and accessible. It treats the cause rather than the symptoms, and that's why it's the worst thing for the pharmaceutical companies to find a solution to Parkinson's disease. Ten million people, five billion dollars a year — as far as they're concerned, let's just treat the symptoms. It's cynical but that's the way it is…. [T] he benefit of the patients is not the paramount interest of the companies or the doctors, because they are waiting for the next seminar in the Seychelles, courtesy of one company or another. [interview December 3, 2017]"

Yet this initial position of "rebels against the pharmaceutical industry" was created by elite members of the Israeli establishment,

With this approach, CliniCrowd obviously found it difficult to gain the trust and support of the medical establishment.

From interviews the authors conducted with patients who started taking mannitol between 2016 and 2018, it appears that those who saw their doctors have encountered substantial resistance to adopting mannitol as a remedy. The doctors' objections included comments such as, "this is a good woman's medicine" and "you had better get a rabbi's blessing."

At a conference of neurologists in early 2017, CliniCrowd delegates had only a few minutes to present their action, and most conference attendees ignored their speech. Such contempt is reminiscent of the opposition to the community production of knowledge about AIDS more than a generation ago.

The interviews clearly showed that the choice to adopt terms such as "dietary supplements" and "functional foods" reflects CliniCrowd's tactical decision to redefine mannitol as a new substance in the food supplement market.

Here's how CEO Sadeh described the change, in a follow-up interview: "We started out thinking we would call the venture Ampha, as opposed to Pharma. But the more we got into it, the more we realized that was not the point. Like Netflix doesn’t mean all movie theatres are closed, and Airbnb hasn’t replaced hotels, and Uber hasn’t replaced taxis, so CliniCrowd won’t replace the pharmaceutical companies. We fill a void and add something extra. If we started out by setting ourselves against the pharmaceutical companies, now we’re not against them, we’ll be in favour. We’ll complement them. Let’s shift the playing field. Instead of acting on the fiery and aggressive pharmaceutical playing field, let’s move the field elsewhere....And as long as the whole world of medicine doesn’t dance according to the interests of the pharmaceutical companies, we’ve done something great. [interview July 7, 2019]"

The rebranding of mannitol as a functional food proved to be a valuable maneuver, enabling CliniCrowd. This has helped promote acceptance of mannitol among physicians and patients.

Indeed, in the second half of 2018, the authors observed a change in attitude among doctors. Three doctors interviewed for the study told us that once they realized it was a dietary supplement, they stopped protesting: “It’s a dietary supplement. It may not help, but it is not harmful”.

As one neurologist explains: "I think no doctor likes it when the patient comes and says, 'Listen, I've found a treatment.' Most of the time I have to make sure his feet are on the ground, and I must explain why, most probably , in his case it won't work. This was also my initial response to mannitol, complete resistance, not wanting them to take it .... The attitude changes when there is already information and a mass of patients who have collated and documented its use in an orderly manner. Moreover, they didn't come and say this is a magic drug, but rather that it may help with some of the symptoms .... I suggest to patients, especially at the beginning, that they should read about mannitol. I definitely don't exclude it, in fact quite the opposite."

To understand how the patients themselves experienced this, consider Menachem [pseudonym], 68, diagnosed four years earlier. Asked about the experience of taking mannitol and participating in the online questionnaire, he replied: "My participation in the experiment has turned my world around. I come to the doctor and update him, see? I, Menachem, taught the neurologist that there is such a thing as mannitol, and that I am taking part in an experiment with other patients. When I go to see him, he immediately stands up! "Welcome", he says, "tell me how you are getting on". There is a sense that we are colleagues, and that I am doing something incredibly important. There is something in [mannitol] that helps, it’s not a magical cure, or maybe I no longer suffer. But there is an improvement in my sleep, my sense of smell, and also my difficulty in movement. [interview Oct. 30, 2019]"

Note the ease Menachem describes in his relationship with the doctor, his feeling of being an expert, his delight and agency he feels about being involved. These are all so important to him that he mentions them even before his improved health, which he attributes to taking mannitol on a regular basis.

In conclusion, CliniCrowd demonstrated a new way of approaching "* unfinished science *", using participatory research to generate public pressure and influence with which to formally attract scientists to test low potential compounds. profit. CliniCrowd represents an intersection of scientific knowledge, technologies, practices, it is also the product of a sustained process of dissemination and decentralization of expertise.

Activisme entrepreneurial, mannitol et la maladie de Parkinson

- Posted in Activisme entrepreneurial, mannitol et la maladie de Parkinson by Français by

Un nouvel article dans la revue BioSocieties, publié par les Drs. Shlomo Guzmen-Carmeli et David A. Rier, du département de sociologie et d'anthropologie de l'Université Bar-Ilan, raconte l'histoire de CliniCrowd, une société israélienne créée pour tester l'efficacité de suppléments nutritionnels comme le mannitol, la cannelle ou les cerises dans les maladies de Parkinson ou d'Alzheimer.

Le modèle de CliniCrowd met l'accent sur la vitesse, l'efficacité et la créativité pour traiter un type particulier de science inachevée, impliquant des médicaments orphelins potentiels qui, d'origine naturelle, ne peuvent pas être brevetés.

En effet les questions scientifiques n'ont pas toutes les mêmes chances d'être explorées par les scientifiques officiellement accrédités.

Le terme de « science inachevée » fait référence en sociologie aux domaines de recherche identifiés par les mouvements sociétaux comme ayant des impacts sociaux potentiellement importants qui ne sont pourtant pas financés, ou incomplets ou encore complètement ignorés. Ces recherches, bien que souvent initiées ne sont finalement pas réalisées pour des raisons financières, théoriques, idéologiques, ou encore politiques.

Le modèle classique de Parsons (1951) du rôle de malade du patient suppose que toute l'action réside chez le médecin (l'expert), qui agit sur les patients passifs qui restent eux-même passifs, car à priori incompétents.

Cependant cela a évolué vers la fin du XX siècle, en particulier avec la lutte contre le SIDA. En 1987, l'Initiative de recherche communautaire, un partenariat de médecins et de patients communautaires, a commencé un essai clinique de base sur la pentamidine en aérosol comme traitement de la pneumonie à pneumocystis, alors la principale menace pour les patients atteints du SIDA.

L'essai a fourni des données cliniques importantes, a rapidement influencé la pratique clinique et a même été utilisé par la Food and Drug Administration (FDA) des États-Unis dans le processus d'approbation.

Les militants ont également formé des groupes pour identifier et obtenir (parfois, via la contrebande) des traitements potentiels non disponibles aux États-Unis. Ils ont critiqué les sociétés pharmaceutiques pour leurs prix élevés et leur incapacité à étudier une gamme plus large de composés. Ils ont particulièrement attaqué la dépendance de la FDA à des essais cliniques randomisés très lents et coûteux (le «gold standard» traditionnel).

En 2004, Le site communautaire PatientsLikeMe avait été lancé par deux frères et un ami d'un patient atteint de sclérose latérale amyotrophique (SLA). Il a ouvert ses portes en 2006 en tant que plate-forme en ligne, permettant aux patients atteints de SLA de mettre en commun leurs données cliniques téléchargées et anonymisées, d'évaluer leurs propres progrès, d'échanger des conseils et de l'assistance, et de contribuer plus généralement aux connaissances cliniques émergentes sur la maladie.

Finalement, PatientsLikeMe est actuellement une entreprise à but lucratif, car rachetée en 2019 par une grande société de gestion des soins. Ils vendent des données agrégées et anonymisées à des clients universitaires et professionnels tels que des sociétés pharmaceutiques et de dispositifs médicaux.

En Israël, les élites de la défense et des start-up high-tech sont souvent considérées parmi les plus brillantes et les plus innovantes de la société, car formées pour penser de manière créative, collaborer et prendre des risques.

Dan Vesely, est un général israélien à la retraite et un entrepreneur en haute technologie. Voici comment il décrit sa réponse à son terrifiant diagnostic de maladie de Parkinson en 2013 : "If there’s a problem, deal with it. No crying over spilled milk or grieving about my misfortune, about what I ‘won’ [said cynically]. Come on, what do we do next? We think of solutions. [interview, January 24, 2018]"

Vesely, évidemment insatisfait des options de traitement qui lui était proposées, a alors demandé de l'aide à des connaissances. Un petit groupe d'entrepreneurs s'est réuni autour de lui pour rechercher les recherches publiées sur la maladie de Parkinson.

Ils ont rapidement remarqué l'étude publiée - et oubliée - sur l'effet possible du mannitol sur les patients atteints de la maladie de Parkinson. Vesely et certains partenaires ont contacté le professeur Dan Segal de l'Université de Tel-Aviv, qui avait co-dirigé l'équipe de recherche, et ont demandé à le rencontrer :

"It had not yet been tested on humans. So I made an appointment....Prof. Segal told us his story, described the experiment, and said it's all simply been shelved, there’s no incentive for the pharmaceutical companies. We looked at each other and said, ’So we’ll take it!’ The professor said, ’Who exactly are you? You brash Israelis, who are you?’ But it was clear to us that if you can’t go through the door, you go through the window. [Vesely interview, Jan. 24, 2018]"

L'histoire navrante de l'étude abandonnée a affecté le groupe d'amis. Vesely a résolu alors de tester le mannitol sur lui-même. Cependant, ses partenaires l'en ont dissuadé comme étant inefficace pour la communauté car totalement inconcluant. Au lieu de cela, ensemble ils ont décidé de tester le mannitol sur un certain nombre de patients atteints de la maladie de Parkinson.

Faute de l'appui d'une entreprise pharmaceutique prête à investir dans la recherche clinique, ils ont alors cherché à tester le mannitol comme s'il s'agissait d'une opération militaire.

Ils ont adopté un modèle, mariant l'auto-expérimentation du patient avec des techniques de crowdsourcing. Inspiré par des projets de crowdsourcing similaires comme PatientsLikeMe, le groupe a alors projeté de créer un site Web pour les patients atteints de la maladie de Parkinson qui accepteraient de prendre régulièrement du mannitol pendant une période prolongée.

Cette alternative n'est cependant pas un véritable substitut aux essais cliniques « classiques ». La plate-forme d'enquête manquerait en effet d'un groupe de contrôle et la surveillance des patients serait effectuée sur le site de manière volontaire et indépendante, et non par un médecin. Néanmoins, cette plate-forme d'enquête générerait des données préliminaires permettant de justifier la nécessité d'une recherche clinique plus formelle ce qui serait un résultat d'une grande valeur en soi.

Les fondateurs de CliniCrowd ont initialement envisagé de commercialiser directement le mannitol, mais ont décidé de ne pas le faire, pour éviter les conflits avec leurs recherches. Mais les fondateurs de CliniCrowd ont néanmoins choisi de l'enregistrer en tant que société plutôt qu'en tant qu'organisation à but non lucratif. Cela reflétait leur motivation principale de « faire le travail » aussi rapidement et efficacement que possible, via des tactiques entrepreneuriales, plutôt que d'adopter l'identité et les tactiques de l'activisme social. Par ailleurs, les organisations à but non lucratif israéliennes sont davantage réglementées que les sociétés commerciales.

Ils ont donc créé la société en août 2016. Ils ont recruté du personnel qualifié expérimenté dans la planification et la conduite d'essais cliniques pour créer la plate-forme de l'entreprise, puis ont commencé à recruter des patients à l'aide de forums de patients et d'une exposition médiatique.

Début 2021, 2 480 patients s'étaient inscrits sur la plateforme dédiée à la recherche de mannitol pour la maladie de Parkinson. Parmi ceux-ci, 1 364 (55 %) avaient rempli des questionnaires à plusieurs reprises. La plateforme permet aux patients d'enregistrer et de suivre les données liées à leur maladie et (tout en préservant l'anonymat) de comparer ces données avec celles d'autres membres de la communauté. Il est également possible de partager les données stockées avec le médecin traitant.

Les efforts de CliniCrowd se sont déployés en plusieurs étapes. Alors que les patients atteints de la maladie de Parkinson sur la plate-forme commençaient à prendre du mannitol et à remplir régulièrement des questionnaires sur leurs symptômes, l'étape suivante était d'attirer des scientifiques accrédités pour mener des essais plus importants.

Les données initiales de CliniCrowd ont permis de susciter une pression publique, menant à son tour à une étude clinique formelle, lancée en 2018 au centre médical Hadassah à Jérusalem. Cette étude (https://clinicaltrials.gov/ct2/show/NCT03823638), menée avec un financement public, examine les effets du mannitol sur la maladie de Parkinson. En juin 2021, l'étude se poursuivait, mais avait quelque peu ralenti en raison du coronavirus et de son grave impact sur le système médical. Des études supplémentaires, dans des universités et des centres médicaux au Royaume-Uni et aux États-Unis, devraient commencer sous peu. Pour autant que les auteurs de cet article le sachent, au moment de la rédaction, il s'agit cependant d'études limitées.

Néanmoins, il y a déjà eu un revirement important concernant la façon dont les scientifiques considèrent la recherche sur le mannitol. Comme l'a fait remarquer Vesely, le patient-fondateur de CliniCrowd :

"It gives me great satisfaction that the studies we are currently talking about [the clinical research underway in Jerusalem and expected further studies] would not have taken place, nor would they have received funding or the attention of the medical establishment and the public, without the buzz and especially the clinical indications that CliniCrowd achieved in the wake of the surveys. [interview, July 7, 2019"

Les chercheurs impliqués dans la planification de l'essai clinique ont confirmé lors d'entretiens avec les auteurs que, sans la pression exercée par le public, il est peu probable qu'un essai ait été initié.

En fait, la position de CliniCrowd vis-à-vis de l'establishment biomédical a évolué au cours de sa courte histoire. Dans les premiers entretiens, les fondateurs ont vivement critiqué l'industrie pharmaceutique. Par exemple, dans le premier entretien avec le PDG Amir Sadeh, il décrit ainsi la décision de créer l'entreprise :

"The goal is to create something that cannot be ignored and make available to the public what the pharmaceutical companies are trying to hide from us. Because they [such ‘ignored’ compounds] do not generate income, they do not make a profit, so it’s better not to know about them at all. But now we’re exposing them, showing their nakedness in public, telling them it's inexpensive and accessible. It treats the cause rather than the symptoms, and that’s why it’s the worst thing for the pharmaceutical companies to find a solution to Parkinson's disease. Ten million people, five billion dollars a year—as far as they’re concerned, let's just treat the symptoms. It's cynical but that's the way it is…. [T]he benefit of the patients is not the paramount interest of the companies or the doctors, because they are waiting for the next seminar in the Seychelles, courtesy of one company or another. [interview December 3, 2017]"

Pourtant, cette position initiale de « rebelles contre l'industrie pharmaceutique" a été créée par des membres d'élite de l'establishment israélien,

Avec cette approche, CliniCrowd a évidemment éprouvé des difficultés à obtenir la confiance et le soutien de l'establishment médical.

D'après les entretiens que les auteurs ont menés avec des patients qui ont commencé à prendre du mannitol entre 2016 et 2018, il apparaît que ceux qui ont consulté leur médecin ont rencontré une résistance substantielle à l'adoption du mannitol comme remède. Les objections des médecins comprenaient des commentaires tels que : « c'est un remède de bonne femme » et « vous feriez mieux d'obtenir la bénédiction d'un rabbin ».

Lors d'une conférence de neurologues au début de 2017, les délégués de CliniCrowd n'ont eu que quelques minutes pour présenter leur action, et la plupart des participants à la conférence ont ignorés leur discours. Un tel mépris rappelle l'opposition contre la production communautaire de connaissances sur le SIDA il y a plus d'une génération.

Les interviews ont clairement montrés que le choix d'adopter des termes tels que « compléments alimentaires » et « aliments fonctionnels » reflète la décision tactique de CliniCrowd de redéfinir le mannitol comme une nouvelle substance dans l'alimentation marché des suppléments.

Voici comment le PDG Sadeh a décrit le changement, dans une interview de suivi : "We started out thinking we would call the venture Ampha, as opposed to Pharma. But the more we got into it, the more we realized that was not the point. Like Netflix doesn’t mean all movie theatres are closed, and Airbnb hasn’t replaced hotels, and Uber hasn’t replaced taxis, so CliniCrowd won’t replace the pharmaceutical companies. We fill a void and add something extra. If we started out by setting ourselves against the pharmaceutical companies, now we’re not against them, we’ll be in favour. We’ll complement them. Let’s shift the playing field. Instead of acting on the fiery and aggressive pharmaceutical playing field, let’s move the field elsewhere....And as long as the whole world of medicine doesn’t dance according to the interests of the pharmaceutical companies, we’ve done something great. [interview July 7, 2019]"

Le changement d’appellation du mannitol en tant qu'aliment fonctionnel s'est avéré une manœuvre précieuse, permettant à CliniCrowd. Cela a contribué à promouvoir l'acceptation du mannitol parmi les médecins et les patients.

En effet, au second semestre 2018, les auteurs ont constaté un changement d'attitude chez les médecins. Trois médecins interrogés pour l'étude nous ont dit qu'une fois qu'ils ont compris qu'il s'agissait d'un complément alimentaire, ils ont cessé de protester : « *C'est un complément alimentaire. Cela n'aide peut-être pas, mais ce n'est pas nocif » *.

Comme l'explique un neurologue : "I think no doctor likes it when the patient comes and says, ‘Listen, I’ve found a treatment.’ Most of the time I have to make sure his feet are on the ground, and I must explain why, most probably, in his case it won’t work. This was also my initial response to mannitol, complete resistance, not wanting them to take it....The attitude changes when there is already information and a mass of patients who have collated and documented its use in an orderly manner. Moreover, they didn’t come and say this is a magic drug, but rather that it may help with some of the symptoms....I suggest to patients, especially at the beginning, that they should read about mannitol. I definitely don’t exclude it, in fact quite the opposite."

Pour comprendre comment les patients eux-mêmes ont vécu cela, considérons Menachem [pseudonyme], 68 ans, diagnostiqué quatre ans plus tôt. Interrogé sur l'expérience de la prise de mannitol et de sa participation au questionnaire en ligne, il a répondu :

""My participation in the experiment has turned my world around. I come to the doctor and update him, see? I, Menachem, taught the neurologist that there is such a thing as mannitol, and that I am taking part in an experiment with other patients. When I go to see him, he immediately stands up! ‘Welcome’, he says, ‘tell me how you are getting on’. There is a sense that we are colleagues, and that I am doing something incredibly important. There is something in [mannitol] that helps, it’s not a magical cure, or maybe I no longer suffer. But there is an improvement in my sleep, my sense of smell, and also my difficulty in movement. [interview Oct. 30, 2019]"

Notez la facilité que Menachem décrit dans sa relation avec le médecin, son sentiment d'être un expert, son ravissement et l'agence qu'il ressent du fait de sa participation. Ceux-ci sont tous si importants pour lui qu'il les mentionne avant même son amélioration de la santé, qu'il attribue à la prise régulière de mannitol.

En conclusion, CliniCrowd a démontré une nouvelle façon d'aborder de la "science inachevée", en utilisant la recherche participative pour générer la pression et l'influence du public avec lesquelles attirer formellement les scientifiques pour tester des composés à faible potentiel de profit. CliniCrowd représente une intersection de connaissances scientifiques, de technologies, de pratiques,elle est aussi le produit d'un processus soutenu de diffusion et de décentralisation de l'expertise.

Somatostatin-evoked Aβ catabolism in the brain: Mechanistic involvement of α-endosulfine-K channel pathway.

- Posted in Somatostatin-evoked Aβ catabolism in the brain: Mechanistic involvement of α-endosulfine-K channel pathway. by English by

Alzheimer's disease is a progressive neurodegenerative disease characterized by the deposition of amyloid β peptide, but given the lack of clinical efficacy of amyloid β inhibitors, this is increasingly disputed.

Yet neprilysin-deficient knockout mice exhibit both Alzheimer's-like behavioral alteration and beta-amyloid deposition in the brain. Since neprilysin is considered to be the step limiting the rate of degradation of beta-amyloid, it has been considered as a potential therapeutic target.

Scientists have previously shown that somatostatin, a neuropeptide, regulates Aβ42 levels in the brain via upregulation of neprilysin. Somatostatin mRNA levels are significantly decreased with aging, especially in Alzheimer's disease. This suggests that the aging-induced downregulation of somatostatin expression may be a trigger for amyloid β peptide pathology in late-onset Alzheimer's disease.

However, the mechanism by which somatostatin signaling regulates neprilysin activity remains unclear. In the present study, the authors used in vitro and in vivo experimental paradigms to identify α-endosulfine (ENSA) as a negative regulator of neprilysin activity downstream of somatostatin signaling.

In vitro and in vivo experiments revealed that neprilysin degrades α-endosulfine (ENSA) as a substrate, suggesting that neprilysin and α-endosulfine (ENSA) form a negative feedback loop. This hypothesis is based on the fact that opioids and substance P, cell-specific ligands in monocytes and bone marrow cells, respectively, regulate neprilysin via a feedback mechanism. It is possible that amyloid β peptide and α-endosulfine (ENSA) compete against each other in neprilysin-mediated degradation, additively exacerbating this feedback loop and inducing a vicious cycle.

A selective KATP channel agonist such as diazoxide (Dz) could serve as a beneficial approach to break this vicious cycle since diazoxide is sometimes used as a drug for antihypertensive and hypoglycemic properties, and has the potential in the preclinical setting. 'improve amyloid β peptide pathology and behavioral abnormalities in Alzheimer's disease.

Diazoxide is used as a vasodilator in the treatment of acute hypertension or malignant hypertension. Diazoxide also inhibits insulin secretion by opening the ATP-sensitive potassium channel of pancreatic beta cells;

The mechanism by which diazoxide (Dz) attenuated amyloid peptide plaque deposition was not clear, however. Their results indicate that diazoxide (Dz) reduced amyloid deposition in AppNL-F mice via the regulation of neprilysin activity in the anterior cortex and the hippocampus. This regional selectivity of the action of neprilysin by diazoxide (Dz) may depend on the dopaminergic system in the brain.

The authors have therefore demonstrated a new preventive approach at the preclinical stage of Alzheimer's disease based on the function of α-endosulfine (ENSA). This negative regulator of neprilysin and of the KATP channel could be a new therapeutic target for lowering the amyloid β peptide.

Read the original article on Pubmed

Impaired Color Discrimination in Alzheimer Disease Dementia.

- Posted in Impaired Color Discrimination in Alzheimer Disease Dementia. by English by

Patients with Alzheimer disease dementia often show impaired orientation and navigation. Signage offers an opportunity to compensate for these deficits, communicate information efficiently and facilitate way finding. Certain properties of signs such as colors and contrasts may beneficially affect the uptake and processing of information particularly in ADD patients.

Thirty-six healthy older adults and 30 ADD patients performed a computerized color perception task that required discriminating different color combinations. The effects of different contrast features on performance accuracy and speed in the 2 experimental groups were examined by nonparametric mixed analysis of variances.

Analyses revealed a significant effect of contrast polarity on reaction times, significant effects of group on reaction times and errors as well as a marginally significant interaction of group×color on errors. All participants benefited from positive contrast polarity as indicated by increased performance speed. Furthermore, ADD patients reacted slower and less accurate than healthy controls, but showed higher accuracy at black-white and red-yellow than at blue-green color combinations.

The authors' findings suggest the implementation of signs with positive contrast polarity to ensure faster reactions. In addition, certain color combinations may enhance accuracy, particularly in patients with ADD.

Read the original article on Pubmed


Please, help us continue to provide valuable information: