Despite the sound epidemiologic and basic science rationales underpinning numerous "disease modification" trials in manifest Parkinson disease, none has convincingly demonstrated that a treatment slows progression.

Rapidly expanding knowledge of the genetic determinants and prodromal features of Parkinson disease now allows realistic planning of prevention trials with initiation of putatively neuroprotective therapies earlier in the disease. In this article, the authors outline the principles of drug selection for Parkinson disease prevention trials, focused on proof-of-concept opportunities that will help establish a methodological foundation for this fledgling field.

The scientists describe prototypical, relatively low-risk drug candidates for such trials, tailored to specific at-risk populations ranging from pathogenic or gene variant carriers to those defined by prodromal Parkinson disease and α-synucleinopathy. Their proposal includes caffeine, Ibuprofen, Albuterol, Ambroxol.

Finally, the authors review gene-targeted approaches currently in development targeting clinically manifest Parkinson disease for their potential in future prevention trials.

Read the original article on Pubmed

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In 2013, Xiang-Dong Fu of the University of California, San Diego, and colleagues found that deleting a single gene converts a variety of cells, including fibroblasts, directly into neurons. This procedure represents one of the simplest methods of generating neurons to date. Since it does not require any foreign DNA, it can bring in-vivo direct cells conversion closer to the clinic.

Cellular reprogramming technology, including the generation of induced pluripotent stem cells, had raised hopes that scientists might one day replace dying cells with new ones derived from patient's healthy tissues. New presentations in 2019 had really made people think that a clinical solution for neurodegenerative diseases like Parkinson's, Alzheimer's or ALS (Charcot's disease) was at hand.

Fu's group proceeded by injecting directly into the substantia nigra of mice, an adeno-associated virus (AAV) carrying an RNA that inhibited PTBP1. To mark infected astrocytes, the vector they used included a fluorescent tag that could only be activated in cells infected with the virus (because it was under the control of the GFAP promoter). Researchers reported that fluorescent cells carrying neural markers formed connections with nearby striatum and reversed motor deficits in an animal model of Parkinson's disease. Obviously we could already be wondering why AAV viruses would only infect astrocytes, and not other cells and among these, neurons.

Indeed, several recent studies suggest that the apparently converted astrocytes would in fact have been neurons. These recent studies have used different cell lineage mapping approaches to label astrocytes. This type of lineage can be studied by marking a cell (with fluorescent molecules or other traceable markers) and following its progeny after cell division. In fact, it is a method quite similar to that used by the San Diego group.

Two of the studies, published in Cell Reports on June 14, reported that Müller's glia (a source of retinal stem cells that can replenish neuronal loss and restore vision) failed to convert into neurons when PTBP1 was deleted (Xie and al., 2022; Hoang et al., 2022). Two others – one published in Life on May 10 and the other published on bioRxiv on May 13 – came to similar conclusions with astrocytes in the substantia nigra and striatum (Chen et al., 2022; Yang et al ., 2022).

Their findings are consistent with a similar report published last year (Wang et al., 2021). Some have also found GFAP promoter expression in neurons, giving the mistaken impression that they were ancient astrocytes.

We can ask ourselves some serious questions, for example why the scientific community did not express as soon as the 2013 announcement was made, the fairly obvious fact that astrocytes were probably not the only ones to be infected, why did they wait 9 years to highlight this point?

Another question concerns the cell lines, these are different in the different studies, the cells are at different stages of maturation, and their phenotype is very different from that of astrocytes, so can we really draw general conclusions?

In addition, Müller's glia are derived from the development of two distinct populations of cells, which are we talking about in these new studies? Finally, they are the only retinal glial cells that share a common cell line with retinal neurons. From a certain point of view Müller's glia are neurons not astrocytes, and therefore this greatly diminishes the value of the analyzes carried out, but this should be known to scientists who have done these contradictory studies?

In response to these and other studies that challenge data for conversion of astrocytes to neurons, Fu recognized that some expression of the GFAP promoter occurs in neurons infected with AAV viruses. For him, about 5% of cells expressing AAV genes soon after infection were neurons. Yet this percentage seems very low.

On the other hand, Fu said that lineage tracing experiments performed in the new studies may have preferentially marked mature Müller cells, leaving open the possibility that the conversion of more immature cells into neurons may have been missed. .

Finally, knocking out PTBP1 effectively restored dopamine levels and boosted motor function in a mouse model of Parkinson's disease. If not by the creation of new neurons, what could e

En 2013, Xiang-Dong Fu, de l'Université de Californie à San Diego, et ses collègues ont découvert que la suppression d'un seul gène convertit une variété de cellules, y compris des fibroblastes, directement en neurones. Cette procédure représente l'une des méthodes les plus simples de génération de neurones à ce jour. Puisque celà ne nécessite aucun ADN étranger, celà rapproche l'espoir que la conversion direct, in-vivo, soit réalisée rapidement.

La technologie de reprogrammation cellulaire, y compris la génération de cellules souches pluripotentes induites, avait fait naître l'espoir que les scientifiques pourraient un jour remplacer les cellules mourantes par de nouvelles dérivées des tissus sains d'un patient. De nouvelles présentations en 2019 avait vraiment fait penser qu'une solution clinique pour les maladies neurodégénérescentes comme Parkinson, Alzheimer ou la SLA (maladie de Charcot) était proche.

Le groupe de Fu avait procédé en injectant directement dans la substantia nigra de souris, un virus adéno-associé (AAV) portant un ARN qui inhibait PTBP1. Pour marquer les astrocytes infectés, le vecteur qu'ils ont utilisés comprenait une étiquette fluorescente qui ne pouvait être activée que chez les cellules infectées par le virus (car sous le contrôle du promoteur GFAP). Les chercheurs ont rapporté que des cellules fluorescentes portant des marqueurs neuronaux formaient des connexions avec le striatum voisin et inversaient les déficits moteurs dans un modèle animal de la maladie de Parkinson. Evidemment on pouvait dors et déjà se demander pourquoi les virus AAV n'infecteraient que les astrocytes, et pas les autres cellules et parmi celles-ci, les neurones.

Effectivement plusieurs études récentes suggèrent que les astrocytes apparement convertis auraient en fait été des neurones. Ces études récentes ont utilisé différentes approches de cartographie de lignées cellulaire pour marquer les astrocytes. Ce type de lignée peut être étudié en marquant une cellule (avec des molécules fluorescentes ou d'autres marqueurs traçables) et en suivant sa descendance après division cellulaire. En fait c'est une méthode assez similaire à celle du groupe de San Diego.

Deux des études, publiées dans Cell Reports le 14 juin, ont rapporté que la glie de Müller (une source de cellules souches rétiniennes qui peuvent reconstituer la perte neuronale et restaurer la vision) ne se convertissait pas en neurones lorsque PTBP1 était supprimé (Xie et al., 2022 ; Hoang et al., 2022). Deux autres - l'un publié dans Life le 10 mai et l'autre publié sur bioRxiv le 13 mai - sont arrivés à des conclusions similaires avec des astrocytes dans la substantia nigra et le striatum (Chen et al., 2022 ; Yang et al., 2022).

Leurs conclusions concordent avec un rapport similaire publié l'année dernière (Wang et al., 2021). Certains ont également trouvé une expression du promoteur GFAP dans des neurones, donnant l'impression erronée qu'il s'agissait d'anciens astrocytes.

On peut se poser quelques questions sérieuses, par exemple pourquoi la communauté scientifique n'a pas exprimé dès l'annonce de 2013, le fait assez évident que les astrocytes n'étaient sans doute pas les seuls à être infectés, pourquoi avoir attendu 9 ans pour mette ce point en évidence?

Une autre question concerne les lignées cellulaires, celles ci sont différentes dans les différentes études, et les cellules sont à des stades différents de maturation, leur phénotype est très différent de celui des astrocytes, peut-on réellement en tirer des conclusions générales? De plus les glies de Müller sont dérivées du développement de deux populations distinctes de cellules, dequels parle-t-on dans ces nouvelles études? Enfin ce sont les seules cellules gliales rétiniennes qui partagent une lignée cellulaire commune avec les neurones rétiniens. D'un certain point de vue ce sont des neurones pas des astrocytes, cela diminue fortement la valeur des analyses effectués, mais celà devrait être connu des scientifiques qui ont faient ces études contradictoires?

En réponse à ces études et à d'autres qui remettent en question les données de conversion des astrocytes en neurones, Fu a reconnu qu'une certaine expression du promoteur GFAP se produit dans des neurones infectés par les virus AAV. Pour lui, environ 5 % des cellules exprimant les gènes AAV peu après l'infection étaient des neurones. Ce pourcentage semble très faible.

D'autre part, Fu a déclaré que les expériences de traçage de lignée réalisées dans les études nouvelles, peuvent avoir marqué de manière préférentielle des cellules de Müller matures, laissant ouverte la possibilité que la conversion de cellules plus immatures en neurones ait pu être manquée.

Enfin, l'inactivation de PTBP1 a effectivement restauré les niveaux de dopamine et stimulé la fonction motrice dans un modèle de souris de la maladie de Parkinson. Si ce n'est par la création de nouveaux neurones, qu'est-ce qui pourrait expliquer ces bienfaits ?

Here is a report that more than twice as many Americans dying from Parkinson disease in 2019 (35,311) compared with 1999 (14,593). The study was published in the November 16, 2021, issue of Neurology.

Using data obtained from the National Vital Statistics System of the National Center for Health Statistics, the researchers calculated a total of 479,059 U.S. deaths from Parkinson disease between 1999 and 2019.

The age-adjusted death rate nearly double in 20 years, from 1999 to 2019. There was an average annual increase of 2.4% over the two decades.

Parkinson disease mortality increased significantly in all age groups, sexes, and racial and ethnic groups, as well as in urban and rural locations. There were, however, several notable differences within these categories. Mortality rates for men were twice those for women throughout the study period. Also, White individuals had higher mortality rates than people from other racial or ethnic groups which implies there is some genetic aspect.

The scientists speculate that that increased exposure to pesticides, herbicides, heavy metals, and air pollution, could raise Parkinson disease risk. However a doubling death rate would mean a rather obvious change in environment The scientists speculate that as people are living longer, thereby contributing to higher Parkinson disease incidence and mortality. Yet in US the life expectancy didn't increase during that period.

Most patients die with Parkinson’s Disease and not from it. The illnesses that kill most people are the same as those that kill people with PD. These are heart conditions, stroke and cancer. As we age we become increasingly aware that more than one bad thing can happen to our bodies.

Paradoxically, the therapy that improves the quality of life of patients with Parkinson's disease is the one that later contributes to the decline in their quality of life. Indeed over time, L-dopa (l-3,4-Dihydroxyphenylalanine), the main treatment for Parkinson's disease, loses its effectiveness and causes involuntary muscle movements and erratic movements and sometimes hallucinations. Although this effect is well identified, scientists did not understand why L-dopa accelerates the progression of the disease.

L-dopa and other pharmacological treatments for Parkinson's disease are designed to replace lost dopamine caused by degenerating nerve cells in the brain. Although dopamine cannot cross the blood-brain barrier, which allows substances such as water and oxygen to pass into the brain, L-dopa can. However, 99% of L-dopa is metabolized outside the brain, so it is given in combination with an enzyme inhibitor to prevent side effects such as nausea and heart problems, and allow more of the drug remains in the blood so as to be percolated through the blood-brain barrier. In this case, 5 to 10% of the ingested dose reaches the brain.

A team of researchers from the University of California, Irvine studied the molecular binding characteristics of L-dopa and related compounds using an optical technology called surface plasmon resonance to measure interactions between the drug and the target proteins. The results of the study were recently published in ACS Chemical Neuroscience.

Their studies aimed to test whether continuous administration of L-dopa in animal models of Parkinson's disease is associated with increased iron accumulation in dopaminergic neurons in the brain and whether this accumulation depends on the binding of L-dopa to siderocalin.

The researchers also wanted to determine whether the complex can be detected in the blood of patients with Parkinson's disease. The relative amount of this complex would then serve as a biomarker to determine when it becomes appropriate to switch to new treatments for the disease.

Indeed l-DOPA chelates iron through its catechol group, is forming the l-DOPA:Fe complex. Siderophore-like catechol compounds are known to bind siderocalin (Scn)/lipocalin-2 to form stable siderophore:Fe:Scn complexes. Scn is up-regulated in the substantia nigra of PD patients and may play a role in the pathophysiology of PD.

Their results demonstrate that L-DOPA forms a stable complex with Scn in the presence of Fe3+.

Expressed more simply, this means that L-dopa and the protein siderocalin combine in the presence of iron to create a complex that can cause cellular iron overload, resulting in an imbalance between free radicals and antioxidants, as well as neuroinflammation.

The authors speculate that as Parkinson's disease progresses, this effect increases, inducing these negative side effects, while the dose needed to relieve disease symptoms increases, resulting in a window narrow therapy.

It remains that the effects of the enzyme inhibitor used to mitigate L-Dopa side effects, are not trivial either, but this study does not address this subject.

Moreover L-Dopa is not a panacea either, indeed its therapeutic effectiveness is different for different types of symptoms. Bradykinesia and rigidity are the most sensitive symptoms to L-Dopa administration, while tremors are less sensitive. Speech disorders, speech and swallowing disorders, postural instability and frozen gait are the least reactive symptoms.

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.

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.