Now you have an opportunity to fast-track the discovery of drugs in some neuro-degenerative diseases.

AstraZeneca, the pharmaceutical company, proposes a challenge in the area of nucleotide repeat expansion disorders, which includes ALS (Charcot/Gehrig) disease, but also Huntington's disease, etc...

Typically you have to be a startup or an academic with a plan to launch a startup because your solution must be translated into practice within a 12–18-month timeframe.

I am willing to provide reasonable help if you hesitate. This will be mostly in terms of shaping your proposal. I believe that AstraZeneca, like other large companies, is not interested in unproven, hypothetical ideas. On the contrary, IMO they search for people with energy and time (and intellectual right) to give blood to ideas where there is a consensus but where nobody cared to develop it in the pre-clinical stage.

I guess also AstraZeneca would prefer a simple implementation, instead of a complex one. So for example, a small molecule proposal would be preferred to a genetic therapy. A compound of two or three existing drugs to an untested drug. You get the idea.

Good luck!

Jean-Pierre Le Rouzic You will find the link to email me at the bottom of this page.

An article on SCMP tells about an observational clinical trial on six patients testing a new gene therapy: SNUG01.

It's about a genetic therapy proposed by a Chinese company: Sineugene.

This is not even a phase I clinical trial, what is known at the present state is that pre-clinical studies were promising (as usual) and it seems to have beneficial effects on one patient. If this is confirmed in larger trials, it would be a first: No ALS therapy has been able to reverse a bit of the disease. Please understand that the patient just slightly improved, it's not a cure.

Similar assertions have been made in the past by Western companies, sometimes going to the point of ridicule, like claiming patients were able again to do gym and motocross, even while the FDA rebuked the drug. I trust the FDA, not those companies. Yichang Jia, Ph.D., Co-founder of SineuGene

There are few scientific publications on this new therapy, here is what I understand: The underlying thesis of the scientists is that ALS (or FTD, PD and even Alzheimer(s disease) happens when there are both: * A genetic variant of some gene (which generates RNA-binding proteins (RBPs)) * A cellular stress (it could be a lot of things including insulin resistance) When those two conditions are met, stress granules which are normal phenomena are not processed correctly, instead in disease-susceptible neurons, stress induces mislocalization of mutant RBPs into stress granules and upregulation of ubiquitin, two hallmarks of disease pathology.

It's not known how SNUG01 (there are other names) works, here are some guesses: As the problem stems from the concomitance of two events, removing one of them could (partially?) solve the problem. We know that Relvyrio, TUDCA, and other drugs try to relieve cellular stress. But they are not very efficacious. One possibility as SNUG01 is a gene therapy, it that it tries to remedy the genetic variant. Hence the large therapeutic target that is announced.

I guess that it would be a knock-in therapy, contrary to the knock-out and ASO technologies that are favored by Western scientists. Or it could combine both: Deleting the wrong sequence and inserting a new correct one. Yet it is an AAV gene therapy so the payload can't be large, and a sophisticated gene therapy is unlikely.

AAV gene therapies have some problems and side effects, let's hope they are solved. One main problem is that there are millions of target cells to infect and trillions that should not be infected. Current gene therapies are unable to reach both goals.

The paper we discuss today focuses on the role of dipeptide repeats, particularly poly(proline-arginine), generated from GGGGCC repeat expansions in the C9orf72 gene. These dipeptides are involved in familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in carriers of certain C9orf72 gene variants.

The study indicates that the evolution of cells carrying certain sequence repeats of the C9orf72 gene (called PR20), is influenced by the distribution of these sequences in the nucleus. But the important point from the point of view of patients and caregivers is that these sequences can be hindered by a nuclear import inhibitor called importazole. As importazole can block the nuclear import of PR20, it suggests that the nuclear localization of PR20 is crucial for its cytotoxic effects. Yet importazole is not a clinically approved drug, the use of importazole is mainly confined to laboratory research to understand cellular functions that involve nuclear transport. In their search for drugs, the scientists investigated BRD4 inhibitors, such as JQ-1 and I-BET762, which restrict the cytoplasmic localization of the PR20 dipeptide of the C9orf72 gene, and thus diminish its cytotoxic effects. BRD4 is involved in the regulation of transcription and the transmission of epigenetic information during cell division.

In 2016, BRD4 was found to possess histone acetyltransferase activity. Histones are essential components of chromatin and play a crucial role in gene regulation. They act like spools around which DNA winds to create structural units called nucleosomes. The nucleosomes are in turn enveloped in very compact chromatin. Histones also protect DNA against possible damage.

The ability of histone acetyltransferases to manipulate chromatin structure makes them essential for cell maintenance and survival, but they have also been implicated in the progression of neurodegenerative diseases.

Inhibition of BRD4 results in increased expression of histones, causing their accumulation in the cytoplasm. These cytoplasmic histones limit the distribution in the nucleus of the PR20 dipeptide derived from the C9orf72 gene.

I-BET762 is a bromodomain and extraterminal (BET) inhibitor. BET inhibitors specifically target bromodomains, which interact with histone proteins. JQ1 is a thienotriazolodiazepine and another potent inhibitor of the BET family of bromodomain proteins.

Interestingly, the introduction of histones alone is sufficient to protect the cells of the dipeptide derived from repeat sequences from cell death induced by the C9orf72 gene.

Phenylephrine, a drug used to treat nasal congestion, also induces cellular hypertrophy and cytoplasmic distribution of histones, providing additional protection against the PR20 dipeptide of the C9orf72 gene.

The researchers propose that temporary induction of the presence of cytoplasmic histones may attenuate the neurotoxic effects of dipeptide repeat proteins.

A problem is that some BRD4 inhibitors have a short half-life in the body, which would require almost continuous administration. On the other hand, phenylephrine is a medication commonly used as a decongestant, but cannot be used by people with hypertension.

As a layperson I have been studying ALS by reading scientific publications for several years, it started after the second time someone went ill in my family. This blog is the result of that effort. Scientists claim to find cures for most chronic diseases every week by targeting one or the other obscure molecule. We know that most of these articles are of very poor quality. What feels important to me are articles that show a good knowledge of human anatomy and physiology. I don't care about molecules in mice.

Nearly one century ago, medical doctors made a parallel between spinal cord injury and spinal-onset ALS. In both cases, there is important muscle wasting. And this is what kills people, so it's important to understand how this develops and what are the consequences. Obviously, a spinal cord injury will sever the link between the brain motor area, some upper motor neurons, and corresponding lower motor neurons and muscles. Yet it does not stop there, which is particularly interesting when we have ALS in mind. In spinal-onset ALS the disease starts in a very localized muscular for example a muscle in the thumb, and it spreads, often until respiratory muscles fail.

Similarly, a spinal cord injury has consequences that are far from being limited to some motor neurons and diseases. For example, pulmonary infection is a leading cause of morbidity after spinal cord injury. Bizarrely this happens because spinal cord injury causes atrophy and dysfunction in the lymphatic system, an organ system in vertebrates that is part of the immune system.

Now scientists from Ohio, describe systemic wasting that affects innervated non-paralyzed skeletal muscles. The muscles that are affected in ALS are also skeletal muscles. This wasting appeared within 1 week after experimental spinal cord injury in mice and in three weeks half of the muscle mass disappeared. This waste affects the whole body. Skeletal muscle fibers are broadly classified as "slow-twitch" (type 1) and "fast-twitch" (type 2). This muscle wasting affects fast type 2 muscles preferentially, and became exacerbated after a third thoracic vertebra (T3) paraplegia compared with low (T9) thoracic paraplegia. The T3 vertebra is situated at the level of the shoulder, while the T9 is at the height of the sternum.

Markus E. Harrigan, Jan M. Schwab et al. remark that the wasting of nonparalyzed muscle and its rapid onset and severity cannot be explained by disuse, so it implies unknown systemic drivers. Mechanisms underlying systemic muscle wasting (including fully innervated non-paralyzed muscles) early after paraplegic SCI would imply the presence of biological signaling which can quickly reach muscles of the entire body. Knowing the cause of this widespread muscle wasting after a T3 paraplegia in spinal cord injury might illuminate the similar phenomena in ALS.

The authors found that muscle transcriptome and biochemical analysis revealed a glucocorticoid-mediated catabolic signature early after T3 spinal cord injury. They generated an inducible skeletal muscle-specific glucocorticoid receptor (GR) knockout mouse model in order to test that hypothesis.

Spinal cord injury-induced systemic muscle wasting was mitigated by (i) endogenous glucocorticoid ablation (adrenalectomy) and (ii) pharmacological glucocorticoid receptor (GR) blockade and was (iii) completely prevented after T3 relative to T9 spinal cord injury by genetic muscle-specific GR deletion.

These results suggest that hypercortisolism contributes to a rapid systemic and functionally relevant muscle wasting syndrome early after paraplegic spinal cord injury in mice. Indeed in humans, hypercortisolism induces central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Hypercortisolism has also been implicated in ALS, maybe it would be interesting to test glucocorticoid inhibitors in a clinical trial. There are studies (here or here) that show that glucocorticoid inhibitors ameliorated the health in an ALS mice model.

There are many hypotheses about the etiology of ALS, and most of them are probably correct. They can be classified in several ways, but one of them is usually to separate a genetic origin from a "sporadic" origin. But even for a genetic origin, it is unlikely that the disease will wait 50 years before striking. The etiology certainly proceeds from multiple causes and stages, and the genetic aspect concerns only one of these stages towards the disease.

Spinal muscular atrophy (SMA) is a genetic disease that closely resembles ALS, but like most diseases resulting from a deleterious variant of the genetic heritage, it strikes toddlers. Infants with this disease have a defective variant of their SMN1 gene and have a very short life expectancy. Children born with type 1 SMA, until recently, died before their second birthday. Although SMA is much more common than ALS, we don't hear much about this disease because most patients die before the age of 3 and there is no significant effort to raise awareness. A few years ago, some therapies appeared, Spinraza, Zolgensma and others. Although hailed as life-saving drugs when they first appeared, they have serious side effects. Drug development continues, often aiming to increase SMN2 production to compensate for the lack of healthy SMN1.

Among the many hypotheses concerning ALS, there is a very minor one: In aging people, senescent motor neurons, exhausted by numerous stresses, reenter the cellular life cycle, perhaps as the result of a mechanism of adaptation to stress. Since it is difficult to imagine how a very elongated motor neuron would divide, they quickly die in this attempt. Usually, cells resume their life cycle after signaling by CDK proteins. CDK proteins constitute a family of proteins involved in the regulation of the cell cycle. Dysregulation of CDKs, particularly cyclin-dependent kinase 5 (Cdk5), is seen in many neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Cdk5 is a unique member of the CDK family because it does not play a critical role in cell cycle progression and is not activated by a cyclin. Instead, Cdk5 is normally activated by the regulatory protein p25. Cdk5/p35/p25 activity is normally an important regulator of the proper development of the mammalian central nervous system.

Scientists from Northwestern University have identified, in a mouse model of SMA, an unexpected role of Cdk5 signaling in the appearance of mitochondrial defects and selective degeneration of motor neurons.

The scientists report that Cdk5 activity is significantly increased in their mouse and pluripotent stem cell (iPSC) models of SMA. The increase in Cdk5 activity occurs before the appearance of SMA phenotypes, suggesting that it may be an initiator of the disease.

The article does not clearly show what causes the transition from the p35 subunit to the p25 activator. In vitro studies have already suggested that aberrant activation of Cdk5 by an endogenous truncated version (p25) of p35 could be a key event in the process of neurodegeneration.

An enzyme responsible for cleaving p35 to form p25 is calpain, a calcium-activated protease implicated in neuronal cell death and notably ALS in the past. There is also evidence that hyperactivation and redistribution of Cdk5 by p25 plays a critical role in the phosphorylation of “pathological” substrates (such as tau which is implicated in Alzheimer's disease).

As inhibition of Cdk5 signaling inhibits the degeneration of motor neurons derived from SMA mice and human iPSC models of SMA disease, this suggests that reducing aberrant Cdk5 activation could potentially improve SMA disease symptoms and benefit patients. patients. This could also have implications for other motor neuron diseases, such as ALS.

From there, we can adopt two attitudes on how to use this new knowledge. - The first is for scientists to learn more about the long chain of molecular events that lead to disease, in the hope that it is not too complex for our limited human cognitive abilities. - The other is that of doctors, it is more pragmatic, for example, it could lead to efforts to develop a Cdk5 inhibitor capable of targeting the pathway to slow down the degeneration of motor neurons. However, thousands of clinical trials on Alzheimer's disease demonstrate every day that a pragmatic approach is rigorous but very ineffective.

Decoding speech from brain activity is a long-awaited goal in the fields of health and neuroscience. Invasive devices have recently taken major steps in this regard: deep learning algorithms trained on intracranial recordings can now begin to decode basic linguistic features such as letters, words, and audio spectrograms.

Alexandre Défossez, Charlotte Caucheteux, Jérémy Rapin, Ori Kabeli and Jean-Rémi King from (Meta/Facebook) and the École Normale Supérieure in France describe a computer model trained to decode representations of perceived speech from non-invasive recordings of a large cohort of healthy individuals.

To evaluate this approach, they used four public datasets, totalizing the recordings of 175 volunteers by magnetoencephalography or electroencephalography while they listened to short stories and isolated sentences. The languages of these texts were English and Dutch. Their results show that the model can identify, from 3 seconds of magnetoencephalographic signals, the corresponding speech segment with up to 41% accuracy, which is, however, lower than previous results. Furthermore, we know that the more complex the sentence, the less precise the results. The texts here are extremely short.

An excellent example of previous work is the one published recently by Francis R. Willet and colleagues which demonstrates a speech-to-text BCI that records spiking activity from intracortical microelectrode arrays.

Their participant who can no longer speak intelligibly owing to bulbar-onset amyotrophic lateral sclerosis attempted speech was decoded at 62 words per minute, which is 3.4 times as fast as the previous record and begins to approach the speed of natural conversation (160 words per minute9 ). The implant needs surgeons to open the skull, and find the optimal location, and when the operation is completed, the patient has a small box on their skull that is connected to a computer via cables. The box could certainly be miniaturized in the future and the cables replaced by Bluetooth or a similar radio device, yet this is quite invasive. Extending this approach to non-invasive brain recordings remains a challenge.

“We were surprised by the decoding performance obtained,” King said. "In most cases, we can retrieve what the participants hear, and if the decoder makes a mistake, it tends to be semantically similar to the target sentence."

“Our team is devoted to fundamental research: to understand how the brain works, and how this functioning can relate and inform AI,” King said. "There is a long road before a practical application, but our hope is that this development could help patients whose communication is limited or prevented by paralysis. The major next step, in this regard, is to move beyond decoding perceived speech and to decode produced speech."

However, such a system, if it uses magnetoencephalography as suggested, is even less practicable than that of Willet. A miniaturized magnetoencephalography helmet currently requires equipment weighing approximately one ton.

However, 29% of the samples used by the French scientists were recorded by EEG, which makes it possible for a patient to use such a headset as well as computer equipment. Here too we could consider replacing the cables with a wireless connection. However, we know that the results obtained by EEG are of lower quality than those obtained with an implant.

The road to easy-to-use brain-speech interfaces is still long ahead of us.

A research group from the University of Brescia in Italy conducted a study to test the effectiveness of a two-week treatment with corticospinal tDCS to improve the quality of life in ALS patients. Specifically, the scientists sought to: (i) Evaluate the long-term effects of multiple sessions of bilateral anodal motor cortex tDCS and cathodal spinal tDCS in patients with ALS; (ii) determine whether two cycles of tDCS treatment are more effective than a single treatment; (iii) explore potential effects on ALS prognostic markers, such as serum neurofilament light chain and survival rates.

This study aimed to determine whether transcranial corticospinal direct current stimulation (tDCS) could alleviate symptoms in ALS patients via a randomized, double-blind, sham-controlled trial followed by an open-label phase.

Thirty-one participants were randomized into two groups for the initial controlled phase.

• Group 1: At baseline (T0), group 1 received placebo stimulation (sham tDCS),

• Group 2: Group 2 received corticospinal stimulation (real tDCS) for five days/week for two weeks (T1), with a randomized, double-blind, sham-controlled 8-week follow-up (T2).

• At the 24-week follow-up (T3), all participants (groups 1 and 2) received a second treatment of bilateral anodal motor cortex and cathodal spinal stimulation (real tDCS) for five days/week for two weeks (T4).

Follow-up assessments were performed at 32 weeks (T5) and 48 weeks (T6) (open phase). At each time point, clinical assessment, blood sampling, and intracortical connectivity measures using transcranial magnetic stimulation (TMS) were assessed. Additionally, they assessed survival rates.

Compared to sham stimulation, corticospinal tDCS improved overall strength, caregiver burden, and quality of life scores, correlating with the restoration of intracortical connectivity measures. Serum neurofilament light levels decreased in patients receiving real tDCS, but not in those receiving sham tDCS. The number of completed 2-week tDCS treatments significantly influenced patient survival. If I extrapolate from Figure 6, patients with two treatments would live 13 years longer than patients without treatment. This improvement is considerable, if we ignore the statistical hallucinations of pharmaceutical companies, the current improvements simply relate to a few months of survival. We will see below that we can doubt this result.

Yet the number of tDCS treatments completed over 2 weeks significantly influenced survival rates, suggesting a possible dose-dependent effect of tDCS on disease progression.

Elevation of serum NfL levels correlates with neuronal damage in a spectrum of neurodegenerative diseases, including ALS. A decrease in serum NfL levels, as observed in their study, could potentially suggest a neuroprotective effect of tDCS.

However, despite certain positive results, their study presents several limitations which deserve to be taken into consideration. First, the very small sample size and high attrition rate (~50%) raises questions about the side effects that must have been difficult to bear.

Furthermore, no significant effect was observed on the ALSFRS-R. We can wonder how a study that announces being capable of significantly extending survival is incapable of at least showing a slowdown in the progression of the disease. This seems a difficult contradiction to resolve. Another example of a statistical anomaly is that the control group appears to have undergone significant improvement as measured by the ALSAQ-40 scale.

Yet the promising results of their study highlight the potential of corticospinal tDCS as a therapeutic intervention for ALS opening several avenues for future research. One possible direction is to explore the synergistic effects of combining in ALS centers, tDCS with other therapeutic interventions, such as pharmacological treatments or physical therapy, which could potentially amplify their effects by modulating neural networks and promoting neuroplasticity, thus leading to better clinical outcomes..

There are multiple subtypes of ALS: It could be of genetic origin, for example, an uncommon version of a SOD1, FUS, or C9orf72 genes might under some unknown conditions lead to ALS in aging people. But most people with ALS have no genetic alleles yet they developed ALS, perhaps due to some environmental conditions, like ingesting some toxins. In most cases people with ALS have a biomarker: They have aggregates of a very common protein, TDP-43, which localizes at an unlikely place in the neuron cells.

Some other things that are a bit weird in ALS, if it's of genetic origin why only aged people are striked? Why does it start with a seemingly innocuous muscular problem that soon extends to the whole body, but only for a specific type of muscle? The only therapy up to now, which seems to be a breakthrough is Qalsody, a genetic therapy by Biogen and Ionis. Unfortunately, it aims at a specific variant of the SOD1 gene which is present only in very few ALS patients. SOD1 variants are implicated in only 2% of ALS cases, and there are hundreds of SOD1 variants, while Qalsody targets only one of them.

In 2019 following the arrival of a SMA therapy, I made a plea for a genetic therapy aiming at TDP-43. Many scientists have been working on it in recent years, and it seems that one of those efforts is starting to show some results.

In 2011, Shulin Ju, Gregory A Petsko and colleagues found that hUPF1, a human gene, rescues the toxicity of FUS/TLS in a yeast model of ALS. This does not mean much as indeed there is an abyss between a yeast model of ALS and human beings. Yeasts are very different from mammal cells, but they are cheap so they are convenient for testing a large array of substances. The scientists identified several human genes that, when over-expressed in yeast, can rescue the cell from the toxicity of mislocalized FUS/TLS. This was confirmed again in 2013.

In 2015 the same team progressed pre-clinical trials research by demonstrating that on a rat model of ALS, human UPF1 exerted protective effects. The rat model was based on an over-expression of TDP-43. What was astonishing was that first there was no mortality between rats, second, it would demonstrate action both on FUS repeats and TDP-43 mislocalization which are very different diseases at the molecular level. This was again confirmed in 2015 by the same team while alluding that possible ALS therapy might also be useful for FTD, a type of dementia.

Astonishingly in 2021 another team led by Benjamin L Zaepfel, in the laboratory of well-known ALS scientist Jeffrey D Rothstein, found that UPF1 reduces C9orf72 neurotoxicity in an iPSC model of the disease. This might at the same time look insignificant (an iPSC model) and very significant (a therapy working for FUS/C9orf73/TDP-43).

Some of the scientists involved in this research work in a biotech MeiraGTx. MeiraGTx among other therapies, has designed a gene therapy for amyotrophic lateral sclerosis.

In a presentation on Oct. 27 at the European Society of Cell and Gene Therapy conference in Brussels, MeiraGTx showed that a single treatment with its gene therapy AAV-UPF1 prevented the loss of motor neurons in mouse and rat models with genetic and cellular defects seen in ALS

What is the significance of this? I do not know. UPF1 is a gene that encodes a protein that is part of a post-splicing multiprotein complex, the exon junction complex, involved in both mRNA nuclear export and mRNA surveillance. This has a relation with FUS and C9orf72, but not with TDP-43 versions of the disease. Any way at least if it works in human patients with FUS/C9orf72 that would mean one in five ALS patients would benefit from it. This would be much larger than Qualsody benefits.

If it works for TDP-43 it would heal most ALS and FTD cases. This would represent a large number of patients, FTD prevalence is 20/100,000 persons.

This presentation was probably a call to investors such as Biogen, to fund clinical studies. Let's hope it works.