Biogen, Roche, Takeda, and Vertex Pharmaceuticals have exited the AAV capsid field. Meanwhile, Pfizer has completely abandoned all work in gene therapy.

This is very unfortunate for the neurodegenerative disease field, where many familial cases could, in theory, be cured with such technologies.

Many gene therapies have received regulatory approval. Most of these approaches use adeno-associated viruses (AAVs) and lentiviruses for gene delivery, in vivo and ex vivo, respectively.

The scientific foundation is solid (we understand how to design vectors and deliver genetic payloads), but industrialization faces many bottlenecks. Manufacturing costs per patient remain very high—hundreds of thousands of dollars.

Since gene therapies primarily target rare diseases, the patient populations are small. Companies cannot rely solely on scaling to lower costs. After the initial cohort is treated, the market shrinks dramatically.

While academia can demonstrate that gene therapies work on a small scale, industry needs to prove that these therapies are reliable, scalable, safe, and financially sustainable—much higher standards. This explains why many promising academic results lead to companies retreating when confronted with the challenges of large-scale production and commercialization.

Alternatives such as mRNA, antisense therapies (ASO), and protein drugs offer different balances of feasibility, durability, safety, and economic viability.

Huntington’s Disease and C9orf72 ALS: Shared Mechanisms and Therapeutic Hopes

Approximately 70,000 people have been diagnosed with Huntington’s disease (HD) in the U.S. and Europe, with hundreds of thousands more at risk of inheriting the condition. Despite the clear genetic cause of HD, there are currently no approved therapies that delay onset or slow progression.

Both Huntington's disease and C9orf72-linked ALS, while clinically distinct, share a common hallmark: long, abnormal repetitions of DNA bases. The success of antisense oligonucleotides (ASOs) in spinal muscular atrophy (SMA, SMN1 gene) in 2017, followed by gene therapy in 2019, gave researchers confidence to pursue similar strategies in HD and C9orf72 ALS. Progress in treating one of these repeat expansion diseases may provide hope for others.

1. Genetic Basis

1.1 Huntington’s disease (HD)

HD is caused by an expanded CAG trinucleotide repeat in the HTT gene. - Normal alleles: up to approximately 26 repeats - Pathogenic threshold: 36 or more repeats

CAG encodes glutamine, leading to a mutant protein with an expanded polyglutamine (polyQ) tract. This toxic protein disrupts neuronal function and accumulates throughout the body, contributing not only to neurodegeneration but also to systemic issues like muscle atrophy, cardiac problems, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.

1.2 C9orf72 ALS/FTD

C9orf72-related ALS and frontotemporal dementia (FTD) are caused by an expanded GGGGCC (G4C2) hexanucleotide repeat in the C9orf72 gene. - Normal alleles: up to approximately 30 repeats - Pathogenic alleles: hundreds to thousands

The expansion causes disease through several mechanisms: - Reduced C9orf72 protein levels - Formation of toxic RNA foci - Production of abnormal dipeptide repeat proteins via repeat-associated non-ATG (RAN) translation

1.3 Other repeat expansion diseases

• Spinocerebellar ataxias (SCAs) – many caused by CAG expansions
• Fragile X syndrome – CGG expansion in FMR1
• Myotonic dystrophy – CTG expansion in DMPK

2. Therapeutic Approaches: Shared Strategies

2.1 Antisense oligonucleotides (ASOs)

ASOs aim to reduce toxic transcripts. - HD: ASOs targeting HTT mRNA have reached clinical trials (e.g., Roche/Ionis). - C9orf72 ALS: ASOs targeting repeat-containing transcripts are in early-stage trials.

2.2 Gene silencing/editing

The most advanced approach in HD is uniQure’s AMT-130 gene therapy: - Uses an AAV vector to deliver microRNAs designed to silence mutant HTT. - Administered through MRI-guided stereotactic neurosurgery directly into the striatum. - Clinical trials (U.S. and Europe) are ongoing, with promising early results showing up to 75% slowing in disease progression in high-dose patients over 36 months.

These approaches are not yet cures, but they show that disease modification is possible. Advances in vector design (AAVs, lipid nanoparticles) are directly transferable to other repeat expansion disorders.

2.3 Targeting RNA structures

Small molecules that bind abnormal RNA structures (hairpins, G-quadruplexes) are under development for C9orf72 ALS and myotonic dystrophy, with potential extension to CAG-repeat disorders like HD.

2.4 Modulating protein homeostasis

Strategies to boost autophagy, proteasome activity, or molecular chaperones could reduce toxic protein aggregates in both HD and C9orf72 ALS.

3. Translating Progress Across Diseases

Research tools—such as assays for RNA foci, protein aggregation, and repeat instability—are shared across laboratories working on different repeat expansion disorders. Breakthroughs in one disease can therefore be rapidly tested in others.

Delivery challenges are also common: therapies must reach neurons in the brain and spinal cord. Advances in intrathecal ASO delivery or viral vector engineering benefit all disorders in this family.

In summary: Huntington’s disease and C9orf72 ALS/FTD are distinct conditions, but they share a unifying principle: DNA repeat expansions that disrupt RNA and protein homeostasis. Therapeutic strategies—including antisense oligonucleotides, RNA-targeting drugs, and gene-editing technologies—are broadly applicable across these diseases. Progress in one field accelerates progress in others, offering shared hope for patients facing these devastating neurodegenerative disorders.

There are often many causes to a non-communicable disease, particularly neurodegenerative diseases are more a consequence of a systemic failure than caused by a specific phenomenon. The multitude of papers assigning a specific mechanism, each time different, to neurodegenerative diseases is just noise that drags down knowledge acquisition in these domains. Some authors have hinted at a phase transition to explain the misfolding of some proteins, but what triggers this phase transition was elusive.

In this post, I discuss a very general paper. https://elifesciences.org/reviewed-preprints/107962v1

In simple terms, the authors have discovered how our innate immune system launches an extremely powerful and rapid response to a tiny signal from a pathogen. This has implications for age-related diseases such as cancer or neurodegenerative diseases.

The Core Problem:

Our immune system needs to react decisively to a single bacterium or virus. This involves a massive cellular response like inflammation or programmed cell death (pyroptosis, apoptosis). However, the initial detection of a pathogen (a single molecule binding to a receptor) provides almost no energy to power this massive response.

The Discovery - "Metastable Supersaturation": The authors found that key immune signaling proteins, specifically those containing Death Fold Domains (DFDs) (like ASC, FADD, BCL10, MAVS, TRADD), exist in a unique physical state inside our cells called metastable supersaturation. These full-length adaptors retain nucleation barriers and are able to exist supersaturated in cells. In contrast, many receptors and effectors do not. This localizes the “spring-loaded” behaviour to central adaptors that link receptor sensing to downstream cell-fate decisions.

A subset of death-fold domains (DFDs) are intrinsically “supersaturable.” Using a systematic screen of 109 human DFDs with a distributed amphifluoric FRET (DAmFRET) assay in yeast, the authors show that a minority of DFDs switch from soluble → assembled in a discontinuous (nucleation-limited) manner — the hallmark of a large intrinsic nucleation barrier. These discontinuous DFDs can therefore exist metastably above their saturation concentration (Csat) while remaining soluble (i.e. supersaturated).

Imagine a supersaturated solution of sugar water. It holds far more dissolved sugar than it should be able to. It remains liquid until you drop in a single sugar crystal, which instantly triggers the entire solution to crystallize.

Similarly, these DFD proteins are present in concentrations far higher than their natural solubility limit. They are kept in a soluble, "primed" state only by a high energy barrier that prevents them from spontaneously assembling (like the sugar needing a seed crystal).

This state acts as a long-term energy reservoir. The cell expends energy to produce and maintain these high levels of protein, storing potential energy for a future immune response. The authors show that tissues/cell types with shorter lifespans (e.g., monocytes) tend to express higher adaptor supersaturation than long-lived cells (neurons), suggesting a trade-off between rapid innate responsiveness and longevity. They also find conservation of nucleation barriers in distant taxa (fish, sponges, bacteria), indicating the mechanism is ancient.

How It Works for Immunity: When a pathogen is detected (the initial signal), the pathogen-bound receptor acts as the "seed crystal." This seed triggers the instantaneous, explosive polymerization of the supersaturated adaptor proteins (like ASC or FADD). This amplification process consumes the stored energy from supersaturation, converting it into a massive biochemical signal that leads to inflammation or cell death.

This allows for a response that is immediate, decisive, and independent of the cell's current metabolic energy (which is often hijacked by pathogens).

The Trade-Off is Immunity vs. Longevity:

This mechanism comes with a cost. Maintaining a supersaturated, "primed" state means there's always a risk of a spontaneous, accidental activation (a stochastic nucleation event). This would lead to unwanted inflammation or cell death without any infection. The authors found evidence that this trade-off is real: short-lived immune cells (like monocytes) have much higher levels of supersaturation than long-lived cells (like neurons). This suggests a fundamental thermodynamic drive where the need for strong immunity may inherently limit a cell's lifespan.

The authors also showed this system is highly specific (DFDs from one pathway don't accidentally trigger others) and that the mechanism is evolutionarily ancient, found in everything from humans to sponges to bacteria, indicating its fundamental importance.

This groundbreaking discovery opens up entirely new avenues for treating a wide range of diseases by targeting this "supersaturation engine."

1. Autoinflammatory and Autoimmune Diseases Examples: Crohn's disease, rheumatoid arthritis, lupus, CAPS (Cryopyrin-Associated Periodic Syndromes), type 1 diabetes.

2. Infectious Diseases Examples: Sepsis, severe viral infections (e.g., COVID-19, flu).

3. Cancer Application: Some cancers evade the immune system by preventing immune cells from initiating cell death (apoptosis) in cancerous cells. They might do this by interfering with the supersaturation or nucleation of proteins like FADD.

4. Neurodegenerative Diseases Examples: Alzheimer's, Parkinson's, ALS.

Therapeutic Strategy: This research provides a deeper biophysical understanding of how proteins form aggregates. Insights into controlling nucleation barriers could lead to strategies for preventing the initial "seed" event that sparks the catastrophic aggregation of proteins like amyloid-beta or alpha-synuclein.

Risks, trade-offs, and practical challenges

Immunity vs longevity trade-off. The authors argue a thermodynamic tradeoff: lowering supersaturation protects cells from spontaneous death but reduces rapid responsiveness to pathogens. Therapies that blunt supersaturation may increase infection susceptibility.

Off-target/cross-seeding risk. Although the interactome is relatively specific, some cross-nucleation exists (e.g., PYD↔DED). Inhibiting one adaptor could have unintended effects on other pathways, or conversely, seeding one adaptor therapeutically could accidentally trigger another.

Drugging interfaces is hard. Filamentizing interfaces and nucleation kinetics are complex to target with small molecules; biologics or degradation approaches may be more tractable but have delivery challenges.

Temporal and quantitative control required. Because the system is switch-like, small quantitative changes in concentration or barrier height can produce large outcome differences; therapies need tight control to avoid tipping the balance toward immunodeficiency or hyperinflammation.

In conclusion This study moves beyond simply listing the components of immune pathways to explaining the fundamental physics and energy dynamics that make them work. By understanding that immunity is powered by a "loaded spring" mechanism of metastable supersaturation, we can now think about designing much smarter, more precise drugs that either stabilize this spring (for autoimmune diseases) or trigger it on command (for cancer).

A tool for ALS or FTD gene carriers.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases. A significant number of cases are linked to a hexanucleotide repeat expansion in the C9orf72 gene, making it the most common known genetic cause of both conditions.

Genetic counseling is essential in informing families about their risk, especially for those with a family history of the disease. Currently, children of C9orf72 mutation carriers are often told they have a 50% chance of inheriting the mutation. While technically correct based on Mendelian inheritance, this figure overlooks a critical factor: age-related penetrance.

Penetrance describes the likelihood that someone carrying a disease-causing gene will develop the disease. In cases of C9orf72-related ALS/FTD, penetrance increases with age, peaking around 58 years old. This means that simply knowing you carry the mutation does not give the full picture of your personal risk.

A new study addresses this limitation by developing a more precise method for calculating risk and providing an online tool for families.

The tool is available here: https://lbbe-shiny.univ-lyon1.fr/ftd-als/

While other research has focused on identifying genetic modifiers of disease risk, this study centers on a readily available and easily measurable factor: age.

The researchers used a Bayesian approach, a statistical method that updates probabilities with new evidence. In this case, the evidence includes the individual's age and family history. By integrating age-related penetrance data, the researchers created a model to estimate the probability of carrying the C9orf72 mutation and developing ALS or FTD within a specific timeframe. This approach is especially relevant for asymptomatic relatives, such as children, siblings, grandchildren, and niblings of mutation carriers.

Importance of this work:

This research is significant because it moves beyond the simplified 50% risk figure, offering a more personalized and accurate risk assessment for individuals at risk of C9orf72-related ALS/FTD. It helps inform decisions about genetic testing and could influence lifestyle choices or participation in clinical trials. As testing for C9orf72 becomes more common, the need for nuanced interpretation of results increases. The findings are highly relevant for families affected by ALS/FTD, providing a more realistic understanding of their individual risk profiles.

Originality:

The study offers original insights beyond the basic concept. Although age-related penetrance is a known idea, this research presents a concrete, mathematically sound method to incorporate it into risk calculations. The online simulator further enhances its practical use. The novelty is in applying a Bayesian framework to refine risk estimates in C9orf72-related ALS/FTD, providing a more sophisticated and personalized approach than traditional Mendelian risk assessments.

Conclusion:

This study makes a valuable contribution to ALS/FTD genetics. By offering a more detailed and personalized risk assessment, it can improve genetic counseling, aid in clinical trial recruitment, and deepen the understanding of the disease. The online simulator makes this complex information accessible to clinicians and families, increasing its practical impact.

I often complain that neurodegenerative literature is of low quality and has little usefulness. Here is an article that may be very different.

It's known that in some diseases, like cord spine injury, some motor neurons reverse to an immature state, and it is thought that this may have a protective effect. The authors reflected that inducing vulnerable mature motor neurons into an immature state might be beneficial, and they tested this hypothesis in-vitro and on mice. Two key transcription factors, ISL1 and LHX3, are the master regulators of the immature motor neuron gene expression program. These factors are naturally expressed during embryonic development but are typically turned off in mature neurons. Yet ISL1 and LHX3 are not the only proteins involved in the maturation process of motor neurons. 7,000 genes change their expression significantly throughout postnatal motor neuron maturation

The developmental stages from a stem cell to a mature motor neuron follow these steps: The process begins with neural stem cells in the developing spinal cord. These cells can develop into various types of neurons and glial cells. Under the influence of signaling molecules (like Sonic Hedgehog), the neural progenitors become motor neuron progenitors, which are now committed to the motor neuron lineage. These progenitor cells multiply. Then these progenitors stop dividing and differentiate into neuroblasts. At this stage, neuroblasts express key transcription factors like ISL1 and LHX3, which establish the fundamental identity of the motor neuron. The neuroblast begins to resemble more to a motor neuron: They extend a long axon out of the spinal cord towards their target muscle. The cell also starts to acquire its specific electrical properties. Then the neuron reaches its target muscle, forms a neuromuscular junction, and becomes a fully functional, electrically active cell. At this point, the early master regulators like ISL1 and LHX3 are largely downregulated, and the neuron enters its final, mature state. The authors designed a genetic therapy with an AAV virus vector to make mature neurons express two proteins that are only expressed in the immature state. The AAVs were specifically engineered to target motor neurons. In the study conducted on mice, the administration mode of the AAV viral vector was able to specifically infect the spinal motor neurons. Once inside the mature motor neurons, the AAV released the therapeutic genes. This caused the neurons to begin expressing ISL1 and LHX3 again By re-expressing ISL1 and LHX3, the researchers essentially re-activate that original "immature" genetic program. This causes the mature neuron to revert to a state that is genetically and functionally similar to its younger self, with renewed resilience and stress-coping abilities. They believe that turning on the immature genetic program essentially re-awakens the neuron's dormant ability to regrow and repair itself. While mature neurons in the central nervous system have very limited regenerative capacity, the authors are suggesting that ISL1 and LHX3 could be flipping a switch that bypasses this limitation.

This was not achieved in a linear process; On the contrary, the study tells of multiple steps to study what was achieved and to learn how to progress.

Their study focussed on SOD1 ALS, so they used a SOD1 mouse model to study dysregulation of SQSTM1 and how ISL1 and LHX3 expression influence it. Large, round aggregates of SQSTM1 (termed “round bodies”) are detectable in the cytoplasm of SOD1 ALS motor neurons At transduction efficiencies greater than ∼80%, SQSTM1 round bodies were almost completely abrogated, pointing to a cell-autonomous effect of ISL1 and LHX3 re-expression on SQSTM1 pathology.

The transfected mice survived longer than the control ones, and the effect is much more pronounced in females than in males. Yet that was not a cure, and the study was only on SOD1 ALS; there are multiple types of ALS, so we don't have a clear idea of the impact of this therapy on other genetic/familial and sporadic ALS. Also, the authors found that the expression of ISL1 and LHX3 lasts only two weeks, so there is little time for the therapy to work. It would be interesting to see a similar study on the other species of nervous cells. The authors also highlight that it is unknown if this therapy would be effective late stages of the disease when motor neuron degeneration is underway and non-cell-autonomous factors such as neuroinflammation contribute to clinical progression.

The number of mice was also very low (8 mice in the treatment group and 6 mice in the control group), to the point where it is not statistically significant.

But for me, this study has a potential that most other studies have not: They try hard to heal motor neurons, not simply to repress some of the hundreds of genes involved in ALS. Gene KO approaches are lazy; it's shooting in the dark. This study is a great step forward, even if therapy is probably one or two decades away.

Les scientifiques n'ont pas une idée très claire sur la genèse (le prodrome) de plusieurs maladies neurodégénératives. Par exemple il y a un débat récurrent sur l'origine anatomique de la SLA, commence-t-elle à la jonction neuro-musculaire ou dans le cerveau. Ce débat naît du fait que souvent les symptômes de la SLA apparaissent à l'extrémité d'un membre et il semble naturel de penser que le maladie naît là et s'étend dans le reste du corps.

Cependant cela n'est pas l'opinion majoritaire qui suit celle du docteur Charcot formée il y a plus de 100 ans, que la SLA naît dans le cerveau. Chaque camp revendique avoir apporté des preuves ou au moins des éléments très convaincants de sa thèse, mais pour un observateur un peu sceptique aucun camp n'est réellement convaincant.

Une nouvelle étude affirme apporter la preuve que la SLA naît dans le cerveau.

En fait c’est la vieille (~40 ans) hypothèse de l’exitotoxicité qui resurgit une nouvelle fois.

Celle-ci suggère qu’une hyperactivité persistante des neurones moteurs supérieures est la cause de leur dégénération. Le glutamate est souvent impliqué par les scientifiques comme cause d’excitotoxicité, mais un médecin présentera le même phénomène de façon plus concrête :

• Après un accident vasculaire cérébral (AVC) affectant le cortex moteur ou le faisceau corticospinal, certains neurones moteurs peuvent devenir hyperexcitables. Cela contribue à la spasticité et au clonus en phase chronique.
• L'hyperthyroïdie peut augmenter l'excitabilité neuronale, affectant parfois le cortex moteur.

• Certains médicaments ou toxines (par exemple, certains stimulants, les organophosphorés notamment utilisés dans l’agriculture, certaines plantes, l’alcool) peuvent abaisser les seuils d'activation neuronale.

• La privation de sommeil sur une longue durée a aussi cet effet.

Dans le cerveau, les neurones moteurs supérieures envoient de longs axones jusqu'à la moelle épinière, où ils se connectent (directement ou indirectement) aux motoneurones inférieurs (neurones moteurs supérieuresI), qui contrôlent à leur tour les muscles. En conditions normales, les neurones moteurs supérieures équilibrent excitation et inhibition pour produire des mouvements fluides et précis.

Lorsque les neurones moteurs supérieures deviennent hyperexcitables, cet équilibre est rompu. Ils déclenchent trop fréquemment leurs signaux en réponse à des entrées normales, car leur seuil d'activation est anormalement bas. Ils peuvent alors générer des pics d'activité qui sur-stimulent les neurones connectés.

Les travaux des auteurs étayent l'idée que (chez la souris de laboratoire) l'hyperexcitabilité corticale n'est pas seulement une conséquence de la SLA, mais peut être un facteur principal de l'apparition et de la progression de la maladie. En effet les auteurs ont testé directement la causalité, et non la corrélation de ces évènements.

Les chercheurs ont utilisé une approche chimio-génétique DREADD pour rendre artificiellement les motoneurones supérieurs du cortex moteur, hyperexcitables pendant des mois chez des souris adultes par ailleurs en bonne santé. Cependant la méthode utilisée est peu sélective du type de cellule (infection par AAV). Non seulement les souris ont présenté des signes comparables à ceux de la SLA chez les humains, mais au niveau moléculaire il y a aussi des éléments convergents comme la formation d’aggrégats de protéine TDP-43 dans le cytoplasme.

Il y a toutefois des éléments étonnants dans cette étude, par exemple le temps de chute ne semble pas avoir beaucoup varié entre le mesure effectuée au début et celle effectué à la fin de l'étude. Et on peut s'interroger pourquoi le groupe des souris traitées n'a pas la même performance en matière de chute que les autres groupes au début de l'étude. De façon similaire, la force des souris modifiés génétiquement est nettement plus basse au début du traitement qu’à la fin, c’est l’inverse de ce qu’on pourrait attendre d’une souris qui serait de plus en plus affaiblie. Et pourquoi ce groupe de souris aurait-il une force plus faible au début de l’expérience ? S’il n’y a pas de sélection à priori, les différents groupes de souris (traités et non traités) devraient avoir la même force.

Pour les auteurs l'hyperexcitabilité seule est suffisante pour produire des symptômes similaires à ceux de la SLA. C’est possible mais cela n’explique pas pourquoi la SLA apparaît en un endroit particulier de l’anatomie, ni n’explique les SLA causées par des anomalies génétiques. Par ailleurs on sait qu’un stress cellulaire persistant peut déclencher une SLA (ou d’autres maladies suivant les tissus atteints) quand la réponse cellulaire (ISR) est inadaptée.

Que conclure ? Les auteurs semblent être des stakhanovistes de la publication scientifique et avoir accès à des fonds conséquents. La plupart d'entre eux ont signé plusieurs articles par mois, quasiment tous les mois depuis des années. Cela semble carrément impossible dans le cadre d’une pratique professionnelle de qualité.

There has been a recent surge in articles about the Integrated Stress Response (ISR) in neurodegenerative diseases. The hypothesis suggests that the ISR, a cellular mechanism for managing stress, becomes excessively prolonged in these conditions. Several refinements of this idea have been proposed, such as the notion that protein misfolding occurs because the endoplasmic reticulum cannot properly process proteins during ISR, leading to the accumulation of misfolded proteins in the cytoplasm, which causes various problems. For example, TDP-43 proteins fail to fold correctly and cannot be transported to the nucleus, where they play critical roles in DNA repair and virus defense.

In this blog, we have discussed this topic multiple times, including the Inflectis Sephin1/IFB-088 drug.

One such article about ISR is ALSUntangled #80, which discusses a drug called ISRIB (Integrated Stress Response Inhibitor).

Several ISR inhibitors have been identified, including Guanabenz, IFB-088, Salubrinal, and ISRIB. Some of these drugs, like Guanabenz, have significant side effects, making them less suitable for long-term and widespread use.

The outcomes of ALSUntangled are usually predictable; they tend to indicate that any drug they evaluate has limited interest for ALS. However, this time, it feels different, possibly because the two main authors, Javier Mascias Cadavid and Anna Mena Bravo, are from Spain.

They discuss ISRIB and how it was informally tested by 42 ALS patients in Spain, who reported subjective improvements and no side effects.

There are additional publications exploring whether ISRIB could be a promising treatment for ALS.

They say that ISR might be the culprit in a rare subtype of ALS, which is caused by a mutation in VAPB gene. The authors suggest that ISRIB might be useful. What should we consider about all this? Maybe we should ask why scientists are searching for new drugs instead of focusing on compounds of drugs that have already shown some effects. Perhaps everyone wants to get rich, so they avoid exploring drugs that can't be patented.

For example, nobody has research on the benefits of Meclofenoxate in ALS in the last 50 years! A recent publication suggests it might be useful in Parkinson's disease.

Les oligonucléotides antisens (ASO) sont de petites séquences d'ADN capables de réduire l'expression d'un gène cible au niveau post-transcriptionnel, ce qui les rend intéressants pour neutraliser les produits génétiques mutants ou toxiques. Les progrès réalisés dans la chimie médicinale des ASO ont amélioré leur profil pharmacodynamique, permettant ainsi une administration sûre et efficace au système nerveux central. Les thérapies ASO pour la SLA se sont rapidement développées au cours des deux dernières décennies, et les ASO ciblant SOD1, C9orf72 et ATXN2 sont actuellement en essais cliniques pour les formes familiales ou sporadiques de SLA.

L'injection directe dans le SNC permet à l'ASO de se distribuer dans tout le SNC, et les ASO ciblant SOD1 (Tofersen/Qalsody) ont démontré que l'administration intrathécale était une approche bien tolérée. De nouvelles approches d'administration, telles que la conjugaison des ASO à des nanoparticules lipidiques ou à des cholestérols, pourraient bientôt permettre une administration moins intrusive et pouvant être effectuée par davantage de professionels.

Les mutations du sarcome fusionné (FUS) sont à l'origine d'une forme rare et agressive de SLA, d'apparition précoce et souvent juvénile. FUS est une protéine de liaison à l'ARN essentielle à la réparation et au métabolisme de l'ADN, notamment à l'épissage et à la traduction de l'ARNm.

Alors que la plupart des formes de SLA présentent généralement une pathologie TDP-43, les tissus post-mortem de patients atteints de SLA présentent une agrégation intracytoplasmique en l'absence de pathologie TDP-43. Identifié par criblage in vitro, l'ASO ION363 développé par la société IONIS qui a aussi développé Tofersen, cible le 6e intron de FUS (SLA avec une mutation P525L). ION363 réduit les taux de protéines de liaison à l'ARN insolubles et insolubles associées aux agrégats, telles que hnRNPA1 et ralentit la neurodégénérescence des motoneurones lombaires et la perte d'innervation de la jonction neuromusculaire.

L'inversion de la neurodégénérescence et la réduction de la prolifération chez les souris P525L ont motivé une demande d'IND (« usage compassionnel ») pour des tests chez l'homme porteur de mutations. Une demande d’IND a été approuvée par la FDA pour l’utilisation d’ION363 chez un patient atteint de SLA porteur d’une mutation P525L (âgé de 26 ans).

Jaci Hermstad, une jeune femme de 25 ans originaire de l'Iowa, a reçu un diagnostic de SLA-FUS, huit ans après avoir perdu sa sœur jumelle, atteinte de la même maladie, à l'âge de 17 ans. La famille Hermstad a contacté Project ALS et le Dr Shneider, qui étudiait le potentiel des ASO dans le traitement des patients atteints de SLA-FUS, pour savoir s'il existait des thérapies susceptibles d'aider Jaci.

« L'histoire des Hermstad a immédiatement attiré l'attention de nombreuses personnes talentueuses et bienveillantes, d'Ionis et du Dr Shneider, expert du gène FUS, aux experts réglementaires bénévoles, aux fabricants et aux conseillers universitaires », a déclaré Valerie Estess, directrice de recherche du Project ALS. Le courage de Jaci, et le travail d'équipe qu'elle a inspiré, peuvent désormais porter leurs fruits pour tous les patients atteints de SLA-FUS.

Grâce au financement de l'ALS Association et du Projet SLA, le Dr Shneider et son équipe de Columbia ont pu proposer le jacifusen à dix patients supplémentaires atteints de SLA-FUS au cours des deux dernières années, tout en suivant en parallèle les données de sécurité du médicament et les biomarqueurs pertinents pour la maladie.

Cela a conduit la Chambre des représentants des États-Unis à adopter le projet de loi de Jaci, autorisant les médecins à administrer l'ASO avant de réaliser des tests toxicologiques sur des rongeurs. Selon sa nécrologie, Hermstad a reçu 12 injections du médicament, appelé Jacifusen, entre juin 2019 et mars 2020 avant de décéder de la SLA le 1er mai 2020.

À l'autopsie, l'ION363 a été largement détecté dans les tissus du cerveau et de la moelle épinière, deux mois après la dernière perfusion. Les signes pathologiques de la SLA-FUS P525L ont diminué, notamment les inclusions cytoplasmiques neuronales positives, les agrégats insolubles de protéines de liaison à l'ARN et d'autres protéines, ainsi que la localisation nucléaire.

Un examen neuropathologique a été réalisé chez le premier participant, ainsi que chez un témoin non atteint de SLA et un patient atteint de SLA porteur de la mutation P525L n'ayant pas reçu de traitement. Par rapport au témoin atteint de SLA, le participant traité par ASO présentait moins de protéines totales et mutantes, y compris de protéines insolubles, dans la moelle épinière lombaire.

Shneider et son équipe à Columbia ont proposé du Jacifusen à dix patients supplémentaires atteints de SLA au cours des deux dernières années.

En juin 2021, Ionis a lancé un essai de phase 3 appelé ION, visant à traiter jusqu'à 77 patients dans le monde. Les participants sont âgés de 11 ans et plus, atteints de SLA causée par une mutation pathogène confirmée du gène ION363 et ne doivent pas être sous ventilation mécanique permanente au moment de l'inscription. Ils reçoivent des injections rachidiennes d'ION363 ou d'un placebo toutes les douze semaines, après une dose de charge à quatre semaines, pendant 61 semaines, suivies d'une prolongation en ouvert de 85 semaines. Le critère d'évaluation principal est l'évolution fonctionnelle selon l'échelle d'évaluation fonctionnelle de la SLA révisée et la durée de vie sans ventilation mécanique. Les critères d'évaluation secondaires incluent la qualité de vie, la fonction pulmonaire et musculaire, la survie et les modifications du biomarqueur des chaînes légères des neurofilaments. Réalisé à L'essai clinique, mené sur 24 sites en Amérique du Nord, en Europe, au Royaume-Uni, à Taïwan et en Corée, devrait se poursuivre jusqu'en juin 2026.

La deuxième partie de l'étude consiste en une période d'extension ouverte de 72 semaines au cours de laquelle tous les participants ont reçu du jacifusen.

Une caractéristique unique de cet essai est la mise en œuvre d'un « sauvetage ». Plus précisément, si un participant présente un déclin fonctionnel significatif au cours de la première partie, il sera transféré vers la deuxième partie/extension ouverte de l'étude. Cela semble suspect du point de vue statistique: L'étude ne conserve que les patients qui évoluent lentement!

Bien que la plupart des participants aient connu un déclin fonctionnel continu (mesuré par l’ALSFRS-R) après le début du traitement par jacifusen, l’un d’eux a présenté une récupération fonctionnelle objective sans précédent après 10 mois, et un autre est resté asymptomatique, avec une amélioration documentée des anomalies électromyographiques.