New Horizons in Motor Neuron Disease Treatment: From Gene to Assistive Technology

New Horizons in Motor Neuron Disease Treatment

 Amyotrophic Lateral Sclerosis (ALS) is one of the most devastating and complex neurodegenerative diseases, gradually destroying the neurons responsible for voluntary movement in the brain and spinal cord. As the disease progresses, patients lose the ability to walk, speak, swallow, and even breathe, while cognitive abilities remain intact in most cases, causing profound physical and psychological suffering. Despite more than a century since its first description, ALS remains without a cure, and current treatments such as riluzole and edaravone only slow the progression of the disease to a limited extent.

However, the last decade has witnessed a fundamental shift in our understanding of the molecular and genetic mechanisms of the disease, opening the door to the development of treatments targeting genetic and protein-based causes. This has coincided with a revolution in gene therapy, neuroscience, and biotechnology, providing new hope for patients with this disease, once considered a slow death sentence. Highlighting these developments now is not a scientific luxury, but a necessary step to understanding the ongoing shift in the concept of treating neurodegenerative diseases, from palliative care to attempts to modify the course of the disease itself.

Scientific Background and Pathophysiology

Motor neuron disease (ALS) is classified as one of the most prominent neurodegenerative diseases affecting both the central and peripheral motor nervous system. It is characterized by progressive damage to upper motor neurons in the cerebral cortex and lower motor neurons in the spinal cord and brainstem. This damage leads to loss of voluntary motor control and manifests clinically as progressive muscle weakness, seizures, difficulty swallowing or speaking, and respiratory failure, which is the leading cause of death.

The mechanism of disease progression is still not fully understood, but recent studies indicate that the disorder extends beyond the neuron itself to its supporting cells, such as microglia and astrocytes, creating a chronic inflammatory environment that accelerates neuronal cell death. The phenomenon of "pathological protein spillover" has also been observed, where abnormal proteins such as TDP-43, SOD1, and FUS accumulate in neurons and spread to neighboring cells, similar to what occurs in Alzheimer's and Parkinson's diseases. This contributes to the progression of neurodegeneration through mechanisms similar to protein infection.

At the molecular level, disturbances in protein metabolism, oxidative stress, mitochondrial dysfunction, and disturbances in axonal transport are among the primary drivers of the disease. The accumulation of free radicals and oxidative products damages DNA and membrane proteins, while diseased mitochondria contribute to the disruption of energy production and creates an environment conducive to programmed cell death (apoptosis).

Genetically, research has shown that approximately 10% of ALS cases are familial, while the remainder are sporadic. Among the genes most closely associated with the disease are:

• SOD1 (Superoxide Dismutase 1): The first gene discovered in ALS, mutations in which lead to the production of unstable proteins that are toxic to neurons.

• C9orf72: The most common genetic mutation, it causes an expansion of abnormal nucleotide repeats that leads to the formation of toxic RNA aggregates and misfolded proteins.

• TDP-43 and FUS: Nuclear proteins involved in RNA regulation, and mutations in these proteins cause impaired gene processing, leading to the accumulation of abnormal proteins and loss of cellular function.

Understanding these genetic and molecular underpinnings has radically changed the outlook on the disease, shifting research from alleviating symptoms to targeting the genetic causes and cellular mechanisms themselves. This has paved the way for the emergence of gene therapies such as Tofersen, which are specifically designed to suppress gene expression associated with pathogenic mutations in SOD1, marking a revolutionary step toward precision medicine in neurological diseases.

Current Treatments and Their Limitations

Despite significant scientific advances in understanding the disease, approved treatment options remain limited, restricted to medications aimed at slowing functional decline without achieving a cure. The most important of these medications are riluzole, edaravone, and the sodium phenylbutyrate/ursodoxicoltaurine combination (commercially known as Relyvrio or Albrioza).

1. Riluzole

Riluzole was the first drug approved for the treatment of ALS in the mid-1990s and remains the mainstay of pharmacological treatment to date. The drug works by inhibiting the release of glutamate, an excitatory neurotransmitter whose excess is associated with excitotoxicity, which leads to neuronal cell death. It is also believed to have antioxidant and sodium channel modulatory effects.

Multiple studies published in PMC and Frontiers in Neurology indicate that riluzole prolongs median survival by approximately 2–3 months, with a slight improvement in motor function when used early in the disease. Although this effect appears to be statistically limited, it is considered clinically significant as it represents the first evidence of disease-modifying potential.

Side effects include fatigue, nausea, and elevated liver enzymes, which require periodic monitoring of liver function during treatment. Its effectiveness also declines in advanced stages, making its use more feasible when diagnosed early. Despite more than two decades of its approval, recent studies continue to investigate optimal doses and newer delivery systems, including dispersible oral formulations for easier use in patients with swallowing difficulties.

2. Edaravone

Edaravone emerged as a second-line treatment option in 2017, after Japanese studies (published in PMC) showed its ability to slow the decline in functional scores in selected patients, particularly those in the early stages of the disease and with slow progression. The drug acts as a potent free radical scavenger, reducing oxidative stress, a major driver of neuronal cell death.

Although its overall efficacy remains controversial, it has been approved in the United States, Japan, Canada, and some countries in Europe and Asia. Reports from Frontiers suggest that Edaravone may offer greater benefit when used with riluzole in a dual-drug regimen. However, the biggest challenge remains the need for prolonged and repeated intravenous infusions, which limits its suitability for home use. Therefore, a new oral formulation, Radicava ORS, has been developed to overcome this limitation and improve treatment adherence.

3. Sodium phenylbutyrate/Ursodoxicoltaurine Combination (Relyvrio/Albrioza)

This combination caused a sensation when it was approved in Canada (under the name Albrioza) and then in the United States (under the name Relyvrio) in 2022. It was the first treatment to be promoted as protecting neurons from mitochondrial breakdown and improving survival. The hypothesized mechanism is based on a combination of protecting mitochondria (via ursodoxicoltaurine) and reducing cellular stress and misfolded protein accumulation (via sodium phenylbutyrate).

Initially, results from the phase II study (CENTRAL-ALS) showed a slight improvement in the ALSFRS-R neurological function scale, leading regulators to conditionally approve its marketing. However, the Phase III clinical trial (PHOENIX Trial), the results of which were published in 2024 in sources such as PMC and Frontiers in Neurology, showed no statistically significant benefit in slowing disease progression or improving survival.

As a result, the manufacturer announced in April 2024 that it was withdrawing the drug from the US and Canadian markets, while retaining some patients enrolled in compassionate use programs. This result was a scientific disappointment, but it demonstrated the importance of conducting large, multicenter trials before adopting any new treatment.

Recent Advances in Targeted Therapies

Recent years have witnessed a scientific revolution in the understanding of motor neuron disease, leading to a shift in research efforts from focusing on symptoms to attempting to modify the disease process itself through genetically and molecularly targeted therapies. These developments represent a new phase in the history of neurology, relying on advanced molecular biology and modern biotechnologies such as gene therapy, precision molecular drugs, and neuroimmunomodulators.

1. Gene Therapy and Antisense Oligonucleotides (ASOs)

Gene therapy is the most significant advance in ALS, especially in cases with a genetic background. This approach relies on inhibiting or correcting the genes that cause disease-causing mutations. In 2023, the approval of Tofersen (Qalsody) marked a major turning point, becoming the first treatment to target one of the direct genetic causes of the disease—mutations in the SOD1 gene.

Tofersen works using antisense oligonucleotides (ASOs), which bind directly to the messenger RNA of the mutant gene, preventing its translation into the abnormal SOD1 protein. In clinical studies published in the New England Journal of Medicine and PMC, the drug demonstrated a significant reduction in levels of the toxic protein in the cerebrospinal fluid, along with a decrease in the neurofilament light (NfL) biomarker, which reflects the degree of neuronal damage.

Although the clinical impact on motor function was limited in initial trials, data extending through 2024 have shown improved survival and a slower rate of motor decline in patients who started treatment early. However, this approach faces significant challenges, most notably the high cost, the difficulty of administering the drug via intracerebrospinal fluid injection, and the need for close monitoring for potential side effects such as aseptic meningitis and elevated protein in the cerebrospinal fluid.

A new generation of ASO therapies is also being developed to target other mutations, such as C9orf72, FUS, and TARDBP. CRISPR-Cas9 and RNA interference (RNAi) gene editing techniques are also being developed, which promise to permanently correct genetic mutations. These approaches are promising, but are still in the preclinical or early human trials stages.

2. New Experimental Drugs

A group of new drugs work on different non-genetic pathways but target the molecular and inflammatory mechanisms contributing to the disease.

• Masitinib: A tyrosine kinase inhibitor, it works by reducing the activation of microglia, which secrete inflammatory mediators that are harmful to neurons. In a clinical trial published in Frontiers in Neurology, the drug showed the ability to slow functional decline by up to 27% when used with riluzole, and also improved some survival indicators. Larger studies are currently underway to confirm these results.

• Sotoletinib (BLZ945): Another experimental drug inhibits the CSF1R receptor responsible for microglia activation, reducing neuroinflammation. Initial trials published in PMC have shown promising results in reducing inflammatory markers and improving neurological function in animal models, and human studies are currently underway to evaluate its safety and efficacy.

• Utreloxastat (PTC857): Regulates the Coenzyme Q10 pathway, improving mitochondrial function and reducing oxidative stress. Although the Phase II trial did not show strong results, researchers consider it an important step toward developing a new generation of neuromodulatory drugs.

In addition to these drugs, research projects are exploring new pathways, including the regulation of protein homeostasis, control of apoptosis, and inhibition of microinflammation. The goal is to develop a combination of treatments that achieves multi-pathway neuronal protection.

3. Potential New Targets

The current trend in ALS research is not based on a single drug, but rather on integrated therapeutic strategies that target a complex network of cellular processes. Among the most prominent of these targets are:

• Neuroinflammation inhibitors: These target glial cells that secrete inflammatory cytokines (such as IL-6 and TNF-α), as animal models have shown that inhibiting these cytokines limits the spread of neurodegeneration.

• Mitochondrial protection: By enhancing energy production and reducing the release of free radicals, using compounds such as CoQ10 and PGC-1α pathway modulators.

• Modulating metabolic pathways: Some research suggests that impaired energy and glucose metabolism in neurons may be a major factor in accelerating disease progression, so neurometabolism-stimulating drugs are being tested.

• Multi-neuroprotection: A strategy that combines antioxidants, anti-inflammatory modulators, and mitochondrial supports in a single protocol, in an effort to provide comprehensive protection for neurons.

These approaches represent the next generation of multi-targeted therapies, which may change the future of motor neuron disease management in the next decade.

Early Diagnosis and Biomarkers

As treatments advance, early diagnosis has become essential to increase the effectiveness of therapeutic interventions. Research shows that initiating treatment in the early stages, before significant neuronal loss, increases the chances of achieving tangible results. For this reason, the development of accurate and measurable biomarkers that help predict and track disease progression has become increasingly important.

1. The Role of Biomarkers (NfL and Others)

Neurofilament Light Chain (NfL) is the most studied and reliable biomarker to date. It can be measured in blood or cerebrospinal fluid, and its levels rise with neuronal damage, making it an effective tool for assessing disease activity and response to treatment. Trials such as that of Tofersen have shown that a decrease in NfL after initiation of treatment is associated with a slower progression of clinical deterioration, strengthening its role as a valid assessment tool in clinical trials.

Other markers such as phosphorylated neurofilament heavy chain (pNfH), microRNAs, and circulating RNAs are also being studied as additional markers that may help predict individual disease course.

2. Genetic Tools and Genomic Profiling

With expanding understanding of the genetic background of ALS, whole-genome sequencing has become an essential tool for identifying patients who could benefit from gene therapies such as Tofersen. Technologies such as Whole-Genome Sequencing (WGS) and Next-Generation Sequencing (NGS) help identify causative mutations and contribute to the creation of genetic subclassifications of disease, opening the door to precision medicine in clinical practice.

3. Advanced Neuroimaging

Neuroimaging has become an important tool for assessing disease progression and subtle changes in neurological structures. Modern techniques such as functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) enable the detection of motor atrophy and impaired connectivity between the cortex and subcortical regions. Integrating these imaging techniques with artificial intelligence has enabled the identification of subtle pathological patterns, contributing to early diagnosis and objective monitoring of progression.

4. Challenges in Adopting These Tools

Despite significant progress, modern biomarkers and diagnostic technologies face several practical challenges, including:

• The lack of standardized standards for measuring NfL and other markers across laboratories.

• The cost of molecular tests and their difficulty in providing them in resource-limited health systems.

• The wide variability of disease patterns across individuals makes it difficult to adopt a single indicator that works for all cases.

• The lack of infrastructure for analyzing the big data generated by imaging and genetic sequencing technologies.

However, global collaborative efforts such as Project MinE and the ALS Biomarker Consortium are expected to lead to the development of standardized protocols that will make these tools an essential part of future clinical practice, transforming the diagnostic process from "late detection of symptoms" to "early detection that is treatable."

Support, Complementary Care, and Assistive Technologies

Motor neuron disease is a disease that requires a comprehensive, multidimensional approach. Disease management goes beyond prescribing medications, but rather encompasses an integrated system of medical, psychological, social, and technological care. Given the limited availability of effective drug treatments to date, complementary care has become the cornerstone of maintaining quality of life and prolonging survival.

1. The Importance of the Multidisciplinary Team

Studies have shown that patients who receive care within a multidisciplinary team live longer and enjoy a better quality of life compared to those under traditional care. This team typically consists of:

• A specialized neurologist who directs the treatment plan and assesses the progress of the condition.

• A physical therapist to help maintain muscle strength and flexibility and prevent contractures.

• A speech and swallowing therapist to gradually address speech and swallowing difficulties and train the patient in the use of alternative communication methods.

• A respiratory therapist who monitors lung function and provides device support when needed.

• A dietitian is available to ensure adequate weight maintenance and provide appropriate nutrition strategies in case of swallowing difficulties.

• Psychosocial support is provided to help the patient and their family cope with the emotional and practical stresses of the disease.

This interdisciplinary integration not only alleviates symptoms, but also reduces complications and enhances the patient's sense of dignity and independence.

2. Respiratory, Nutritional, and Rehabilitation Therapy

Respiratory support is a critical component of advanced care for ALS patients, as respiratory muscle failure leads to death in most cases. The timely use of non-invasive ventilation (NIV) via respirator masks improves sleep quality, reduces fatigue, and significantly prolongs life expectancy. In advanced stages, invasive ventilation via a tracheal tube may be used for those who choose to use it.

Nutritional support is essential from the early stages to prevent muscle wasting. When swallowing difficulties increase, the placement of a percutaneous gastric (PEG) feeding tube is recommended to ensure adequate calorie intake and prevent choking or malnutrition.

In addition, physical and occupational therapy helps maintain mobility for as long as possible through stretching and strengthening exercises and wheelchair or support training. Speech therapy also helps train patients to use an alternative language (such as communication boards or voice programs) when speech declines.

3. Assistive Technology and Artificial Intelligence

The last decade has witnessed remarkable developments in assistive technologies aimed at enabling ALS patients to communicate and control their environment, even in the stages of complete paralysis. The most notable of these innovations are:

• Brain-Computer Interfaces (BCI): These allow patients to send commands to a computer directly via the brain's electrical activity recorded by electrodes, enabling them to type messages or control household appliances without any muscle movement. This technology has achieved tangible success in restoring the ability to communicate in patients with "locked-in" syndrome.

• Artificial Intelligence in Remote Monitoring: Deep learning algorithms are used to analyze breathing, sleep, and speech data recorded by smart home devices to assess the progress of the condition without the need for repeated medical visits.

• Audio and video analysis: Research teams have developed artificial intelligence models capable of tracking subtle changes in voice tone, speech rate, and facial expressions as early indicators of disease progression. This type of digital monitoring enables doctors to proactively adjust treatment.

4. The impact of these technologies on quality of life

Real-world experiences show that integrating these technologies with multidisciplinary care preserves independence and human connection even in advanced stages of disease. For example, some patients have been able to communicate with their families and write texts using brain-based interfaces, while mobile ventilators and intelligent systems have helped extend active lifespans. Thus, care is no longer merely a "palliative" measure but rather a means of enabling patients to continue performing their social and professional roles for as long as possible.

Current Challenges and Future Prospects

Despite this significant progress, motor neuron disease (MLD) still poses complex scientific and clinical challenges that limit access to a definitive cure.

1. Genetic and Clinical Variations

ALS is characterized by a high degree of genetic and clinical heterogeneity, with causative mutations, the speed of deterioration, and the pattern of symptoms varying among patients. This diversity makes it difficult to standardize response to treatments or adopt standardized treatment protocols. To overcome this, research is moving toward precision medicine, which aims to tailor treatment to each patient's genetic and biological makeup. The development of global databases and advanced genomic analyses will enable the identification of populations most responsive to gene or molecular therapies.

2. Optimized Clinical Trial Design

Clinical trials for ALS face unique challenges, including small patient numbers, significant variation in disease course, and the difficulty of identifying effective short-term indicators. Therefore, a new paradigm is proposed that relies on:

• Precise patient selection using biomarkers such as NfL and genetic testing.

• Using objective measures based on digital data (such as audio and movement monitoring).

• Shortening study duration by adopting early indicators of progress rather than waiting for major functional changes.

This approach could make trials more efficient and speed up regulatory approvals for promising treatments.

3. Potential for Combining Treatments

One future trend is to combine treatments rather than relying on a single approach. Protocols combining:

• Gene therapy (such as Tofersen) to suppress causative mutations.

• Molecular drugs that reduce oxidative stress or neuroinflammation.

• Assistive technologies to improve quality of life and maintain vital functions.

This integration of genetic, pharmacological, and technological interventions may represent the most effective approach to achieving tangible results in the near future.

4. Future Outlook

The near future holds promise thanks to advances in stem cell science and gene editing. Research is currently underway on neural stem cell transplantation to replace damaged neurons and stimulate their regeneration. CRISPR-Cas9 technology also holds promise for correcting causative genetic mutations before symptoms appear, potentially transforming the disease from a fatal condition into a manageable disorder.

In parallel, multi-target drugs are being developed that act on more than one biochemical pathway, such as combating inflammation, oxidation, and mitochondrial dysfunction simultaneously.

Although there is still a long way to go, the integration of genetic medicine, artificial intelligence, and biotechnology is heralding a new era in motor neuron disease treatment—one that not only slows the disease, but also seeks to radically transform it and turn hope into reality.

Conclusion

Motor neuron disease (MND) represents a highly complex medical and humanitarian challenge, where molecular, genetic, and environmental factors combine to undermine one of the most important pillars of daily life: the ability to move and express. This article reviews the scientific background of the disease, its mechanisms of development, and the limits of currently approved treatments, along with key developments in gene therapy, experimental drugs, biomarkers, and assistive technologies.

Although the road to a cure is still long, recent years have brought a paradigm shift in the understanding of the disease and its therapeutic approach. The focus today is on early diagnosis using biomarkers, the development of gene-targeted therapies, and the integration of smart technology into daily monitoring and care, giving patients better opportunities to maintain their vital functions and independence.

Therefore, the scientific and medical communities are urged to continue supporting collaborative genetic and clinical research and to promote access to early diagnosis and integrated treatment within multidisciplinary teams. The public and institutions must also support patients and their families psychologically and socially, as the fight against ALS is not just a medical one, but a humanitarian one at its core.

While hope for a complete cure is still emerging, ongoing advances in neuroscience, artificial intelligence, and gene therapy herald a more hopeful future—one in which ALS may transform from a final judgment into a surmountable challenge.

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