Although meaningful progress is being made, developing treatments for ALS continues to be one of the biggest challenges facing the biomedical research field. Despite decades of research, there are still no treatments that can slow or stop progression for most people with the disease.

Many factors make developing treatments for ALS a uniquely difficult problem. Researchers still do not fully understand all the mechanisms that drive ALS pathology. The variability between individual cases suggests that there may be many different biological pathways involved. This means that it will almost certainly take many different treatment options to end ALS.

Rigorous research, better biomarkers, and large-scale drug discovery are critical to addressing these challenges. The good news is that researchers now have more tools than ever before to address these challenges. Advances in genetics, biomarkers, artificial intelligence, disease modeling, and precision medicine are changing how scientists study ALS and creating new opportunities to develop more effective treatments.

• ALS is complex, highly variable, and there is still much we don’t understand about the disease
• ALS is driven by multiple biological mechanisms and will likely require multiple treatment approaches. The brain and spinal cord are difficult to target therapeutically
• Though we have made progress, measuring disease progression reliably remains a challenge
• Model systems for testing potential treatments are imperfect reflections of the disease in humans

Challenge #1: ALS Is Heterogeneous — Every Case Is Unique

ALS is heterogeneous, meaning that it can be variable in its onset, progression, and biology from person to person. The heterogeneity of ALS goes far beyond the differences between sporadic and familial forms of the disease. Every case of ALS is unique in some way:

• Many ALS cases begin with symptoms in the arms or legs (limb onset), while others begin in the head and neck (bulbar onset.) Some cases may start with trouble breathing (respiratory onset.)
• The speed of progression varies greatly – some people may lose function quickly, while others might be able to continue walking and talking for years.
• Progression from one part of the body to the other can also be highly variable. Some people may experience severe symptoms in one part of the body for months, weeks, or years while retaining function elsewhere. Others may consistently progress throughout their body. Scientists do not have a clear understanding of the mechanisms that drive the spread of ALS neurodegeneration throughout the body.
• While the average lifespan after symptom onset is three to five years, some people have lived for decades with the disease. Others may pass away after only a matter of months.
• The age of onset is highly variable. Most people get ALS when they’re older, but there are many cases of people in their 40s, 30s, and 20s with the disease. There are also rare cases of juvenile ALS.

Why this Matters for Treatments

The heterogeneity of ALS is poorly understood – and learning what makes ALS similar in a group of individuals could help identify treatments.

For example, learning more about why some people progress more slowly than others might reveal strategies for slowing progression for others with ALS. Understanding the differences in the biology of the disease among different groups of people with ALS might help identify the targets, and ultimately the combination of treatments that could help someone living with the disease. This could be achieved by identifying markers in someone’s blood or spinal fluid, for example, that reveal insights into their specific form of ALS.

Challenge #2: We Still Don't Fully Understand the Causes and Biology of ALS

Understanding the biology that drives a disease helps researchers identify targets for new treatments. For some diseases, those targets are relatively straightforward. ALS, however, is far more complex.

For example, we know that to treat a virus, we can look to medications that reduce the viral load in the body, or develop a vaccine to train the immune system to fight it off when it becomes present. ALS, on the other hand, is less straightforward.

In about 15% of cases, ALS is associated with inherited genetic mutations that can be passed down from generation to generation. These include mutations in genes such as C9orf72, SOD1, FUS, and TARDBP. 

Most cases of ALS are sporadic, meaning there is no known family history or clearly defined cause.

Researchers believe both genetics and environmental factors likely contribute to ALS, but the interactions between these factors are still poorly understood. Multiple biological mechanisms may also contribute to disease progression simultaneously, including, but not limited to:

• Protein aggregation
• Neuroinflammation
• RNA processing abnormalities
• Mitochondrial dysfunction
• Axonal transport disruption
• Excitotoxicity
• Peripheral immune system involvement

Why this Matters for Treatments

Because ALS likely involves multiple biological mechanisms—and those mechanisms may differ from person to person—it is unlikely that a single treatment will work for everyone. Instead, researchers may need to utilize precision medicine—different therapeutic approaches for different forms of the disease. Understanding how genetic, environmental, and lifestyle factors contribute to ALS may help researchers identify who is at risk, uncover new biological pathways involved in the disease, and reveal new opportunities for prevention and treatment.

Challenge #3: Delivering Treatments to the Nervous System Is Difficult 

For a treatment to be effective, it needs to be able to access the cells and tissues it’s targeting.  Many treatments, including most oral and intravenous drugs, reach their targets through the bloodstream. However, reaching the central nervous system in this way is a challenge because of the blood-brain barrier (BBB), which protects the brain and spinal cord from pathogens and toxins by preventing foreign objects from entering the central nervous system through the bloodstream.

Why this Matters for Treatments

While the BBB is an important line of defense for our bodies, it can also prevent therapeutic molecules from reaching the central nervous system. Thus, an important aspect of drug development for ALS is utilizing technologies to actively get ALS drugs across the BBB. Approaches that can be effective in delivering drugs to the central nervous system include:

• Inventing specific molecules that will cross the BBB
• Finding ways to coat the drugs so that they can get through the BBB
• Directly delivering drugs into the spinal fluid that bathes the brain and spinal cord

Discovering effective mechanisms for delivering treatments across the BBB could create new opportunities for a variety of therapeutic approaches to treat the disease. 

Challenge #4: Measuring ALS Progression Is Difficult

Further complicating matters is the lack of reliable biomarkers to track ALS symptoms and progression. The most widely used measure is the ALSFRS-R, a survey that assigns a score from zero to 48 based on an individual’s or clinician’s assessment of a person with ALS’ ability to complete certain daily tasks. While the ALSFRS-R remains valuable, researchers are increasingly working to develop more sensitive tools that can detect changes in disease progression earlier and more precisely.

These include:

• Blood-based biomarkers
• Neurofilament light chain (NfL) measurements
• Digital voice biomarkers
• Movement and accelerometer-based biomarkers
• Machine learning approaches to disease monitoring

Why this Matters for Treatments

To discover treatments for a disease, researchers need data that demonstrate that a drug is working. This is extremely difficult in a disease like ALS, which has few reliable biomarkers associated with severity and progression. More sensitive measures of disease progression could help researchers conducting clinical trials better understand if treatments are having an effect.

Challenge #5: Available Disease Models Do Not Completely Capture ALS Biology

Before a potential treatment can be tested in people, it must first be evaluated in laboratory models. These models play a critical role in helping researchers understand disease biology and determine whether a therapy is likely to be safe and effective before testing in humans.

However, every disease model has limitations. Many ALS models are created by introducing mutations in genes associated with the disease, such as SOD1, profilin 1, or C9orf72, to mice or other small animals. Because they rely on specific genetic mutations, these models may only reflect certain aspects of ALS biology. The heterogeneity of the disease means that no single model can fully capture the disease's complexity or predict how a potential treatment will perform in all people with ALS.

Why this Matters for Treatments

Developing more predictive disease models is essential for improving drug discovery. Better models can help researchers identify the most promising therapies, eliminate ineffective approaches earlier, and increase the likelihood that successful laboratory discoveries translate into effective treatments for people living with ALS. Expanding the range of disease models available also allows researchers to evaluate therapies across different forms of ALS, helping ensure that promising treatments are tested in the populations they are intended to help.

How ALS TDI is Addressing The Biggest Challenges in ALS Research?

Every major advance in ALS research depends on overcoming the scientific challenges that have slowed progress for decades. At ALS TDI, our research programs are designed to address these challenges—from understanding the biology of ALS to developing better ways to measure the disease and discover new treatments.

Developing Many Drugs to Treat the Many Types of ALS

Because ALS is highly heterogeneous, researchers increasingly believe multiple therapies will likely be needed to effectively treat the disease.

ALS TDI conducts in-house drug discovery research focused on identifying, testing, and advancing multiple potential therapeutic approaches for ALS.

This includes programs involving, but not limited to:

• mRNA therapies
• PRMT inhibitors
• copper complex therapeutics
• biomarker development
• disease model validation

Delivering Treatments Across the Blood-Brain Barrier

A particular focus of our drug discovery team is investigating methods to advance therapeutics that can cross the BBB to reach the central nervous system. In 2025, we announced a partnership with Dr. Michael Mitchell at the University of Pennsylvania to develop lipid nanoparticle (LNP) technology for delivering mRNA treatments across the BBB.

Understanding the Biology of ALS

ALS TDI researchers have published studies helping advance scientific understanding of ALS biology and identify potential therapeutic targets.

This includes the discovery of Type-I PRMT inhibitors as a potential therapeutic strategy for C9orf72-related ALS, which became the foundation for one of ALS TDI’s active research programs.

Researchers are also working to better understand the environmental, occupational, lifestyle, and biological factors that may contribute to ALS risk.

In 2023, ALS TDI received a grant from the Centers for Disease Control to undertake an unprecedented study, using ARC Study data, to search for lifestyle ALS risk factors.

ALS TDI is also collaborating on the Champion Insights study, a research initiative focused on populations believed to have elevated ALS risk, including military veterans, elite athletes, and first responders.

By comparing data across these populations, researchers hope to better understand how genetics, metabolism, environmental exposures, physical activity, and other biological factors may interact to influence ALS risk and progression.

Identifying ALS Subtypes Through the ARC Study

One of the major goals of ALS TDI’s ALS Research Collaborative (ARC) Study is to learn more about the different types of ALS, which could help researchers understand what causes the disease’s heterogeneity.

ARC is a global natural history study that collects:

• genetics data
• clinical information
• movement data
• voice recordings
• blood samples
• lifestyle and environmental histories

These de-identified data are shared with researchers through the ARC Data Commons to help accelerate ALS research across the field.

Understanding common biological patterns among groups of people with ALS may help researchers develop more targeted and personalized treatment approaches.

Developing Better Biomarkers to Measure ALS

Another major focus of ARC is biomarker discovery.

ALS TDI has worked with collaborators including Google researchers to develop machine learning-powered digital biomarkers designed to track ALS progression using voice and movement data.

ARC also includes an in-home blood collection program to identify biomarkers that may:

• track disease progression
• improve clinical trials
• identify patient subgroups
• help evaluate treatment response

Developing Better Disease Models

Developing more representative disease models is a critical part of ALS TDI's drug discovery strategy. Our researchers work to develop, characterize, and validate the animal and cell models used to evaluate potential therapies before they advance toward clinical trials.

In 2025, ALS TDI researchers published the first comprehensive characterization of a Profilin-1 (PFN1) mouse model, demonstrating that it closely reproduces many of the clinical and pathological features of PFN1-related ALS. This work provides researchers with a valuable new tool for studying disease biology and evaluating potential treatments for this genetic form of ALS.

ALS TDI is also helping expand the availability of patient-derived cell models through collaborations such as PRISM ALS, an initiative to create and distribute high-quality induced pluripotent stem cell (iPSC) models representing both sporadic and genetic forms of ALS. By making these models available to researchers around the world, PRISM ALS aims to improve the way potential therapies are evaluated before they enter clinical trials.

Together, these efforts help create more predictive research models, allowing scientists to better evaluate promising therapies, reduce the risk of clinical trial failures, and increase the likelihood that laboratory discoveries translate into meaningful treatments for people living with ALS.

Looking Forward

ALS remains one of the most scientifically challenging diseases in medicine. But researchers today have more tools, more data, and a deeper understanding of the disease than ever before.

Advances in genetics, biomarkers, disease modeling, artificial intelligence, and precision medicine are creating new opportunities to develop more effective therapies for people living with ALS.

Solving ALS will likely require many approaches — and continued collaboration between researchers, clinicians, people living with ALS, and the broader ALS community.

At ALS TDI, our mission is to help accelerate that progress by rigorously discovering, testing, and advancing potential ALS treatments.

Frequently Asked Questions About ALS

Why is ALS harder to treat than some other diseases?

ALS is less straightforward than many other diseases because its causes are largely unknown, it is highly variable from person to person, and treatments must overcome the blood-brain barrier to reach motor neurons in the central nervous system. Most cases are sporadic, with no known cause, making it difficult to identify targets for treatment.

Is ALS actually multiple diseases?

ALS is heterogeneous, meaning it can be variable in its onset, progression, and biology from person to person. Only about 15% of ALS is currently known to have a clear genetic origin. Researchers believe a combination of genetics and environmental factors are at play in both genetic and sporadic ALS, but there is limited understanding of how the two influence the onset of ALS.

Why are biomarkers important in ALS?

ALS has few reliable biomarkers associated with severity and progression, forcing researchers and clinicians to rely primarily on subjective observations. More sensitive measures – like blood-based biomarkers or digital measures – could help researchers conducting clinical trials see if treatments are having an effect with more precision.

What makes ALS clinical trials difficult?

Across all diseases, less than 10% of drugs that enter clinical trials succeed and receive approval. In ALS, drugs have historically failed due to poor translation from models to humans, one-size-fits-all approaches that don’t account for disease heterogeneity, and tools that do not fully capture whether a treatment is meaningfully changing disease progression. Developing better disease models, biomarkers, and patient stratification approaches are ways ALS TDI is working to change this.