The majority of people diagnosed with ALS today do not have a significantly different prognosis than when Lou Gehrig was famously diagnosed with the disease in June of 1939. This is a common, heartbreaking observation often expressed by people in the ALS community to emphasize the slow progress of ALS research and treatment development. Despite more than 85 years of scientific innovation, there are still no drugs that can stop or reverse progression for most ALS.

Many factors have contributed to this – a lack of awareness about the disease, a need for more research funding, and misconceptions about its rarity. However, perhaps the biggest hurdle is the fact that the disease is heterogenous and complex and, despite decades of research, there is still much we need to learn about ALS in order to solve it.  

What Causes ALS?

Knowing the cause behind a disease can give researchers clues about potential targets to hit when creating treatments. 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 in the body. For bacterial infections, we know antibiotics can help to neutralize the invasive bacteria. In the case of many cancers, surgery to remove a tumor, chemotherapy, or a combination of both might be an effective treatment strategy.  ALS, on the other hand, is less straightforward.

In some cases, ALS is known to be caused by mutations in genes that can be passed down from generation to generation. Even then, only about 15% of ALS is currently known to have a genetic origin. This includes both cases in which an identified genetic mutation is present or when there is a family history of the diseases but any relevant genetics remain unknown. Most cases are sporadic, with no known cause. Researchers believe a combination of genetics and environmental factors are at play in both genetic and sporadic ALS, but there is little understanding of how the two influence the onset of ALS.

Heterogeneity of ALS

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:

  • Some ALS cases begin with symptoms in the arms or legs (limb onset), while others begin in the head and neck (bulbar 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 progress all over their body relatively consistently. 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 pediatric ALS.

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 slower 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.


ALS Symptom Measurement

Further complicating matters is the lack of reliable ways to track ALS symptoms and progression. 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.

This means ALS researchers – as well as doctors and clinicians who work with patients – must rely primarily on subjective observations to record the progression of a person’s disease. The most widely used measure is the ALSFRS-r, a survey that assigns a score from zero to 48 based on their answers to several questions. More sensitive measures of disease progression – like blood-based biomarkers or digital measures of progression – could help researchers conducting clinical trials see if treatments are having an effect with more precision.

Treating a Disease of the Central Nervous System

For a treatment to be effective, it needs to be able to access the cells and tissues it’s targeting.  For example, blood cancer treatments need to be active in the bloodstream. To treat skin infections, treatments may need to be applied topically. In diseases of the central nervous system, there is an extra challenge of developing treatments that can enter the central nervous system which, by design, keeps many foreign substances out via the blood brain barrier (BBB).  

Many drugs will not cross the BBB, and so a part of drug development for ALS is to utilize technologies to actively get ALS drugs into the central nervous system. This limitation forces researchers to invent specific molecules that will cross the BBB, to find ways to coat the drugs so that they can get through it, or to directly deliver drugs into the spinal fluid which bathes brain and spinal cord.  

Another example of challenges with delivery of therapeutics to the central nervous system can be noted with CRISPR-Cas9 based gene editing. While CRISPR is now widely used in cell models in laboratory research for ALS, this technology is currently not being applied in humans with diseases of the nervous system like ALS, partly because there are challenges in delivering it safely and specifically into the central nervous system. This is an obstacle that may be overcome over time with the development of improved delivery techniques.

How Can We Address Challenges in ALS Research?

At the ALS Therapy Development Institute (ALS TDI), addressing these issues is the bedrock of our mission:

  • Drug Discovery ­– Because of the heterogeneity of ALS, we know it will take many drugs to end it. That’s why ALS TDI is dedicated to doing the preclinical research needed to invent and advance many potential ALS drugs to human clinical trials – and not to stop until there are treatments for everyone with ALS.
  • Learning more about the biology of ALS – ALS TDI researchers have published several papers advancing our understanding of the disease and identifying new drug targets for potential therapies. This includes our 2020 discovery of Type-I PRMT inhibitors as a target for C9orf72-related ALS, which led to one our promising current drug programs
  • Identifying subtypes of ALS – The more we learn about the common biology in groups of people with ALS, the better we will be able to target therapies to these specific groups. Finding clues to unlock the heterogeneity of ALS is one of the main goals of ALS TDI’s ALS Research Collaborative (ARC). ARC is a global natural history study that partners with people with ALS to collect data about their disease, medical history, genetics, and more. These de-identified data are shared and analyzed by scientists at ALS TDI and beyond.
  • Finding ALS Biomarkers – Another goal of ARC is to identify ALS biomarkers that could make clinical trials more efficient. In recent years, ALS TDI has worked with partners including Google to publish research using ARC data to design machine-learning powered digital biomarkers for ALS progression. ARC also includes an in-home blood collection program to search for biomarkers that could diagnose ALS, track progression, or identify subgroups of ALS with a blood test. In 2022, we received a  grant from the Department of Defense to undertake an innovative study to find protein biomarkers for the disease.
  • Investigating the causes of ALS – The ARC Study also aims to learn more about what might cause ALS by investigating participant’s medical, work, and lifestyle histories. This data could reveal patterns that point the way to factors that might increase the risk for developing ALS. 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 non-genetic ALS risk factors.
  • For more on this topic, watch this video:  https://ed.ted.com/lessons/why-is-it-so-hard-to-cure-als-fernando-vieira

To learn more about ALS TDI and our research to end ALS, click here.

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