Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. ALS causes loss of muscle control, paralysis, and eventually respiratory failure. There is currently no cure for ALS and no effective treatments to halt or reverse the progression of the disease.
What is ALS?
ALS is characterized by the gradual degeneration and death of motor neurons. Motor neurons are nerve cells in the brain and spinal cord that provide the controlling signals for muscle movement. As motor neurons degenerate, the brain loses the ability to initiate and control muscle movement. Individuals with ALS progressively lose the ability to speak, eat, move, and breathe.
The majority of ALS cases (90-95%) are sporadic, meaning the disease occurs randomly with no clearly associated risk factors. About 5-10% of cases are familial, meaning the disease runs in the family. In familial cases, there is often a mutation in a gene that triggers the onset of ALS when inherited.
The first symptoms of ALS often include muscle weakness or slurred speech. Eventually all voluntary muscles are affected, including those involved in breathing, swallowing, and eye movement. Although ALS does not directly affect the senses or a person’s cognitive abilities, several related issues can occur including emotional lability (uncontrolled laughter or crying), mild memory loss, and changes in personality. Without respiratory support, muscle weakness affecting breathing often leads to respiratory failure and death typically within 2-5 years from the onset of symptoms.
What causes ALS?
The exact causes of ALS development are still unknown, however research has uncovered several of the main factors that can lead to motor neuron degeneration:
- Genetics – Several genes have been linked to ALS, including SOD1, TARDBP, FUS, OPTN, TBK1, and C9ORF72 among others. Mutations in these genes can trigger ALS in familial cases.
- Protein misfolding – Misfolded proteins can accumulate in motor neurons and form toxic aggregates that impair neuronal function.
- Mitochondrial dysfunction – Defects in mitochondria and impaired energy production in neurons.
- Glutamate toxicity – Excess glutamate can overstimulate motor neurons, leading to cell damage.
- Oxidative stress – Imbalances between free radicals and antioxidants can damage motor neurons.
- Impaired RNA regulation – Defects in processing and metabolism of RNA can affect neurons.
- Neuroinflammation – Overactive immune responses and inflammation stress and kill neurons.
Research into all of these potential mechanisms continues in order to find targets for treating ALS.
Who gets ALS?
ALS can affect any adult, but typical onset is between 40 and 70 years of age. Men have a slightly higher risk of developing ALS than women. Military veterans are approximately twice as likely to develop ALS as the general population.
In the US, ALS affects approximately 5 out of every 100,000 people. ALS is estimated to affect 16,000 Americans at any given time. The incidence and prevalence of ALS is projected to increase in the coming decades as the population ages.
| Age of onset | Proportion of cases |
|---|---|
| Younger than 30 | 5% |
| 30-39 | 10% |
| 40-49 | 15% |
| 50-59 | 30% |
| 60-69 | 25% |
| Older than 70 | 15% |
What treatments are available for ALS?
Riluzole (Rilutek) is currently the only FDA-approved drug for treating ALS. Riluzole aims to reduce glutamate excitotoxicity, which damages motor neurons. Clinical trials have shown riluzole can modestly slow disease progression and prolong survival by 2-3 months on average.
In addition to riluzole, other treatments focus on providing relief from symptoms and improving quality of life:
- Physical therapy can help maintain muscle strength and function.
- Speech therapy can assist with communication as speaking becomes difficult.
- Occupational therapy helps retain independence through assistive devices.
- Breathing support such as CPAP or BiPAP machines can aid respiration.
- Nutritional supplements can help maintain weight and nutrition.
- Medications can treat issues like muscle cramps, excess saliva, pain, depression, and insomnia.
These palliative treatments aim to maximize comfort and daily functioning, but do not significantly impact disease progression or mortality.
Emerging experimental therapies
Several experimental therapies for ALS are also being investigated in clinical trials:
- Antisense oligonucleotides – Small DNA/RNA molecules that can inactivate target genes, such as those involved in ALS like SOD1.
- Gene therapy – Delivering functional genes to replace mutated genes in familial ALS cases.
- Stem cell therapy – Introducing stem cell transplants to help replace lost motor neurons.
- Immunotherapy – Using antibodies or immunomodulators to target neuroinflammation.
- Growth factors – Administering brain-derived neurotrophic factor (BDNF) to stimulate neuron growth and survival.
While some of these approaches have shown promising results in slowing ALS progression in clinical trials, there is not yet sufficient evidence of efficacy and safety for FDA approval and widespread therapeutic use.
What progress has been made toward finding a cure?
While there is not yet a cure for ALS, progress continues to be made through extensive research on understanding the disease and developing potential treatments. Some key advances include:
- Identifying several genetic mutations involved in familial ALS, such as SOD1, TARDBP, FUS, and C9ORF72.
- Developing animal models with ALS mutations to study disease mechanisms and test treatments.
- Elucidating multiple involved disease processes like protein aggregation, mitochondrial dysfunction, RNA metabolism, and axonal transport defects.
- Demonstrating proof-of-concept for therapies like antisense oligonucleotides and gene therapy in ALS animal models.
- Establishing stem cell models using induced pluripotent stem cells (iPSC) from ALS patients to screen potential drugs.
- Launching large collaborative genetic databases and biobanks to uncover ALS risk factors.
- Identifying biochemical markers in blood or cerebrospinal fluid that may help track ALS progression.
While an effective cure for ALS does not yet exist, the last few decades of research have greatly expanded our understanding of ALS and potential therapeutic targets. Ongoing research continues to make important steps toward finding a cure.
Challenges in finding an ALS cure
There are still substantial challenges facing ALS researchers in their pursuit of a cure:
- ALS has a complex etiology with interplay between genetic and environmental factors.
- There are no validated biomarkers to definitively diagnose or track progression.
- ALS pathogenesis involves damage across motor neurons in the brain and spinal cord.
- ALS likely requires a combinatorial therapy targeting multiple mechanisms.
- Treatments need to not only slow progression but also repair damage.
- Clinical trials require large cohorts due to heterogeneity among patients.
- Treatments must cross the blood-brain barrier to reach affected neurons.
- Therapies need to balance efficacy with minimizing toxicity.
While finding an effective ALS cure remains difficult, researchers continue to leverage an expanding range of scientific tools and collaboration to make incremental progress toward this goal.
What are the most promising current directions toward a cure?
Based on the latest scientific advances, some of the most promising emerging directions toward developing an effective ALS treatment or cure include:
- Genetic therapies – Gene silencing techniques like antisense oligonucleotides and gene replacement strategies using viral vector delivery hold promise for familial ALS patients with known mutations.
- Stem cell therapies – Introducing neural stem cell populations into the spinal cord could help replace lost motor neurons and neural connections.
- Neuroprotection approaches – Using drug compounds or antibodies to target neuroinflammation, oxidative stress, and protein misfolding underlying neurodegeneration.
- Growth factor delivery – Supplying neurotrophic factors like GDNF, BDNF, IGF-1, or VEGF could protect motor neurons and support nerve regrowth.
- Combination therapies – Attacking multiple targets simultaneously could provide synergistic benefits in stopping disease progression.
- Personalized medicine – Matching treatments to an individual’s specific genetic mutation or biomarkers could improve efficacy.
Research on all of these approaches is active, with optimism that one or a combination of these strategies could eventually provide a way to cure or meaningfully alter the course of ALS.
When could an ALS cure become a reality?
Predicting a timeline for when an ALS cure could become available remains challenging. While emerging treatments like gene therapy and stem cell transplantation show promise in preclinical studies, there are still major hurdles in translating these findings into clinically proven therapies shown to stop or reverse ALS progression and mortality.
Most experts caution that an ALS cure is likely still several years if not decades away. However, progress continues to accelerate thanks to expanded tools for drug discovery, increased research funding, improvements in clinical trial efficiency, and enhanced data sharing among researchers. Academic researchers, pharmaceutical companies, organizations like the ALS Association, and frustrated patients/caregivers are all galvanized toward the shared goal of making an ALS cure a reality.
Cautious optimism remains that the combination of scientific persistence, financial investment, patient advocacy, and innovative thinking across multiple disciplines will eventually converge toward disease-modifying ALS treatments and ultimately a cure. While the exact timeframe is impossible to predict, most researchers agree that it is a matter of ‘when’ rather than ‘if’ an ALS cure will arrive. Maintaining momentum in the fight against ALS will be the key to reaching the finish line.
Conclusion
In summary, no definitive cure for ALS exists yet, but meaningful progress continues to be made through a determined research effort to understand ALS biology and translate discoveries into safe and effective treatments. As a complex neurodegenerative disease, ALS presents substantial challenges for developing therapies that are efficacious, multi-targeted, and able to cross into the central nervous system. While timeframes are difficult to forecast, cautious optimism remains that combinations of emerging genetic therapies, neuroprotective agents, regenerative approaches, and personalized strategies could eventually provide a comprehensive cure for ALS. With new discoveries unfolding each year, there are compelling reasons to believe major breakthroughs for halting or reversing ALS are on the horizon.